domingo, 31 de mayo de 2015
The Cancer Genome Atlas (TCGA)
The Cancer Genome Atlas (TCGA): The next stage
The Cancer Genome Atlas (TCGA), the NIH research program that has helped set the standards for characterizing the genomic underpinnings of dozens of cancers on a large scale, is moving to its next phase.
TCGA was launched by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) in 2006 as a pilot project to comprehensively characterize the genomic and molecular features of ovarian cancer and glioblastoma multiforme. The program grew to include samples from 11,000 patients across 33 tumor types and represents the largest tumor collection ever to be analyzed for key genomic and molecular characteristics. Findings for 13 cancer types have already been published, and as of late 2014, TCGA scientists had nearly completed sequencing protein-coding regions (exomes) for most tumor types, and completed whole-genome sequencing (WGS) for 1,000 tumor samples. The latter characterizes the complete DNA sequence in the genome. Results from TCGA analyses to date have led to more than 2,700 articles in research journals.
“TCGA was the project that needed to be done; there had to be a large scale profiling of tumors to figure out the genetics of cancer,” said D. Neil Hayes, M.D., associate professor, hematology/oncology, University of North Carolina, Chapel Hill, and a co-principal investigator of the TCGA project to characterize head and neck cancers.
Importantly, most of the funding for TCGA came from the 2009 American Recovery and Reinvestment Act (ARRA) and did not divert any of the funding that helped fund ongoing and future research grants. Indeed, the ARRA funding probably enabled TCGA to explore more cancer genomes than would have been possible with just traditional funding allocations.
“Every paper has shown novel mutations and helped explain pathways and mechanisms in cancer development and its growth and spread,” Hayes said. “These papers have helped focus our research efforts and suggested new directions for therapy. The work also dovetails with increased use of clinical sequencing on cancer patients that we are beginning to see in some places. Many of these centers are turning to TCGA data and analyses to make this possible.”
TCGA’s success inspired another project: the International Cancer Genome Consortium (ICGC). This organization, launched in 2008, coordinates over 70 international research projects across five continents with the shared goal of generating a comprehensive catalog of genomic abnormalities in cancer. TCGA is a core data and analysis contributor to ICGC, providing about 60 percent of the patient data housed in ICGC’s Data Coordination Center.
While TCGA sample collection ended in 2013, the data continue to be analyzed and papers continue to be published in scientific journals. If TCGA data can be considered a foundation on which further research and pharmaceutical development can be built, their use in the clinic remains a work in progress.
New Projects: PanCanAtlas, PCAWGs, and CDDP
TCGA is building upon the success of its Pan-Cancer Analysis, published in Cell in August 2014 and on Nature’s TCGA microsite in 2013. The depth and breadth of TCGA's extensive characterization of cancer genomes allowed a cross-cancer analysis over multiple data platforms, resulting in the Pan-Can analysis. This research showed that some cancer subtypes may be more similar to each other than to others from the same organ-of-origin. They also might share common genetic features that could be susceptible to some targeted therapies on the market, but not yet considered for the particular subtype. In other words, seemingly dissimilar cancer types may share a vulnerability for which a drug is already available.
To expand on the TCGA's Pan-Cancer Analysis, two new projects are underway: PanCanAtlas and Pan-Cancer Analysis of Whole Genomes (PCAWGs). PanCanAtlas takes advantage of the additional data generated by TCGA since the original Pan-Cancer project, which examined 12 tumors types. PanCanAtlas expands on this project by analyzing data from all TCGA tumor types. These additional data will allow researchers to discover even more complex relationships across cancer types.
PCAWGs is a collaboration with ICGC to analyze whole genome data from 2,000 pairs of tumor and normal samples and integrate the results with clinical and other molecular data available on those same cases. Investigators from around the world will lead working groups in the analysis in a number of scientific areas, such as mutation identification algorithms and patterns of structural variation in genomes. The data generated by whole genome sequencing will enable researchers to develop and examine a variety of hypotheses.
The Future of Genomics Research within the Center for Cancer Genomics
TCGA is part of the Center for Cancer Genomics (CCG) at NCI, which combines many genomic research activities. In CCG, TCGA joins projects that complement the data generated to date. Two examples are Exceptional Responders, a project to identify genomic changes in patients who respond remarkably well to treatments that fail most patients, and ALCHEMIST, a clinical trial to find mutations in early stage lung cancer patients and evaluate drug treatments designed to improve clinical outcomes. TCGA's comprehensive genome characterization pipeline will be used to analyze samples in these studies.
One other program that is kicking off is the Cancer Driver Discovery Project (CDDP), which aims to characterize driver genetic events that occur in two percent or more cases of three common tumors: lung adenocarcinoma, colorectal cancer and ovarian cancer. Many of these cases will be drawn from completed NCI clinical trials, allowing the program to determine if molecular features of the tumors influenced the therapeutic response.
“We can declare quite a few successes from TCGA based on our great sample collection and comprehensive molecule analysis, which has allowed us to identify genetic drivers of some cancers at frequencies as low as 5 to 10 percent.” said CCG Director, Louis M. Staudt, M.D., Ph.D. “TCGA has led to an appreciation of cancer pathways that weren't even considered 5 or 10 years ago. The program has created a basis for exciting future research and the CCG will carry the torch forward to fulfill TCGA's original goal: to improve our ability to diagnose, treat and prevent cancer."
viernes, 29 de mayo de 2015
Economist Proposes a $30 Billion Megafund for New Cancer Drugs
Economist Proposes a $30 Billion Megafund for New Cancer Drugs
A hedge fund manager aims to solve the funding problems facing early-stage biomedical research.
By Jessica Leber on November 19, 2012
Why It Matters
The next generation of drug therapies could depend on funding more early-stage biomedical research than is feasible today.
Hedge fund manager and prominent economist Andrew Lo is recognized for developing theories about how markets function and why they failed during the financial crisis. Now Lo, who is also the director of the MIT Sloan School of Management’s Laboratory for Financial Engineering, thinks he can also help create a better market for investing in promising treatments for cancer.
His proposal is to structure a new kind of financial tool, a “megafund,” for funneling up to $30 billion into the discovery of cancer drugs. The project would be unprecedented in scale at a time when the biomedical sector is searching for fresh funding ideas. As Lo says, the community is “ripe for something new.”
In a paper published in Nature Biotechnology earlier this fall, Lo and his coauthors note that large pharmaceutical companies are no longer nurturing early-stage drug development. Venture capitalists, too, are deserting life science startups, which averaged them negative 1 percent returns over the last decade. The result is a growing funding gap between basic lab research and commercial drug development. And fewer drugs are surviving the costly gauntlet of clinical trials to eventually reach FDA approval.
Lo’s proposal would expand the pool of capital available for life science investment by bringing together investors who would not normally fund research at top biomedical universities in exchange for a small percentage of all royalties from successful drugs or licensing revenues that result.
About five drug royalty investment companies already exist, Lo says, but they only invest in drugs that are already approved. His plan would do this at an earlier and riskier stage, and spread the risk using techniques found elsewhere in finance—and familiar from the mortgage crisis—securitizing future revenues, in this case from drug compound licenses, into debts called “research-backed obligations.”
Boosting funding this way could have a big payoff, Lo says. The sheer size of the megafund would reduce risk by diversifying investments across many more projects, and therefore could provide investors stronger guarantees of returns than any smaller fund. Just one blockbuster drug, the paper notes, can net $2 billion in income a year over a decade.
Lo’s computer models, based on historical data, indicate a $5 to $15 billion megafund would yield 9 to 12 percent returns for equity investors, and 5 to 8 percent returns for “research-backed obligation” holders—rates that could be attractive to pension funds, for example. Careful and realistic planning could avoid the “pitfalls” that sank the mortgage companies during the financial crisis, the Nature paper says.
So far, all of this is just words on paper and code in a software model (which Lo has released for others to tinker with).
Melissa Stevens, deputy executive director of Faster Cures, a nonprofit think tank, sees promise in the idea, but says there would also be lots of details to get right—cataloging the assets that exist, and deciding how to choose them, and assessing the levels of risk and time until reward. Hammering out workable agreements between researchers and investors would be a challenge, but not “insurmountable,” she says.
Nor will the concept solve all of the problems involved with life science investing. More money won’t fix, for example, the scientific and regulatory slowdowns that contribute to decreased productivity of each research dollar. “The question is not only how we can attract more capital into R&D, but how we can decrease the amount of capital that we need,” Stevens says. (Lo imagines a megafund could actually help this too, providing shared resources like basic legal support or lab resources among portfolio projects.)
The megafund idea is a relatively radical example of a growing number of new drug research funding models being tried in the face of the industry’s recent challenges.
Meanwhile, to attract more funding, “hybrid” funds are emerging that bring in nontraditional venture capital investors, like governments and philanthropies, willing to absorb more risk or wait longer for a reward, says Stevens.
Lo is organizing a conference for next year to bring together investors, researchers, executives, and the National Cancer Institute to hammer out more details. He thinks it should all be an easier sell in the post-financial crisis, post-bailout world: “We spent billions on General Motors, which sells cars people don’t want to buy. So $30 billion for cancer research should not be a big deal. These numbers don’t look that big to me now.”
A hedge fund manager aims to solve the funding problems facing early-stage biomedical research.
By Jessica Leber on November 19, 2012
Why It Matters
The next generation of drug therapies could depend on funding more early-stage biomedical research than is feasible today.
Hedge fund manager and prominent economist Andrew Lo is recognized for developing theories about how markets function and why they failed during the financial crisis. Now Lo, who is also the director of the MIT Sloan School of Management’s Laboratory for Financial Engineering, thinks he can also help create a better market for investing in promising treatments for cancer.
His proposal is to structure a new kind of financial tool, a “megafund,” for funneling up to $30 billion into the discovery of cancer drugs. The project would be unprecedented in scale at a time when the biomedical sector is searching for fresh funding ideas. As Lo says, the community is “ripe for something new.”
In a paper published in Nature Biotechnology earlier this fall, Lo and his coauthors note that large pharmaceutical companies are no longer nurturing early-stage drug development. Venture capitalists, too, are deserting life science startups, which averaged them negative 1 percent returns over the last decade. The result is a growing funding gap between basic lab research and commercial drug development. And fewer drugs are surviving the costly gauntlet of clinical trials to eventually reach FDA approval.
Lo’s proposal would expand the pool of capital available for life science investment by bringing together investors who would not normally fund research at top biomedical universities in exchange for a small percentage of all royalties from successful drugs or licensing revenues that result.
About five drug royalty investment companies already exist, Lo says, but they only invest in drugs that are already approved. His plan would do this at an earlier and riskier stage, and spread the risk using techniques found elsewhere in finance—and familiar from the mortgage crisis—securitizing future revenues, in this case from drug compound licenses, into debts called “research-backed obligations.”
Boosting funding this way could have a big payoff, Lo says. The sheer size of the megafund would reduce risk by diversifying investments across many more projects, and therefore could provide investors stronger guarantees of returns than any smaller fund. Just one blockbuster drug, the paper notes, can net $2 billion in income a year over a decade.
Lo’s computer models, based on historical data, indicate a $5 to $15 billion megafund would yield 9 to 12 percent returns for equity investors, and 5 to 8 percent returns for “research-backed obligation” holders—rates that could be attractive to pension funds, for example. Careful and realistic planning could avoid the “pitfalls” that sank the mortgage companies during the financial crisis, the Nature paper says.
So far, all of this is just words on paper and code in a software model (which Lo has released for others to tinker with).
Melissa Stevens, deputy executive director of Faster Cures, a nonprofit think tank, sees promise in the idea, but says there would also be lots of details to get right—cataloging the assets that exist, and deciding how to choose them, and assessing the levels of risk and time until reward. Hammering out workable agreements between researchers and investors would be a challenge, but not “insurmountable,” she says.
Nor will the concept solve all of the problems involved with life science investing. More money won’t fix, for example, the scientific and regulatory slowdowns that contribute to decreased productivity of each research dollar. “The question is not only how we can attract more capital into R&D, but how we can decrease the amount of capital that we need,” Stevens says. (Lo imagines a megafund could actually help this too, providing shared resources like basic legal support or lab resources among portfolio projects.)
The megafund idea is a relatively radical example of a growing number of new drug research funding models being tried in the face of the industry’s recent challenges.
Meanwhile, to attract more funding, “hybrid” funds are emerging that bring in nontraditional venture capital investors, like governments and philanthropies, willing to absorb more risk or wait longer for a reward, says Stevens.
Lo is organizing a conference for next year to bring together investors, researchers, executives, and the National Cancer Institute to hammer out more details. He thinks it should all be an easier sell in the post-financial crisis, post-bailout world: “We spent billions on General Motors, which sells cars people don’t want to buy. So $30 billion for cancer research should not be a big deal. These numbers don’t look that big to me now.”
Managing Breast Cancer in 2015
Managing Breast Cancer in 2015
A Conversation With Larry Norton, MD
By Ronald Piana
May 25, 2015, Volume 6, Issue 9
If we can simultaneously hit the abnormal cell division of the cancer cells and their migratory capacity, then we’re killing the cells everywhere they live.
—Larry Norton, MD
Since 1990, we have seen an approximate 35% reduction in breast cancer mortality among women in the United States. Three protagonists can share this clinical success story: prevention, early detection, and better therapies. To shed light on the current state of breast cancer research and therapy, The ASCO Post spoke with internationally regarded breast cancer expert and ASCO past president Larry Norton, MD, Medical Director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center in New York.
Reinvention of Clinical Trials
Please tell the readers what has been the most significant advance in breast cancer treatment over the course of your career?
This may surprise some, but I believe the most significant advance has been the development of clinical trial methodology. Innovative scientific ideas come along frequently, but they still have to be tested. Not everything logical is true, but everything that is true should be confirmed. And the major leap forward in that confirmation process was the emergence of the randomized controlled prospective trial. Over the past few decades, we’ve seen many good ideas sorted out by rigorous trials, which ultimately developed into active therapies.
This is particularly relevant to this time in history, because we’re seeing a potential reinvention of clinical trials due to the advent of precision medicine: that is, defining a particular target, developing an intervention to hit that target, and then examining the results. Seeing responses in this setting is the most important step in the development of active therapeutics. However, it is a first step, and we then need to see how durable the response is, determine the optimal time in which to give the drug, learn how to use it in combination, and then compare the drug with other approaches. That said, we are currently ruminating over the best way to use molecularly targeted therapies in clinical trials to answer those vital questions quicker and more accurately.
This critical evaluation process is important, because we’ve had times in medical oncology in which a dramatic response was seen as the endpoint, stifling further critique. For example, autologous bone marrow transplant with high-dose chemotherapy produced dramatic responses in breast tumor shrinkage. Investigators judged this a huge clinical win, which in effect created a consensus among the oncology community that further confirmatory randomized trials were not needed. It took us 10 years to discover that bone marrow transplant with high-dose chemotherapy was no better than standard chemotherapy, which was also less toxic.
This episode offers an important cautionary lesson that shouldn’t be forgotten. Clearly, with the advent of molecularly targeted therapies, our opportunities are greater than ever, but we have to think very long about how we’re going to test these new therapies in trials that ensure their benefit before bringing them into the clinic.
Dissecting Resistance Pathways
Chemoresistance has been a persistent problem in breast cancer. Are we making headway in this area?
Drug resistance is a major problem throughout all medical disciplines where drugs are delivered. In cancer, it’s especially difficult because we’re treating a disease that comprises the host’s own cells. And evolution has taught these cells how to survive in a noxious environment of toxins. Drug resistance develops from a wide variety of cellular mechanisms, and one of the great powers of the modern molecular revolution is being able to dissect those resistance pathways and find ways to diagnose and prevent them.
This is one of the most exciting areas we’re investigating in molecular therapeutics. We’re seeing a lot of the newer agents being developed as initial therapies. For instance, we have many effective hormone therapies for breast cancer; the next step is to combine a hormone therapy with a promising drug de novo, which might overcome potential mechanisms of resistance. This approach is meritorious, but what might be more important in the long run is to treat a patient with a drug and if a resistance mechanism emerges, have another drug in place that will halt the resistance mechanism in its tracks.
Both of these approaches tie into my leading argument about clinical trial methodology, which, if properly designed, can be used to find the mechanisms of drug resistance and then develop drugs specially engineered to “turn off” those mechanisms. I think that’s the kind of clinical trial we’ll see more of in the future.
Immunotherapy
Immunotherapy is emerging as one of the most promising therapeutic opportunities in several cancers. Please discuss the future role of immunotherapy in breast cancer.
Immunotherapy is part of the molecular revolution we’re talking about, because what made it possible is the discovery of particular mechanisms by which our cells can avoid attacking their host, in particular the CTLA-4 (cytotoxic T-lymphocyte antigen 4) mechanism, which has opened up this exciting area of molecularly targeted therapies. What truly makes this interesting is that this process exists at the interface of the cancer cell and a host’s white blood cell, which is an important topic for future development; it is not the cell itself but the cell’s relationship with other cells. Nobody ever died of breast cancer cells; you die of tumors, which are complex organs involving cancer cells, white blood cells, and host tissues such as fibroblasts. And those cells in the tumor environment have a functional relationship, and the communication among those cells is a valuable target—I think that is the core of immunotherapy in cancer.
We’re currently doing a trial at Memorial Sloan Kettering in which we use cryoablation, radiotherapy, and other techniques, such as introducing DNA into the cancer cell to make it secrete its own immunostimulatory components, which are all methods to make the cancer cell a better target for the immune response. Then, if you combine that method with drugs that inhibit the checkpoint blockade for preventing cellular self-against-self attack, you’ve opened the door for promising immune therapies.
Targeting Both Growth and Migration
The metastatic process remains, to a certain extent, still a mystery. Are we getting closer to a full understanding of the process? And can you please bring our readers up to speed on your fascinating work on tumor self-seeding.
Cancer is basically two things: growth and migration. Over the decades, we’ve gotten much better at treating the growth abnormalities with chemotherapy. We’re seeing targeted therapies such mTOR inhibiters and anti-CDK4/6 drugs, which are effective at perturbing the abnormal cell division of cancer, but we’ve lagged behind in attacking the other component of cancer—the ability of cancer cells to migrate. And evidence suggests that cell migration may be key to the malignant process, because when migratory cells return to their original primary site, they bring white blood cells and blood vessels, which are tools to reinvigorate the malignant process.
To that end, there is tremendous interest in developing antimigratory drugs, which is a better term then antimetastatic. I think that moving forward this will be one of the most important areas of research in modern medical science. If we can simultaneously hit the abnormal cell division of the cancer cells and their migratory capacity, then we’re killing the cells everywhere they live. In other words, if we can inhibit the circulating cancer cells from lodging and forming tumors, it doesn’t matter how many cancer cells are in the blood, because the patient will never get sick.
We’re also making headway in a very novel technique, which is a trap that can actually capture circulating cancer cells. The immediate application is to capture the cells for study, hopefully to lead us to better molecular targets. However, it may have therapeutic value in being able to rid the body of cancer cells before they have the opportunity to root in an organ and form tumors.
Closing Thoughts
Please share a closing thought or two about the state of breast cancer research and care from your perspective as Director of the MSKCC Evelyn H. Lauder Breast Center.
We have never had a period like this in all the history of cancer research and treatment. Compared to just a few decades ago, our growing knowledge of cancer biology is nothing short of incredible, but we have challenges ahead. For one, funding for research is very tight, and it’s a problem that we all wrestle with, one that ASCO has taken a lead on. I also think that the business model used to develop early ideas needs to be reinvented.
The brilliant MIT economist Andrew Lo has written extensively about this. He’s also organized a yearly meeting in Boston that is attempting to find better ways to finance drug trials. I have great confidence that if the oncology community partners with innovators such as Andrew Lo and others, we will generate the creative juices needed to reinvigorate the clinical trial process and bring these novel ideas to fruition. ■
Disclosure: Dr. Norton reported no potential conflicts of interest.
A Conversation With Larry Norton, MD
By Ronald Piana
May 25, 2015, Volume 6, Issue 9
If we can simultaneously hit the abnormal cell division of the cancer cells and their migratory capacity, then we’re killing the cells everywhere they live.
—Larry Norton, MD
Since 1990, we have seen an approximate 35% reduction in breast cancer mortality among women in the United States. Three protagonists can share this clinical success story: prevention, early detection, and better therapies. To shed light on the current state of breast cancer research and therapy, The ASCO Post spoke with internationally regarded breast cancer expert and ASCO past president Larry Norton, MD, Medical Director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center in New York.
Reinvention of Clinical Trials
Please tell the readers what has been the most significant advance in breast cancer treatment over the course of your career?
This may surprise some, but I believe the most significant advance has been the development of clinical trial methodology. Innovative scientific ideas come along frequently, but they still have to be tested. Not everything logical is true, but everything that is true should be confirmed. And the major leap forward in that confirmation process was the emergence of the randomized controlled prospective trial. Over the past few decades, we’ve seen many good ideas sorted out by rigorous trials, which ultimately developed into active therapies.
This is particularly relevant to this time in history, because we’re seeing a potential reinvention of clinical trials due to the advent of precision medicine: that is, defining a particular target, developing an intervention to hit that target, and then examining the results. Seeing responses in this setting is the most important step in the development of active therapeutics. However, it is a first step, and we then need to see how durable the response is, determine the optimal time in which to give the drug, learn how to use it in combination, and then compare the drug with other approaches. That said, we are currently ruminating over the best way to use molecularly targeted therapies in clinical trials to answer those vital questions quicker and more accurately.
This critical evaluation process is important, because we’ve had times in medical oncology in which a dramatic response was seen as the endpoint, stifling further critique. For example, autologous bone marrow transplant with high-dose chemotherapy produced dramatic responses in breast tumor shrinkage. Investigators judged this a huge clinical win, which in effect created a consensus among the oncology community that further confirmatory randomized trials were not needed. It took us 10 years to discover that bone marrow transplant with high-dose chemotherapy was no better than standard chemotherapy, which was also less toxic.
This episode offers an important cautionary lesson that shouldn’t be forgotten. Clearly, with the advent of molecularly targeted therapies, our opportunities are greater than ever, but we have to think very long about how we’re going to test these new therapies in trials that ensure their benefit before bringing them into the clinic.
Dissecting Resistance Pathways
Chemoresistance has been a persistent problem in breast cancer. Are we making headway in this area?
Drug resistance is a major problem throughout all medical disciplines where drugs are delivered. In cancer, it’s especially difficult because we’re treating a disease that comprises the host’s own cells. And evolution has taught these cells how to survive in a noxious environment of toxins. Drug resistance develops from a wide variety of cellular mechanisms, and one of the great powers of the modern molecular revolution is being able to dissect those resistance pathways and find ways to diagnose and prevent them.
This is one of the most exciting areas we’re investigating in molecular therapeutics. We’re seeing a lot of the newer agents being developed as initial therapies. For instance, we have many effective hormone therapies for breast cancer; the next step is to combine a hormone therapy with a promising drug de novo, which might overcome potential mechanisms of resistance. This approach is meritorious, but what might be more important in the long run is to treat a patient with a drug and if a resistance mechanism emerges, have another drug in place that will halt the resistance mechanism in its tracks.
Both of these approaches tie into my leading argument about clinical trial methodology, which, if properly designed, can be used to find the mechanisms of drug resistance and then develop drugs specially engineered to “turn off” those mechanisms. I think that’s the kind of clinical trial we’ll see more of in the future.
Immunotherapy
Immunotherapy is emerging as one of the most promising therapeutic opportunities in several cancers. Please discuss the future role of immunotherapy in breast cancer.
Immunotherapy is part of the molecular revolution we’re talking about, because what made it possible is the discovery of particular mechanisms by which our cells can avoid attacking their host, in particular the CTLA-4 (cytotoxic T-lymphocyte antigen 4) mechanism, which has opened up this exciting area of molecularly targeted therapies. What truly makes this interesting is that this process exists at the interface of the cancer cell and a host’s white blood cell, which is an important topic for future development; it is not the cell itself but the cell’s relationship with other cells. Nobody ever died of breast cancer cells; you die of tumors, which are complex organs involving cancer cells, white blood cells, and host tissues such as fibroblasts. And those cells in the tumor environment have a functional relationship, and the communication among those cells is a valuable target—I think that is the core of immunotherapy in cancer.
We’re currently doing a trial at Memorial Sloan Kettering in which we use cryoablation, radiotherapy, and other techniques, such as introducing DNA into the cancer cell to make it secrete its own immunostimulatory components, which are all methods to make the cancer cell a better target for the immune response. Then, if you combine that method with drugs that inhibit the checkpoint blockade for preventing cellular self-against-self attack, you’ve opened the door for promising immune therapies.
Targeting Both Growth and Migration
The metastatic process remains, to a certain extent, still a mystery. Are we getting closer to a full understanding of the process? And can you please bring our readers up to speed on your fascinating work on tumor self-seeding.
Cancer is basically two things: growth and migration. Over the decades, we’ve gotten much better at treating the growth abnormalities with chemotherapy. We’re seeing targeted therapies such mTOR inhibiters and anti-CDK4/6 drugs, which are effective at perturbing the abnormal cell division of cancer, but we’ve lagged behind in attacking the other component of cancer—the ability of cancer cells to migrate. And evidence suggests that cell migration may be key to the malignant process, because when migratory cells return to their original primary site, they bring white blood cells and blood vessels, which are tools to reinvigorate the malignant process.
To that end, there is tremendous interest in developing antimigratory drugs, which is a better term then antimetastatic. I think that moving forward this will be one of the most important areas of research in modern medical science. If we can simultaneously hit the abnormal cell division of the cancer cells and their migratory capacity, then we’re killing the cells everywhere they live. In other words, if we can inhibit the circulating cancer cells from lodging and forming tumors, it doesn’t matter how many cancer cells are in the blood, because the patient will never get sick.
We’re also making headway in a very novel technique, which is a trap that can actually capture circulating cancer cells. The immediate application is to capture the cells for study, hopefully to lead us to better molecular targets. However, it may have therapeutic value in being able to rid the body of cancer cells before they have the opportunity to root in an organ and form tumors.
Closing Thoughts
Please share a closing thought or two about the state of breast cancer research and care from your perspective as Director of the MSKCC Evelyn H. Lauder Breast Center.
We have never had a period like this in all the history of cancer research and treatment. Compared to just a few decades ago, our growing knowledge of cancer biology is nothing short of incredible, but we have challenges ahead. For one, funding for research is very tight, and it’s a problem that we all wrestle with, one that ASCO has taken a lead on. I also think that the business model used to develop early ideas needs to be reinvented.
The brilliant MIT economist Andrew Lo has written extensively about this. He’s also organized a yearly meeting in Boston that is attempting to find better ways to finance drug trials. I have great confidence that if the oncology community partners with innovators such as Andrew Lo and others, we will generate the creative juices needed to reinvigorate the clinical trial process and bring these novel ideas to fruition. ■
Disclosure: Dr. Norton reported no potential conflicts of interest.
miércoles, 27 de mayo de 2015
CancerLinQ and Precision Medicine
Big Data and the Promise of Precision Medicine in Cancer
By Peter Paul Yu, MD, FACP, FASCO
March 10, 2015, Volume 6, Issue 4
Peter Paul Yu, MD, FACP, FASCO, Director of Cancer Research, Palo Alto Medical Foundation
The promise of CancerLinQ is, at its core, the promise of precision medicine. More than ever, our nation is expecting us to deliver on this promise.
—Peter Paul Yu, MD, FACP, FASCO
Precision medicine—and its promise to revolutionize how we understand disease and care for our patients—is a concept that oncology has understood and embraced for well over a decade. But millions of Americans recently heard about the concept for the first time when President Obama announced a high-profile Precision Medicine Initiative during his annual State of the Union address in January.
The President has called on Congress to allocate $215 million in federal funds in the next fiscal year to back this effort. The lion’s share of the funding would be used to establish a new research cohort of a million or more people and to increase research on the genetic mechanisms that lead to cancer and other diseases.
Broader Innovations Needed
The President’s proposal is hugely welcome, and ASCO hopes that it will find bipartisan support in Congress. Federal research financing has driven extraordinary medical progress, and these new investments could yield important new knowledge.
Along with new research, however, broader innovations are needed. In fact, the full potential of precision medicine will be realized only if we rethink how we collect, analyze, and learn from all of the cancer care that patients receive, whether at major clinical trial sites or in small oncology practices across the country. It will require creating digital health systems that support population health; the identification of special populations of cancer patients based on clinical and molecular characteristics and aggregation of data across such populations.
We all recognize that too few of our patients participate in clinical trials—just about 3%, in fact. That pool of patients is not just small. It’s also not representative of many of the patients we see in our practices every day—patients who are often older or less healthy than the people who are eligible for trials.
Meanwhile, most cancer doctors already find it difficult, if not impossible, to constantly review and interpret new research findings and rapidly incorporate this knowledge into day-to-day care. Over time, the President’s new initiative will produce even more information for physicians to track, understand, and apply.
Put simply, cancer doctors need more: We need more information to inform the care of our patients, and we need more support to make sense of it all.
CancerLinQ Will Transform Cancer Care
That’s why ASCO is building CancerLinQ™, an ambitious “big data” initiative to transform cancer care and improve patient outcomes through the generation of new knowledge based on real-world patients and learning tools that aid in the application of that knowledge to patient care. When complete, it will seamlessly and securely aggregate and analyze data from electronic health records and other sources in order to do three things:
CancerLinQ will provide clinical decision support to help physicians choose the right therapy at the right time for each patient. This functionality will draw on published guidelines from ASCO and other expert groups and eventually on conclusions drawn from real-world patient care.
The system will provide rapid, quality feedback to allow providers to compare their care against guidelines and against the care of their peers. We will be able to see, right away, if there are ways to improve the care we’re providing and to monitor that care in real time as we work to close those gaps.
CancerLinQ’s analytic tools will help improve care by uncovering hidden patterns in patient characteristics, treatments, and outcomes. These kinds of insights will generate strong new hypotheses for clinical research and help us improve trial designs.
Rollout Later This Year
Building this system will take several years and require substantial, ongoing investments. But I believe that CancerLinQ is well on its way to becoming the platform of choice for oncologists by the end of this decade.
We recently announced that CancerLinQ will be built on a big data software platform developed by SAP, a leading data processing and database management company. This technology, known as HANA, is already being used by thousands of institutions worldwide, including many health and medical organizations.
With the technology platform selected, we are on a fast track to roll out the first version of CancerLinQ by the end of this year with at least 12 oncology practices nationwide, which collectively serve about 500,000 cancer patients. Insights from this first phase will allow us to develop smarter, more advanced versions, which will ultimately be available to all oncology practices in the United States, no matter their affiliations or choice of electronic health record systems.
As excited as we are about CancerLinQ’s progress and potential, important challenges lie ahead. For one, CancerLinQ is an extremely ambitious and complex technical project. We will need to overcome a host of technological challenges as we seek to build a platform that is powerful, versatile, and easy to use. Like any health data initiative, CancerLinQ will need to guarantee the security and privacy of patient information. We are deeply committed to doing so and have engaged patient advisors and other experts to make sure we maintain patients’ trust every step of the way.
Fulfilling the Promise of Precision Medicine
There are also a number of other health data initiatives competing for oncologists’ attention and patients’ data. As the only nonprofit, physician-led initiative in this arena, I believe CancerLinQ is well positioned to succeed. But its impact on patient care will ultimately depend on the participation of ASCO’s members and other physicians nationwide.
In the coming months, we will have exciting news and updates to share as we continue to bring CancerLinQ from vision to reality. I invite you to visit our newly revamped website, CancerLinQ.org, for more information.
More important, I ask my fellow oncologists to join us as we roll out CancerLinQ in the years ahead. The promise of CancerLinQ is, at its core, the promise of precision medicine. More than ever, our nation is expecting us to deliver on this promise. ■
Disclosure: Dr. Yu is the President of ASCO for 2014–2015.
Dr. Yu is President of ASCO for 2014–2015 and Director of Cancer Research at Palo Alto Medical Foundation in California.
By Peter Paul Yu, MD, FACP, FASCO
March 10, 2015, Volume 6, Issue 4
Peter Paul Yu, MD, FACP, FASCO, Director of Cancer Research, Palo Alto Medical Foundation
The promise of CancerLinQ is, at its core, the promise of precision medicine. More than ever, our nation is expecting us to deliver on this promise.
—Peter Paul Yu, MD, FACP, FASCO
Precision medicine—and its promise to revolutionize how we understand disease and care for our patients—is a concept that oncology has understood and embraced for well over a decade. But millions of Americans recently heard about the concept for the first time when President Obama announced a high-profile Precision Medicine Initiative during his annual State of the Union address in January.
The President has called on Congress to allocate $215 million in federal funds in the next fiscal year to back this effort. The lion’s share of the funding would be used to establish a new research cohort of a million or more people and to increase research on the genetic mechanisms that lead to cancer and other diseases.
Broader Innovations Needed
The President’s proposal is hugely welcome, and ASCO hopes that it will find bipartisan support in Congress. Federal research financing has driven extraordinary medical progress, and these new investments could yield important new knowledge.
Along with new research, however, broader innovations are needed. In fact, the full potential of precision medicine will be realized only if we rethink how we collect, analyze, and learn from all of the cancer care that patients receive, whether at major clinical trial sites or in small oncology practices across the country. It will require creating digital health systems that support population health; the identification of special populations of cancer patients based on clinical and molecular characteristics and aggregation of data across such populations.
We all recognize that too few of our patients participate in clinical trials—just about 3%, in fact. That pool of patients is not just small. It’s also not representative of many of the patients we see in our practices every day—patients who are often older or less healthy than the people who are eligible for trials.
Meanwhile, most cancer doctors already find it difficult, if not impossible, to constantly review and interpret new research findings and rapidly incorporate this knowledge into day-to-day care. Over time, the President’s new initiative will produce even more information for physicians to track, understand, and apply.
Put simply, cancer doctors need more: We need more information to inform the care of our patients, and we need more support to make sense of it all.
CancerLinQ Will Transform Cancer Care
That’s why ASCO is building CancerLinQ™, an ambitious “big data” initiative to transform cancer care and improve patient outcomes through the generation of new knowledge based on real-world patients and learning tools that aid in the application of that knowledge to patient care. When complete, it will seamlessly and securely aggregate and analyze data from electronic health records and other sources in order to do three things:
CancerLinQ will provide clinical decision support to help physicians choose the right therapy at the right time for each patient. This functionality will draw on published guidelines from ASCO and other expert groups and eventually on conclusions drawn from real-world patient care.
The system will provide rapid, quality feedback to allow providers to compare their care against guidelines and against the care of their peers. We will be able to see, right away, if there are ways to improve the care we’re providing and to monitor that care in real time as we work to close those gaps.
CancerLinQ’s analytic tools will help improve care by uncovering hidden patterns in patient characteristics, treatments, and outcomes. These kinds of insights will generate strong new hypotheses for clinical research and help us improve trial designs.
Rollout Later This Year
Building this system will take several years and require substantial, ongoing investments. But I believe that CancerLinQ is well on its way to becoming the platform of choice for oncologists by the end of this decade.
We recently announced that CancerLinQ will be built on a big data software platform developed by SAP, a leading data processing and database management company. This technology, known as HANA, is already being used by thousands of institutions worldwide, including many health and medical organizations.
With the technology platform selected, we are on a fast track to roll out the first version of CancerLinQ by the end of this year with at least 12 oncology practices nationwide, which collectively serve about 500,000 cancer patients. Insights from this first phase will allow us to develop smarter, more advanced versions, which will ultimately be available to all oncology practices in the United States, no matter their affiliations or choice of electronic health record systems.
As excited as we are about CancerLinQ’s progress and potential, important challenges lie ahead. For one, CancerLinQ is an extremely ambitious and complex technical project. We will need to overcome a host of technological challenges as we seek to build a platform that is powerful, versatile, and easy to use. Like any health data initiative, CancerLinQ will need to guarantee the security and privacy of patient information. We are deeply committed to doing so and have engaged patient advisors and other experts to make sure we maintain patients’ trust every step of the way.
Fulfilling the Promise of Precision Medicine
There are also a number of other health data initiatives competing for oncologists’ attention and patients’ data. As the only nonprofit, physician-led initiative in this arena, I believe CancerLinQ is well positioned to succeed. But its impact on patient care will ultimately depend on the participation of ASCO’s members and other physicians nationwide.
In the coming months, we will have exciting news and updates to share as we continue to bring CancerLinQ from vision to reality. I invite you to visit our newly revamped website, CancerLinQ.org, for more information.
More important, I ask my fellow oncologists to join us as we roll out CancerLinQ in the years ahead. The promise of CancerLinQ is, at its core, the promise of precision medicine. More than ever, our nation is expecting us to deliver on this promise. ■
Disclosure: Dr. Yu is the President of ASCO for 2014–2015.
Dr. Yu is President of ASCO for 2014–2015 and Director of Cancer Research at Palo Alto Medical Foundation in California.
martes, 26 de mayo de 2015
E-Cigarettes to Stop Smoking: Does It Work?
Should We Recommend E-Cigarettes to Help Our Patients Stop Smoking: Does It Work?
Cary Presant, MD, Oncology, Hematology/Oncology, 09:05PM May 25, 2015
Smoking is a problem in our patients, since continued smoking produces worse outcomes in colorectal cancer survivorship. Also, it leads to increased cancer mortality and cardiovascular mortality. And we are often asked by our patients about what we suggest for helping in smoking cessation. These questions usually include inquiries about recommendations for or against use of e-cigarettes (also called ENDS – electronic nicotine delivery systems).
A recent article by TH Brandon and coauthors (J Clin Oncol 2015; 33: 952) gives a good overview of ENDS and their benefits (or lack thereof). It also includes the ASCO policy recommendations.
I was most impressed by the low effectiveness of use of ENDS in helping patients to stop combustible cigarette use. In Table 2, the largest trials were surprisingly unsuccessful in helping patients. In the largest trial of 6000 patients, quit rates were highest for ENDS users 20%, only slightly higher than 15% in controls and 10% in nicotine replacement therapy. In the second largest reviewed trial, in 5939 patients, 85% of ENDS users were using them to quit smoking, and surprisingly the 11% rate of successful quitting was no higher than in patients not using ENDS.
I have been recommending that patients may try ENDS (and many of my friends and patients have succeeded in quitting with the “help” of ENDS), but now I need to be careful in setting their expectations appropriately. This review by ASCO and the well-articulated policy statement will help in my ability to take care of my patients.
I recommend you read the review and think about how you, an expert in the outcomes of smoking, can use this information in promoting healthier habits in your patients, among your colleagues and PCPs, in your community, and even in your families.
Cary Presant, MD, Oncology, Hematology/Oncology, 09:05PM May 25, 2015
Smoking is a problem in our patients, since continued smoking produces worse outcomes in colorectal cancer survivorship. Also, it leads to increased cancer mortality and cardiovascular mortality. And we are often asked by our patients about what we suggest for helping in smoking cessation. These questions usually include inquiries about recommendations for or against use of e-cigarettes (also called ENDS – electronic nicotine delivery systems).
A recent article by TH Brandon and coauthors (J Clin Oncol 2015; 33: 952) gives a good overview of ENDS and their benefits (or lack thereof). It also includes the ASCO policy recommendations.
I was most impressed by the low effectiveness of use of ENDS in helping patients to stop combustible cigarette use. In Table 2, the largest trials were surprisingly unsuccessful in helping patients. In the largest trial of 6000 patients, quit rates were highest for ENDS users 20%, only slightly higher than 15% in controls and 10% in nicotine replacement therapy. In the second largest reviewed trial, in 5939 patients, 85% of ENDS users were using them to quit smoking, and surprisingly the 11% rate of successful quitting was no higher than in patients not using ENDS.
I have been recommending that patients may try ENDS (and many of my friends and patients have succeeded in quitting with the “help” of ENDS), but now I need to be careful in setting their expectations appropriately. This review by ASCO and the well-articulated policy statement will help in my ability to take care of my patients.
I recommend you read the review and think about how you, an expert in the outcomes of smoking, can use this information in promoting healthier habits in your patients, among your colleagues and PCPs, in your community, and even in your families.
WHO Model List of Essential Medicines
WHO Model List of Essential Medicines Revised
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New anticancer medicines included in the list
Date: 22 May 2015
Topic: Bioethics, legal and economic issues / Anticancer agents & Biologic therapy
On 8 May 2015, the World Health Organization (WHO) published the new edition of its Model List of Essential Medicines which includes ground-breaking new treatments for a variety of cancers. The move opens the way to improve access to innovative medicines that show clear clinical benefits and could have enormous public health impact globally.
New breakthroughs have been made in cancer treatment in the last years, which prompted WHO to revise the full cancer segment of the Model List of Essential Medicines: 52 products were reviewed and 30 treatments confirmed, with 16 new medicines included in the list.
The committee of expert reviewers underscored the urgent need to take action to promote equitable access and use of several new highly effective medicines, some of which are currently too costly even for high-income countries.
Several important anticancer drugs have been added to the list, including three targeted therapies (rituximab, imatinib and trastuzumab), and a number of drugs for solid tumours (capecitabine, gemcitabine, filgrastim, irinotecan, oxaliplatin, vinorelbine, anastrozole, bicalutamide and leuprorelin) and other for haematologic malignancies.
Also new in this edition is the tumour specific indication for all the drugs.
WHO Model List of Essential Medicines
WHO Global Action Plan on Prevention and Control of Noncommunicable Diseases (NCDs) 2013-2020 has as a target 80% availability of essential medicines and technologies for NCDs by 2025.
The first WHO Essential Medicines List was published in 1977 with 6 cancer drugs included. In 1984, the first review of oncology medicines on the list was performed that resulted with 14 cancer drugs included in the list. In 1995, the second review was performed and the list was expanded to 24 anticancer drugs. In 1999, the third review has occurred. In 2013, 30 anticancer medicines were published in the WHO list. The latest review has started last year; albeit not perfect, the new list represents an important advance.
In 2014, the UICC responded to an invitation by the WHO to convene a task team charged with creating a new framework for evaluation of drugs for inclusion. The Core Task Team included representatives of UICC, Dana Farber Cancer Institute, ESMO, ASCO, SIOP, US National Cancer Institute, NCCN International plus collaborations from the outset with the WHO was critical to this work.
All authors, peer reviewers, and coordinating team were volunteers. Only Secretariat role was hired, with the kind support of NCI Center for Global Health, USA and the Livestrong Foundation.
ESMO has been actively participating in the latest revision, in the process of defining the criteria and providing information for the proposal documents, through the Emerging Countries Committee and active participation of Dr Alexandru Eniu, ESMO Board member and Chair of the Emerging Countries Committee.
Methodology
Methodology to develop proposal for revisions decisions focused on diseases/treatment outcomes and not individual medicines. Two primary axes were considered: What is the burden of disease and what is the clinical benefit from systemic therapies. More specifically, what is the potential harms/benefit of regimens of medicines for a particular disease and what are the supportive services that are required and does that influence the recommendation (such as blood product availability, pathology testing for genomic mutations and hormone receptor status).
The publishing of this new edition of WHO's Model List of Essential Medicines comes on the heels of the First Strategic and Technical Meeting on Management of Cancer hosted by WHO at its headquarters on 27-28 April, 2015. With technical experts from around the world, a set of priority actions has been identified that WHO will undertake to best support national efforts to develop and strengthen the early detection, diagnosis and treatment of cancer.
These actions include expansion of the WHO Package of Essential NCD Interventions for Primary Health Care; updates of the WHO cancer fact sheets and WHO modules on cancer control; guidance on screening; and regional trainings on cancer control. Participants underlined the need to encourage countries and international donors to invest in cancer control as many lives could potentially be saved if more resources were available.
Share on facebookShare on twitterShare on emailShare on linkedinShare on printShare on facebookShare on twitterShare on emailShare on linkedin
New anticancer medicines included in the list
Date: 22 May 2015
Topic: Bioethics, legal and economic issues / Anticancer agents & Biologic therapy
On 8 May 2015, the World Health Organization (WHO) published the new edition of its Model List of Essential Medicines which includes ground-breaking new treatments for a variety of cancers. The move opens the way to improve access to innovative medicines that show clear clinical benefits and could have enormous public health impact globally.
New breakthroughs have been made in cancer treatment in the last years, which prompted WHO to revise the full cancer segment of the Model List of Essential Medicines: 52 products were reviewed and 30 treatments confirmed, with 16 new medicines included in the list.
The committee of expert reviewers underscored the urgent need to take action to promote equitable access and use of several new highly effective medicines, some of which are currently too costly even for high-income countries.
Several important anticancer drugs have been added to the list, including three targeted therapies (rituximab, imatinib and trastuzumab), and a number of drugs for solid tumours (capecitabine, gemcitabine, filgrastim, irinotecan, oxaliplatin, vinorelbine, anastrozole, bicalutamide and leuprorelin) and other for haematologic malignancies.
Also new in this edition is the tumour specific indication for all the drugs.
WHO Model List of Essential Medicines
WHO Global Action Plan on Prevention and Control of Noncommunicable Diseases (NCDs) 2013-2020 has as a target 80% availability of essential medicines and technologies for NCDs by 2025.
The first WHO Essential Medicines List was published in 1977 with 6 cancer drugs included. In 1984, the first review of oncology medicines on the list was performed that resulted with 14 cancer drugs included in the list. In 1995, the second review was performed and the list was expanded to 24 anticancer drugs. In 1999, the third review has occurred. In 2013, 30 anticancer medicines were published in the WHO list. The latest review has started last year; albeit not perfect, the new list represents an important advance.
In 2014, the UICC responded to an invitation by the WHO to convene a task team charged with creating a new framework for evaluation of drugs for inclusion. The Core Task Team included representatives of UICC, Dana Farber Cancer Institute, ESMO, ASCO, SIOP, US National Cancer Institute, NCCN International plus collaborations from the outset with the WHO was critical to this work.
All authors, peer reviewers, and coordinating team were volunteers. Only Secretariat role was hired, with the kind support of NCI Center for Global Health, USA and the Livestrong Foundation.
ESMO has been actively participating in the latest revision, in the process of defining the criteria and providing information for the proposal documents, through the Emerging Countries Committee and active participation of Dr Alexandru Eniu, ESMO Board member and Chair of the Emerging Countries Committee.
Methodology
Methodology to develop proposal for revisions decisions focused on diseases/treatment outcomes and not individual medicines. Two primary axes were considered: What is the burden of disease and what is the clinical benefit from systemic therapies. More specifically, what is the potential harms/benefit of regimens of medicines for a particular disease and what are the supportive services that are required and does that influence the recommendation (such as blood product availability, pathology testing for genomic mutations and hormone receptor status).
The publishing of this new edition of WHO's Model List of Essential Medicines comes on the heels of the First Strategic and Technical Meeting on Management of Cancer hosted by WHO at its headquarters on 27-28 April, 2015. With technical experts from around the world, a set of priority actions has been identified that WHO will undertake to best support national efforts to develop and strengthen the early detection, diagnosis and treatment of cancer.
These actions include expansion of the WHO Package of Essential NCD Interventions for Primary Health Care; updates of the WHO cancer fact sheets and WHO modules on cancer control; guidance on screening; and regional trainings on cancer control. Participants underlined the need to encourage countries and international donors to invest in cancer control as many lives could potentially be saved if more resources were available.
domingo, 24 de mayo de 2015
American Society of Medical Oncology meeting, 2015.
Medscape Medical News > Conference News
What's Hot at ASCO 2015?
Zosia Chustecka May 21, 2015
So here we are again ― it's late May, and once again we are caught up in the buildup to the American Society of Clinical Oncology (ASCO) annual meeting
Chicago is hosting the meeting for the sixth year in a row, and more than 25,000 oncology professionals from around the world are expected to descend in the city for what ASCO president Peter Paul Yu, MD, describes as "the premier scientific meeting for clinical and translational oncology."
This year's theme is Innovation and Illumination ― Transforming Data Into Learning.
This is key, Dr Yu told journalists in a premeeting presscast. Noting the progress that has already been achieved with decades of clinical data, resulting in hard-won knowledge that can improve the treatment and care of our patients, he said, "The key to even greater, more rapid progress lies within these data and our ability to transform it into knowledge."
"By sharing data, we can accelerate learning and make faster strides against cancer," he said.
The annual meeting is a great place to exchanging ideas and learning, but it takes place just once a year. "Just imagine if this wealth of data could be transformed into learning in real time throughout the year," Dr Yu said. "This is where we are heading in oncology...."
Many Abstracts Already Released
The media buildup to the meeting is already intense. Most of the 5000 abstracts to be presented at the meeting have already been released online, and there has been an avalanche of press releases and notes from investors eyeing up new therapies in pharmaceutical R&D pipelines.
However, key abstracts from plenary and other sessions will not be released until the meeting is under way. The meeting takes place from May 29 to June 2.
There continues to be a buzz about immunotherapy, and particularly the programmed death (PD) inhibitors, such as nivolumab (Opvido, Bristol-Myers Squibb Company) and pembrolizumab (Keytruda, Merck & Co, Inc). Both these drugs have already been launched, but there are similar drugs coming through the pipeline, including MPDL3280A (Genentech/Roche), MEDI4736 and MED10680 (Medimmune Inc), avelumab (Merck Serono), pidilizumab (CureTech), and others.
Although the first evidence of clinical benefit of these agents was seen in melanoma, many other tumor types have now been shown to also respond to this immunotherapy approach. Among the data that will be released on Friday, May 29, are results from early clinical trials in advanced liver disease with nivolumab (abstract LBA100) and in head and neck cancer with pembrolizumab (abstract LBA6008).
In addition, details from a phase 3 trial of nivolumab in non–small cell lung cancer (abstract LBA109) will be released on May 29. There will be a lot of interest in these clinical data, because they have already had a huge impact. The manufacturer released the topline result in January 2015, announcing that the immunotherapy produced a significant improvement in overall survival when it was compared with chemotherapy as a second-line therapy, and these results led to the FDA approval of the first immunotherapy for lung cancer in March 2015 (3 months ahead of schedule).
The approval was warmly welcomed by lung cancer experts ― David Carbone, MD, PhD, director of the James Thoracic Center at the Ohio State University, in Columbus, said, "Immunotherapy is a quantum leap for lung cancer treatments," and Julie Brahmer, MD, thoracic cancer director at the Johns Hopkins Kimmel Cancer Center and associate professor of oncology at Johns Hopkins, in Baltimore, Maryland, said, "Immunotherapy is transforming the lung cancer treatment paradigm, providing the most promising option yet in the second-line treatment for squamous cell lung cancer patients."
What's Hot at ASCO 2015?
Zosia Chustecka May 21, 2015
So here we are again ― it's late May, and once again we are caught up in the buildup to the American Society of Clinical Oncology (ASCO) annual meeting
Chicago is hosting the meeting for the sixth year in a row, and more than 25,000 oncology professionals from around the world are expected to descend in the city for what ASCO president Peter Paul Yu, MD, describes as "the premier scientific meeting for clinical and translational oncology."
This year's theme is Innovation and Illumination ― Transforming Data Into Learning.
This is key, Dr Yu told journalists in a premeeting presscast. Noting the progress that has already been achieved with decades of clinical data, resulting in hard-won knowledge that can improve the treatment and care of our patients, he said, "The key to even greater, more rapid progress lies within these data and our ability to transform it into knowledge."
"By sharing data, we can accelerate learning and make faster strides against cancer," he said.
The annual meeting is a great place to exchanging ideas and learning, but it takes place just once a year. "Just imagine if this wealth of data could be transformed into learning in real time throughout the year," Dr Yu said. "This is where we are heading in oncology...."
Many Abstracts Already Released
The media buildup to the meeting is already intense. Most of the 5000 abstracts to be presented at the meeting have already been released online, and there has been an avalanche of press releases and notes from investors eyeing up new therapies in pharmaceutical R&D pipelines.
However, key abstracts from plenary and other sessions will not be released until the meeting is under way. The meeting takes place from May 29 to June 2.
There continues to be a buzz about immunotherapy, and particularly the programmed death (PD) inhibitors, such as nivolumab (Opvido, Bristol-Myers Squibb Company) and pembrolizumab (Keytruda, Merck & Co, Inc). Both these drugs have already been launched, but there are similar drugs coming through the pipeline, including MPDL3280A (Genentech/Roche), MEDI4736 and MED10680 (Medimmune Inc), avelumab (Merck Serono), pidilizumab (CureTech), and others.
Although the first evidence of clinical benefit of these agents was seen in melanoma, many other tumor types have now been shown to also respond to this immunotherapy approach. Among the data that will be released on Friday, May 29, are results from early clinical trials in advanced liver disease with nivolumab (abstract LBA100) and in head and neck cancer with pembrolizumab (abstract LBA6008).
In addition, details from a phase 3 trial of nivolumab in non–small cell lung cancer (abstract LBA109) will be released on May 29. There will be a lot of interest in these clinical data, because they have already had a huge impact. The manufacturer released the topline result in January 2015, announcing that the immunotherapy produced a significant improvement in overall survival when it was compared with chemotherapy as a second-line therapy, and these results led to the FDA approval of the first immunotherapy for lung cancer in March 2015 (3 months ahead of schedule).
The approval was warmly welcomed by lung cancer experts ― David Carbone, MD, PhD, director of the James Thoracic Center at the Ohio State University, in Columbus, said, "Immunotherapy is a quantum leap for lung cancer treatments," and Julie Brahmer, MD, thoracic cancer director at the Johns Hopkins Kimmel Cancer Center and associate professor of oncology at Johns Hopkins, in Baltimore, Maryland, said, "Immunotherapy is transforming the lung cancer treatment paradigm, providing the most promising option yet in the second-line treatment for squamous cell lung cancer patients."
sábado, 23 de mayo de 2015
Cancer Immunotherapies in Europe
News Alerts > Medscape Medical News
Green Light for Cancer Immunotherapies in Europe
Zosia Chustecka
Disclosures May 22, 2015
The European Medicines Agency (EMA) has recommended granting marketing authorization for three cancer immunotherapies ― pembrolizumab (Keytruda, Merck & Co, Inc) for melanoma, nivolumab (Opdivo, Bristol-Myers Squibb Company) for lung cancer, and dinutuximab (Unituxin, United Therapeutics Corporation) for neuroblastoma.
In addition, the EMA recommended approval for the additional indication of Waldenstrӧm's macroglobulinaemia for ibrutinib (Imbruvica, Pharmacyclics, Inc, Janssen Biotech, Inc) and also for a generic version of bortezomib (Bortezomib Accord, Accord Healthcare) for use in the treatment of multiple myeloma and mantle cell lymphoma.
Pembrolizumab for Advanced Melanoma
Pembrolizumab will be the second drug that acts as a programmed death inhibitor for the treatment of advanced melanoma in Europe, joining nivolumab, which was recommended for approval for this indication just a few weeks ago. Both drugs are already approved in the United States for use in advanced melanoma.
The data supporting the recommendation for approval come from one uncontrolled study and early results from two ongoing randomized, controlled trials, one comparing pembrolizumab with standard chemotherapy, and the other comparing pembrolizumab with ipilimumab (Yervoy, Bristol-Myers Squibb Company), another immunotherapy but with a slightly different mechanism of action.
The Committee for Medicinal Products for Human Use (CHMP) says the data so far have demonstrated the efficacy of pembrolizumab in adults with unresectable or metastatic melanoma, both in patients who had and in those who had not previously received ipilimumab. The committee also looked at safety information from more than 1000 patients enrolled in clinical studies and regarded the safety profile to be manageable.
Nivolumab for Lung Cancer
Nivolumb was recommended for approval for use in the treatment of squamous non–small cell lung cancer (NSCLC) when the disease is advanced and the patient has already been treated with chemotherapy. It is the first immunotherapy to be approved for use in lung cancer, and was welcomed by experts when this approval was announced in the United States. In Europe, for this indication the product will have the trade name Nivolumab BMS, whereas for the treatment of melanoma, it will be marketed as Opvido, the tradename used in other countries.
The CHMP notes that this recommendation for approval is based on data from a phase 3 trial in 272 patients with squamous NSCLC in whom chemotherapy had failed. These patients were randomly assigned to receive either nivolumab or chemotherapy with docetaxel. This study found that nivolumab improved overall survival compared with docetaxel (median, 9.2 months, compared with 6.0 months). After 12 months, 42% of patients treated with nivolumab were still alive compared with 24% of patients treated with docetaxel, the CHMP notes. Details of this study are due to be presented next week at the annual meeting American Society of Clinical Oncology.
There were also further data from an uncontrolled study involving 117 patients with squamous NSCLC who had undergone at least two previous chemotherapy treatments and who were then treated with nivolumab, the CHMP noted.
Dinutuximab for Neuroblastoma
Dinutuximab was recommended for approval for use in the treatment of high-risk neuroblastoma in children who had already responded to an induction treatment with chemotherapy, followed by myeloablative therapy and autologous stem-cell transplant. The product should be administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin.
The product was recently approved in the United States.
Neuroblastoma is a rare cancer, so dinutuximab has orphan drug designation for this indication. The tumor forms from immature nerve cells and is usually seen as a lump in the abdomen or around the spine. It typically occurs in children younger than 5 years, the EMA explained in a press release. In many cases, it is present at birth, but the diagnosis is made only later, when the cancer has already spread to other parts of the body, and the child begins to show symptoms of the disease.
Dinutuximab is a monoclonal antibody designed to recognize and attach to disialoganglioside (GD2), an antigen that is present in high amounts on the surface of neuroblastoma cells but in lower amounts in normal cells. When the product attaches to the neuroblastoma cells, it marks them as targets for the body's immune system, which is then expected to attack the cancer cells and thereby reverse or slow down the progression of the disease, the EMA explained.
The recommendation for approval was based on data from a clinical trial in children with high-risk neuroblastoma who had already responded to chemotherapy (showing at least a partial response) and were further treated with myeloablative therapy and autologous stem-cell transplant. The study randomly assigned 230 patients to receive dinutuximab combined with GM-CSF and IL-2 and oral isotretinoin, or isotretinoin alone.
After 2 years, 66% of patients receiving the dinutuximab combination were alive and free from recurrence or tumor growth, compared with 48% of patients treated with isotretinoin alone.
Dinutuximab "provides a much-needed treatment option to prolong survival" of patients who are considered to have high-risk neuroblastoma, the agency commented.
The most common side effects of dinutuximab are pain, allergic reactions, and hypotension. Because the protein targeted by the product is also present on normal nerve cells, its use may cause irritation and severe pain of the nerve cells, so pain relief is recommended both before and during treatment. Despite prophylaxis, two thirds of children experience pain, and about 40% experience severe pain.
The CHMP recommended that the safety profile be further assessed post authorization, and the agency required the company to include this in their risk management plan for dinutuximab.
Ibrutinib for Rare Lymphoma
An indication extension was recommended for ibutinib (Imbruvica, Pharmacyclics, Inc, Janssen Biotech, Inc). This drug is already approved for use in chronic lymphocytic leukemia and mantle cell lymphoma. The new indication covers its use in Waldenstrӧm's macroglobulinemia (also known as lymphoplasmacytic lymphoma), a type of non-Hodgkin's lymphoma. Ibrutinib will be the first drug for the treatment of this rare blood cancer. It has orphan drug designation for this indication.
Waldenstrӧm's macroglobulinemia is characterized by an excess of abnormal B lymphocytes and plasma cells in the bone marrow and sometimes in other organs, the EMA explains. These abnormal cells produce large amounts of an immunoglobulin M (IgM), which can make the blood thicker than normal. This cancer usually begins in people older than 60 years. Five years after diagnosis, between 36% and 87% of patients are still alive, depending on their individual risk factors.
Ibrutinib offers a novel strategy in the treatment of malignancies involving B lymphocytes. It acts as an inhibitor of Bruton's tyrosine kinase (Btk), which has a key role in the survival of B lymphocytes and their migration to the organs where these cells normally divide. By blocking Btk, ibrutinib decreases survival and migration of B lymphocytes, thereby delaying the progression of the cancer, the agency explains.
The recommendation for approval is based on the results of a phase 2 study in 63 patients with previously treated Waldenstrӧm's macroglobulinemia. Around 90% of the patients treated with ibrutinib responded positively to the treatment, and approximately 80% of patients were alive without disease progression after 18 months.
The adverse events reported during the clinical trial were similar to those observed in the already approved indications of ibrutinib, the agency noted. They include neutropenia and thrombocytopenia.
Generic Bortezomib for Multiple Myeloma
In addition, the EMA recommended for approval a generic version of bortezomib (Bortezomib Accord, Accord Healthcare) for the treatment of multiple myeloma and mantle cell lymphoma.
Bortezomib Accord is a generic version of Velcade (Takeda/Millennium), which has been authorized for use in the European Union since April 2004, the agency noted. "Studies have demonstrated the satisfactory quality," it added, stating that because Bortezomib Accord is administered intravenously and is 100% bioavailable, a bioequivalence study vs the reference product Velcade was not required.
jueves, 21 de mayo de 2015
Muscle-Invasive Bladder Cancer
Adjuvant Chemotherapy and Overall Survival in Muscle-Invasive Bladder Cancer: Still Climbing the Mountain
By Maha Hussain, MD, FACP, FASCO
April 10, 2015, Volume 6, Issue 6
Meta-analysis indicates a favorable effect of adjuvant cisplatin-based therapy—however, that does not equal level 1 evidence.
—Maha Hussain, MD, FACP, FASCO
Muscle-invasive bladder cancer can be a lethal disease despite curative intent local therapy, with 5-year survival that can be as low as 30% based on the extent of T status and/or lymph node involvement. The use of neoadjuvant chemotherapy with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or CMV (cisplatin, methotrexate, and vinblastine) has been shown to significantly improve overall survival, based on the results of two randomized phase III trials.1,2 Yet adopting this approach in the general patient population has been less than optimal in the United States.
Clinical Trials in High-Risk Patients
The desire to optimize the risk/benefit ratio based on better patient selection and to avoid delay of potentially curative local therapy has fueled several adjuvant clinical trials in high-risk patients, particularly those with pT3-4 disease or those with node-positive disease post radical cystectomy and pelvic lymph node dissection. Historically, several phase II trials have been conducted, but they had multiple design and conduct limitations.
Since 2001, three randomized phase III trials were attempted in high-risk patients based on pT or N+ status, testing the survival impact of adjuvant cisplatin-based chemotherapy post radical cystectomy and pelvic lymph node dissection. One of these trials was negative,3 whereas the other was reportedly positive, although no manuscript has been published to date.4 The third trial (European Organisation for Research and Treatment of Cancer [EORTC] 30994) was recently reported by Dr. Sternberg and colleagues in Lancet Oncology5 and is reviewed in this issue of The ASCO Post.
Trial Similarities and Differences
There are several common features across these three trials, including the key eligibility criteria and type of chemotherapy. Gemcitabine-cisplatin was used in one trial, and the combination of gemcitabine, cisplatin, and paclitaxel was used in another. EORTC 30994 allowed the institution’s choice of gemcitabine-cisplatin, MVAC, or high-dose MVAC, although most of the patients (108 of 128) received gemcitabine-cisplatin. Unfortunately, all of these trials were closed due to slow accrual and were thus underpowered for the primary endpoint.
However, relative to the other trials, EORTC 30994 had a larger number of patients recruited: 284 of a planned 660 patients. Despite significant improvements with immediate treatment in 5-year progression-free survival (47.6% vs 31.8%) and median progression-free survival (3.11 vs 0.99 years, hazard ratio = 0.54, P < .0001), there was no “statistically” significant difference in overall survival. There was, however, a trend in favor of the immediate treatment group: 5-year overall survival was 53.6% (95% confidence interval [CI] = 44.5%–61.8%) vs 47.7% (95% CI = 39.1%–55.8%), and median overall survival was 6.74 years (95% CI = 3.85 years to not reached) vs 4.60 years (2.15–6.25 years), with a hazard ratio of 0.78 (95% CI = 0.56–1.08, P = .13). Technically, this study is negative for a confirmed overall survival advantage; however, it is rather difficult to ignore the significant difference in progression-free survival in a disease in which relapse invariably predicts death and the trends in median and 5-year overall survival all favoring adjuvant chemotherapy. It is also difficult to resist the speculation of “what if”—specifically, could these results have been statistically significant if the study had reached full accrual? The genitourinary medical oncology community in general has adopted gemcitabine-cisplatin for managing advanced bladder cancer based on what is deemed to be clinically comparable outcomes, better toxicity profile, and better feasibility in metastatic disease; yet to date, the only positive prospective level 1 evidence for overall survival in the perioperative setting has been with MVAC or CMV, and no combination chemotherapy in metastatic disease has eclipsed MVAC. So “what if” the three adjuvant trials had been conducted with MVAC? Could the results have been different despite the small sample size? “Absence of proof” is not “proof of absence,” so when there are no definitive data from prospective randomized trials, large data pools can serve to provide some guidance. In the setting of adjuvant chemotherapy, a recent updated systematic review and meta-analysis of randomized trials indicated a pooled hazard ratio in favor of adjuvant cisplatin-based chemotherapy of 0.77 (95% CI = 0.59–0.99, P = .049), translating into a 23% relative decrease in risk of death with adjuvant chemotherapy vs control.
Weighing the Pros and Cos
So, with the totality of the data from perioperative chemotherapy trials to date, what should the standards be for patients with muscle-invasive bladder cancer in 2015? I would argue that the best available level 1 evidence to date with regard to survival, feasibility, safety, and tolerance supports the use of “neoadjuvant” cisplatin-based chemotherapy when possible. Adjuvant chemotherapy-based trials have not been feasible to conduct successfully. Meta-analysis indicates a favorable effect of adjuvant cisplatin-based therapy—however, that does not equal level 1 evidence.
Managing patients requires both the “science and art” of medicine. When the scientific evidence is not conclusive, informed joint decisions based on considering the pros and cons of adjuvant chemotherapy are certainly warranted in the setting of high-risk patients with resected muscle-invasive bladder cancer who did not receive neoadjuvant chemotherapy but who are medical candidates for chemotherapy.
New Treatment Strategies
Moving forward, it is critical that new treatment strategies/paradigms be expeditiously investigated to overcome the stagnation and current limitations of our therapies. With the exciting preliminary data from the PD-L1 (programmed death-ligand 1) inhibitors, including their overall promising safety profile, and other biologic discoveries in this disease come the promise of improving outcomes for patients with advanced urothelial carcinoma in general and muscle-invasive bladder cancer in the perioperative setting in particular—where cure is possible. ■
Disclosure: Dr. Hussain reported no potential conflicts of interest.
By Maha Hussain, MD, FACP, FASCO
April 10, 2015, Volume 6, Issue 6
Meta-analysis indicates a favorable effect of adjuvant cisplatin-based therapy—however, that does not equal level 1 evidence.
—Maha Hussain, MD, FACP, FASCO
Muscle-invasive bladder cancer can be a lethal disease despite curative intent local therapy, with 5-year survival that can be as low as 30% based on the extent of T status and/or lymph node involvement. The use of neoadjuvant chemotherapy with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or CMV (cisplatin, methotrexate, and vinblastine) has been shown to significantly improve overall survival, based on the results of two randomized phase III trials.1,2 Yet adopting this approach in the general patient population has been less than optimal in the United States.
Clinical Trials in High-Risk Patients
The desire to optimize the risk/benefit ratio based on better patient selection and to avoid delay of potentially curative local therapy has fueled several adjuvant clinical trials in high-risk patients, particularly those with pT3-4 disease or those with node-positive disease post radical cystectomy and pelvic lymph node dissection. Historically, several phase II trials have been conducted, but they had multiple design and conduct limitations.
Since 2001, three randomized phase III trials were attempted in high-risk patients based on pT or N+ status, testing the survival impact of adjuvant cisplatin-based chemotherapy post radical cystectomy and pelvic lymph node dissection. One of these trials was negative,3 whereas the other was reportedly positive, although no manuscript has been published to date.4 The third trial (European Organisation for Research and Treatment of Cancer [EORTC] 30994) was recently reported by Dr. Sternberg and colleagues in Lancet Oncology5 and is reviewed in this issue of The ASCO Post.
Trial Similarities and Differences
There are several common features across these three trials, including the key eligibility criteria and type of chemotherapy. Gemcitabine-cisplatin was used in one trial, and the combination of gemcitabine, cisplatin, and paclitaxel was used in another. EORTC 30994 allowed the institution’s choice of gemcitabine-cisplatin, MVAC, or high-dose MVAC, although most of the patients (108 of 128) received gemcitabine-cisplatin. Unfortunately, all of these trials were closed due to slow accrual and were thus underpowered for the primary endpoint.
However, relative to the other trials, EORTC 30994 had a larger number of patients recruited: 284 of a planned 660 patients. Despite significant improvements with immediate treatment in 5-year progression-free survival (47.6% vs 31.8%) and median progression-free survival (3.11 vs 0.99 years, hazard ratio = 0.54, P < .0001), there was no “statistically” significant difference in overall survival. There was, however, a trend in favor of the immediate treatment group: 5-year overall survival was 53.6% (95% confidence interval [CI] = 44.5%–61.8%) vs 47.7% (95% CI = 39.1%–55.8%), and median overall survival was 6.74 years (95% CI = 3.85 years to not reached) vs 4.60 years (2.15–6.25 years), with a hazard ratio of 0.78 (95% CI = 0.56–1.08, P = .13). Technically, this study is negative for a confirmed overall survival advantage; however, it is rather difficult to ignore the significant difference in progression-free survival in a disease in which relapse invariably predicts death and the trends in median and 5-year overall survival all favoring adjuvant chemotherapy. It is also difficult to resist the speculation of “what if”—specifically, could these results have been statistically significant if the study had reached full accrual? The genitourinary medical oncology community in general has adopted gemcitabine-cisplatin for managing advanced bladder cancer based on what is deemed to be clinically comparable outcomes, better toxicity profile, and better feasibility in metastatic disease; yet to date, the only positive prospective level 1 evidence for overall survival in the perioperative setting has been with MVAC or CMV, and no combination chemotherapy in metastatic disease has eclipsed MVAC. So “what if” the three adjuvant trials had been conducted with MVAC? Could the results have been different despite the small sample size? “Absence of proof” is not “proof of absence,” so when there are no definitive data from prospective randomized trials, large data pools can serve to provide some guidance. In the setting of adjuvant chemotherapy, a recent updated systematic review and meta-analysis of randomized trials indicated a pooled hazard ratio in favor of adjuvant cisplatin-based chemotherapy of 0.77 (95% CI = 0.59–0.99, P = .049), translating into a 23% relative decrease in risk of death with adjuvant chemotherapy vs control.
Weighing the Pros and Cos
So, with the totality of the data from perioperative chemotherapy trials to date, what should the standards be for patients with muscle-invasive bladder cancer in 2015? I would argue that the best available level 1 evidence to date with regard to survival, feasibility, safety, and tolerance supports the use of “neoadjuvant” cisplatin-based chemotherapy when possible. Adjuvant chemotherapy-based trials have not been feasible to conduct successfully. Meta-analysis indicates a favorable effect of adjuvant cisplatin-based therapy—however, that does not equal level 1 evidence.
Managing patients requires both the “science and art” of medicine. When the scientific evidence is not conclusive, informed joint decisions based on considering the pros and cons of adjuvant chemotherapy are certainly warranted in the setting of high-risk patients with resected muscle-invasive bladder cancer who did not receive neoadjuvant chemotherapy but who are medical candidates for chemotherapy.
New Treatment Strategies
Moving forward, it is critical that new treatment strategies/paradigms be expeditiously investigated to overcome the stagnation and current limitations of our therapies. With the exciting preliminary data from the PD-L1 (programmed death-ligand 1) inhibitors, including their overall promising safety profile, and other biologic discoveries in this disease come the promise of improving outcomes for patients with advanced urothelial carcinoma in general and muscle-invasive bladder cancer in the perioperative setting in particular—where cure is possible. ■
Disclosure: Dr. Hussain reported no potential conflicts of interest.
The Science, the Money, the Applications
Policy Issues in Molecularly Targeted Therapy: The Science, the Money, the Applications
By Margot J. Fromer
December 15, 2014, Volume 5, Issue 20
In the past decade, much new knowledge about the molecular underpinnings of cancer has accumulated, and the array of molecular aberrations in each individual tumor can be assessed through genomic sequencing and other tests. The rationale for and feasibility of developing molecularly targeted therapies have never been stronger, and there are hundreds of candidate drugs in the development pipeline,” said Adrian Senderowicz, MD, Chief Medical Officer, IGNYTA, Inc, and Planning Committee Chair of the National Cancer Policy Forum’s workshop, “Policy Issues in the Development and Adoption of Molecularly Targeted Therapies for Cancer,” held recently in Washington, DC.
That said, many challenges remain in the development and appropriate implementation of these new therapies, Dr. Senderowicz added.
Too Much of a Good Thing?
Bruce Johnson, MD, Chief Clinical Research Officer, Dana-Farber Cancer Institute, Boston, traced the beginnings of these issues to April 2004, when three three different laboratories from the Dana-Farber Cancer Institute, Massachusetts General Hospital, and Memorial Sloan Kettering Cancer Center discovered a link between dramatic responses to treatment with the epidermal growth factor receptor (EGFR) inhibitors (gefitinib and erlotinib) and mutations of EGFR in lung cancer patients. Investigators at the Boston hospital believed that it was important to routinely test lung cancers for the mutations of EGFR so they could be initially treated with gefitinib or erlotinib rather than chemotherapy. Therefore, the hospitals sent tumor slides to the Laboratory of Molecular Medicine at Harvard for EGFR mutation testing in a CLIA environment.
One year later (2005), Genzyme Corporation announced commercial availability of an EGFR mutation test to identify patients likely to respond to targeted therapies to treat non–small cell lung cancer. Without the testing in unselected patients, only about 10% of them responded to gefitinib or erlotinib. The patients with sensitizing mutations of EGFR responded more than 50% of the time.
Between then and now, hundreds of compounds have been or are being tested. They belong to two broad groups: therapeutic monoclonal antibodies, which target specific antigens found on the cell surface, and small molecules that penetrate the cell membrane to interact with targets inside a cell.
According to My Cancer Genome (www.mycancergenome.org), a personalized cancer medicine resource managed by the Vanderbilt-Ingram Cancer Center, Nashville, there are now 74 targets for kinase inhibitors, with 324 compounds in development; 65 targets for therapeutic antibodies, with 106 compounds in development; 12 targets for immunotherapies, with 39 compounds in development; and 34 “other” targets, with 79 compounds in development. In addition, 54 agents have been approved by the U.S. Food and Drug Administration (FDA) to date.
Mycancergenome.org provides current information on the mutations that cause cancer and their related therapeutic implications, including available clinical trials. It is chock full of data—so much, in fact, that clinicians can be overwhelmed, not knowing what to do with them, and some just stay away, said Mia Levy, MD, PhD, Ingram Assistant Professor of Cancer Research and Director of Cancer Clinical Informatics, Vanderbilt University.
Testing the Molecules
Before designing therapies, the molecules themselves must be tested. Dr. Levy described the four main types of gene alterations:
•Single-nucleotide variants, also known as point mutations, result from a base substitution at one nucleotide, producing a change in the amino acid sequence or premature truncation of an encoded protein.
•Small duplications of consecutive nucleotides, insertions, or deletions involving one or more nucleotides, or more complex mutations involving simultaneous deletions and insertions of one or more bases. They may result in addition or subtraction of amino acids in a protein or cause its premature truncation.
•Exon or gene copy number changes, including large duplications or deletions of entire exons affecting protein function or changes in the entire gene.
•Structural variants or large structural anomalies of genetic material, including translocations or inversions that result from breakpoints between multiple chromosomes or within a single chromosome, often resulting in fusion genes and associated fusion proteins.
Mutations can cluster in “hotspots” where tumors from different patients harbor the same recurrent mutation. Some hotspots are frequent, others rare. For example, the BRAF V600E mutation occurs in 40% of all melanomas, whereas BRAF L597S occurs in less than 1% of all melanomas.
“Tumor-specific genetic alterations can also be detected in the bloodstream. This presents a great opportunity for cancer diagnostics and for detecting the mutational makeup of tumors without doing a tissue biopsy. Such a ‘liquid biopsy’ is, however, like finding a needle in a haystack,” said Matthias Holdhoff, MD, Assistant Professor of Oncology, Johns Hopkins University School of Medicine, Baltimore.
In the blood of cancer patients, Dr. Holdhoff explained, the fraction of DNA fragments that harbor tumor-specific mutations is very small compared to the abundant amounts of normal DNA fragments from healthy cells. This problem is tackled by using highly sensitive polymerase chain reaction–based assays that essentially count DNA fragments in blood one by one. For example, these techniques can detect even 5 fragments of tumor-derived DNA in a pool of 10,000 normal DNA fragments from healthy cells.
The following tests are in current use:
•Allele-specific polymerase chain reaction detects a specific single-nucleotide variant. It can find mutant DNA if present in 1% to 5% of tumors tested, but it cannot detect other mutations that may be present.
•Sanger dideoxynucleotide sequencing can find unknown mutations, including single-nucleotide variants, small duplications, insertions, deletions, and indels. It can detect gene fusions if RNA from the fusion transcript is first extracted from the specimen. It requires mutant DNA to be present at a frequency of 20% to 25%.
•Pyrosequencing can detect unknown mutations in a small targeted region. It can be done quickly and can detect mutant DNA at 5%, but the types are limited.
•Mass spectrometry and single-base extension assay both detect targeted single-nucleotide variants in mutant DNA at 5% to 10% and in more than one gene.
•Multiplex ligation-dependent probe amplification finds exon and gene copy number, and depending on the experimental design, can also detect single-nucleotide variants. It requires mutant DNA to be present at 20% to 40% and works best on fresh frozen tissue.
•Fluorescence in situ hybridization detects gene copy number changes and targeted structural variants but not in solid tumors.
•Next-generation sequencing: custom panels, hybridization capture, and whole-exome sequencing detect substitutions, duplications, insertions, deletions, indels, exon and gene copy number changes, and select translocations—for a total of 1,144 exomes sequenced.
•Next-generation sequencing: whole-genome sequencing detects substitutions, duplications, insertions, deletions, indels, gene copy number changes, and chromosome inversions and translocations. It is the most comprehensive of all, but it requires more tumor tissue, sophisticated bioinformatics, and large computational demands for data storage.
Next-generation sequencing is one of the most powerful assay methods to date, said P. Mickey Williams, MD, Director, Molecular Characterization Laboratory, Frederick National Laboratories for Cancer Research. “It is popular in all aspects of cancer research and clinical management,” he noted. For example, the National Cancer Institute’s MATCH study is a multiarm basket study in which each arm includes multiple tissues. The goal is first to identify mutations, amplifications, and gene fusions to determine eligibility and then to assign patients to a relevant agent regimen using a rules-based approach. “This type of study requires screening large numbers of tumors, and it needs many targeted treatments,” he explained.
Companion Diagnostics
Targeted therapies are a good thing—if they work. But they don’t always, and for this reason there are companion diagnostics. A companion diagnostic is a diagnostic test whose results are essential for the safe and effective use of a particular drug or biologic agent. These devices can be used to identify patients who are most likely to benefit from a therapeutic product, identify patients who are likely to be at increased risk of serious side effects, and monitor response to treatment.
If a diagnostic test is inaccurate, said E. David Litwack, PhD, a member of the FDA’s Division of in Vitro Diagnostics and Radiological Health, then the treatment decision based on it may not be correct.
Ideally both the companion diagnostic and drug should be developed together, preferably before the drug enters clinical trials. In fact, the FDA may require a companion diagnostic if a new drug is designed to treat patients with a specific molecular target. One of the Agency’s recommendations, said Dr. Litwack, is for pharmaceutical and diagnostic companies to partner early in the process.
Dr. Senderowicz added a note about benefit and risk. “A false-positive test would cause a patient to receive unneeded treatment, along with its potential risks, without benefit. A false-negative means a patient would not receive needed treatment.”
Use of companion diagnostics began in 1998 with a companion that detects excessive levels or extra copies of HER2 in breast tumors. Since then, manufacturers have increasingly accepted the fact that diagnostic tests can greatly increase clinical success. For instance, there are now two companions for cetuximab (Erbitux), one for deferasirox (Exjade), one for afatinib (Gilotrif), one for imatinib (Gleevec), and seven for trastuzumab (Herceptin).
Using and Paying for All This
High technology is always exhilarating, but is molecular targeting of practical clinical use, and if so, who’s going to pay for it?
David Eberhard, MD, PhD, Director, Pre-Clinical Genomic Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, posed four critical questions that are frequently addressed with laboratory assays and diagnostic tests: (1) Diagnostic: Does the patient have a condition, and if so, what is it and what caused it? (2) Prognostic: How is the patient going to do? (3) Predictive: How will the patient respond to an intervention? (4) Pharmacodynamic: Is the intervention having an effect?
The usefulness of laboratory results for answering these questions requires analytical validation—that is, how well an assay will measure a molecular event: its range, accuracy, precision, bias, and reproducibility. It also requires clinical validation—that is, its strength of association with the condition of interest: What can it be used for, and does it have actual value in health care? And the key question, said Dr. Eberhard: “Does it offer more than what we have now?”
As to who will pay for the technology, that remains to be seen, said
Donna Messner, Vice President and Senior Research Director, Center for Medical Technology Policy, a Baltimore company that looks at quality and relevance of clinical research.
“Molecular diagnostic tests have the potential to transform oncology practice, but integration of biomarkers into practice has been inefficient so far because evidence of clinical utility is inadequate, studies of clinical validity have been incomplete or flawed, there is no shared evidentiary framework, and clear and predictable methodologic standards are lacking.”
She added that there has been explosive growth in the number, complexity, and costs of tests in the past 20 years. For example, genetic testing is now available for more than 2,000 conditions, and more than 125,000 variants have been discovered in thousands of genes. “But the consequences of wrong information and/or decisions can be disastrous.”
What’s more, payers are demanding ever-closer scrutiny as tests proliferate. Coverage policies vary widely among payers because they serve different patient populations, they have differing financial and organizational models, they may not have reviewed the same evidence for each test, and corporate cultures differ.
For instance, some companies think that a test is medically necessary if it has a direct effect on clinical care. Others believe that the disease in question must be preventable or treatable, and still others require that the test results in a change in the intensity of surveillance and/or treatment. Some companies want to see improvement in outcomes when a test is used, and almost all will ask whether another, extant clinical tool is available for the same purpose.
Other reasons that insurers balk at covering genomic tests include too few published studies demonstrating clinical utility, the often-minor role of genetics in complex diseases, and the availability of alternative effective screening methods.
Even without the coverage issues, there are still clinical problems in precision medicine, said Lillian Siu, MD, Professor, University of Toronto, Princess Margaret Cancer Centre Drug Development Program. “It is difficult to keep up with a fast-growing body of knowledge, ensure that patients understand test results, find treatments (either approved drugs or appropriate clinical trials) to match the mutations found, and realize value generated through these agents.” ■
Disclosure: Dr. Levy is a consultant and a scientific advisor for Personalis and a consultant for GenomOncology. Drs. Litwack, Eberhard, Holdhoff, and Siu reported no potential conflicts of interest.
By Margot J. Fromer
December 15, 2014, Volume 5, Issue 20
In the past decade, much new knowledge about the molecular underpinnings of cancer has accumulated, and the array of molecular aberrations in each individual tumor can be assessed through genomic sequencing and other tests. The rationale for and feasibility of developing molecularly targeted therapies have never been stronger, and there are hundreds of candidate drugs in the development pipeline,” said Adrian Senderowicz, MD, Chief Medical Officer, IGNYTA, Inc, and Planning Committee Chair of the National Cancer Policy Forum’s workshop, “Policy Issues in the Development and Adoption of Molecularly Targeted Therapies for Cancer,” held recently in Washington, DC.
That said, many challenges remain in the development and appropriate implementation of these new therapies, Dr. Senderowicz added.
Too Much of a Good Thing?
Bruce Johnson, MD, Chief Clinical Research Officer, Dana-Farber Cancer Institute, Boston, traced the beginnings of these issues to April 2004, when three three different laboratories from the Dana-Farber Cancer Institute, Massachusetts General Hospital, and Memorial Sloan Kettering Cancer Center discovered a link between dramatic responses to treatment with the epidermal growth factor receptor (EGFR) inhibitors (gefitinib and erlotinib) and mutations of EGFR in lung cancer patients. Investigators at the Boston hospital believed that it was important to routinely test lung cancers for the mutations of EGFR so they could be initially treated with gefitinib or erlotinib rather than chemotherapy. Therefore, the hospitals sent tumor slides to the Laboratory of Molecular Medicine at Harvard for EGFR mutation testing in a CLIA environment.
One year later (2005), Genzyme Corporation announced commercial availability of an EGFR mutation test to identify patients likely to respond to targeted therapies to treat non–small cell lung cancer. Without the testing in unselected patients, only about 10% of them responded to gefitinib or erlotinib. The patients with sensitizing mutations of EGFR responded more than 50% of the time.
Between then and now, hundreds of compounds have been or are being tested. They belong to two broad groups: therapeutic monoclonal antibodies, which target specific antigens found on the cell surface, and small molecules that penetrate the cell membrane to interact with targets inside a cell.
According to My Cancer Genome (www.mycancergenome.org), a personalized cancer medicine resource managed by the Vanderbilt-Ingram Cancer Center, Nashville, there are now 74 targets for kinase inhibitors, with 324 compounds in development; 65 targets for therapeutic antibodies, with 106 compounds in development; 12 targets for immunotherapies, with 39 compounds in development; and 34 “other” targets, with 79 compounds in development. In addition, 54 agents have been approved by the U.S. Food and Drug Administration (FDA) to date.
Mycancergenome.org provides current information on the mutations that cause cancer and their related therapeutic implications, including available clinical trials. It is chock full of data—so much, in fact, that clinicians can be overwhelmed, not knowing what to do with them, and some just stay away, said Mia Levy, MD, PhD, Ingram Assistant Professor of Cancer Research and Director of Cancer Clinical Informatics, Vanderbilt University.
Testing the Molecules
Before designing therapies, the molecules themselves must be tested. Dr. Levy described the four main types of gene alterations:
•Single-nucleotide variants, also known as point mutations, result from a base substitution at one nucleotide, producing a change in the amino acid sequence or premature truncation of an encoded protein.
•Small duplications of consecutive nucleotides, insertions, or deletions involving one or more nucleotides, or more complex mutations involving simultaneous deletions and insertions of one or more bases. They may result in addition or subtraction of amino acids in a protein or cause its premature truncation.
•Exon or gene copy number changes, including large duplications or deletions of entire exons affecting protein function or changes in the entire gene.
•Structural variants or large structural anomalies of genetic material, including translocations or inversions that result from breakpoints between multiple chromosomes or within a single chromosome, often resulting in fusion genes and associated fusion proteins.
Mutations can cluster in “hotspots” where tumors from different patients harbor the same recurrent mutation. Some hotspots are frequent, others rare. For example, the BRAF V600E mutation occurs in 40% of all melanomas, whereas BRAF L597S occurs in less than 1% of all melanomas.
“Tumor-specific genetic alterations can also be detected in the bloodstream. This presents a great opportunity for cancer diagnostics and for detecting the mutational makeup of tumors without doing a tissue biopsy. Such a ‘liquid biopsy’ is, however, like finding a needle in a haystack,” said Matthias Holdhoff, MD, Assistant Professor of Oncology, Johns Hopkins University School of Medicine, Baltimore.
In the blood of cancer patients, Dr. Holdhoff explained, the fraction of DNA fragments that harbor tumor-specific mutations is very small compared to the abundant amounts of normal DNA fragments from healthy cells. This problem is tackled by using highly sensitive polymerase chain reaction–based assays that essentially count DNA fragments in blood one by one. For example, these techniques can detect even 5 fragments of tumor-derived DNA in a pool of 10,000 normal DNA fragments from healthy cells.
The following tests are in current use:
•Allele-specific polymerase chain reaction detects a specific single-nucleotide variant. It can find mutant DNA if present in 1% to 5% of tumors tested, but it cannot detect other mutations that may be present.
•Sanger dideoxynucleotide sequencing can find unknown mutations, including single-nucleotide variants, small duplications, insertions, deletions, and indels. It can detect gene fusions if RNA from the fusion transcript is first extracted from the specimen. It requires mutant DNA to be present at a frequency of 20% to 25%.
•Pyrosequencing can detect unknown mutations in a small targeted region. It can be done quickly and can detect mutant DNA at 5%, but the types are limited.
•Mass spectrometry and single-base extension assay both detect targeted single-nucleotide variants in mutant DNA at 5% to 10% and in more than one gene.
•Multiplex ligation-dependent probe amplification finds exon and gene copy number, and depending on the experimental design, can also detect single-nucleotide variants. It requires mutant DNA to be present at 20% to 40% and works best on fresh frozen tissue.
•Fluorescence in situ hybridization detects gene copy number changes and targeted structural variants but not in solid tumors.
•Next-generation sequencing: custom panels, hybridization capture, and whole-exome sequencing detect substitutions, duplications, insertions, deletions, indels, exon and gene copy number changes, and select translocations—for a total of 1,144 exomes sequenced.
•Next-generation sequencing: whole-genome sequencing detects substitutions, duplications, insertions, deletions, indels, gene copy number changes, and chromosome inversions and translocations. It is the most comprehensive of all, but it requires more tumor tissue, sophisticated bioinformatics, and large computational demands for data storage.
Next-generation sequencing is one of the most powerful assay methods to date, said P. Mickey Williams, MD, Director, Molecular Characterization Laboratory, Frederick National Laboratories for Cancer Research. “It is popular in all aspects of cancer research and clinical management,” he noted. For example, the National Cancer Institute’s MATCH study is a multiarm basket study in which each arm includes multiple tissues. The goal is first to identify mutations, amplifications, and gene fusions to determine eligibility and then to assign patients to a relevant agent regimen using a rules-based approach. “This type of study requires screening large numbers of tumors, and it needs many targeted treatments,” he explained.
Companion Diagnostics
Targeted therapies are a good thing—if they work. But they don’t always, and for this reason there are companion diagnostics. A companion diagnostic is a diagnostic test whose results are essential for the safe and effective use of a particular drug or biologic agent. These devices can be used to identify patients who are most likely to benefit from a therapeutic product, identify patients who are likely to be at increased risk of serious side effects, and monitor response to treatment.
If a diagnostic test is inaccurate, said E. David Litwack, PhD, a member of the FDA’s Division of in Vitro Diagnostics and Radiological Health, then the treatment decision based on it may not be correct.
Ideally both the companion diagnostic and drug should be developed together, preferably before the drug enters clinical trials. In fact, the FDA may require a companion diagnostic if a new drug is designed to treat patients with a specific molecular target. One of the Agency’s recommendations, said Dr. Litwack, is for pharmaceutical and diagnostic companies to partner early in the process.
Dr. Senderowicz added a note about benefit and risk. “A false-positive test would cause a patient to receive unneeded treatment, along with its potential risks, without benefit. A false-negative means a patient would not receive needed treatment.”
Use of companion diagnostics began in 1998 with a companion that detects excessive levels or extra copies of HER2 in breast tumors. Since then, manufacturers have increasingly accepted the fact that diagnostic tests can greatly increase clinical success. For instance, there are now two companions for cetuximab (Erbitux), one for deferasirox (Exjade), one for afatinib (Gilotrif), one for imatinib (Gleevec), and seven for trastuzumab (Herceptin).
Using and Paying for All This
High technology is always exhilarating, but is molecular targeting of practical clinical use, and if so, who’s going to pay for it?
David Eberhard, MD, PhD, Director, Pre-Clinical Genomic Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, posed four critical questions that are frequently addressed with laboratory assays and diagnostic tests: (1) Diagnostic: Does the patient have a condition, and if so, what is it and what caused it? (2) Prognostic: How is the patient going to do? (3) Predictive: How will the patient respond to an intervention? (4) Pharmacodynamic: Is the intervention having an effect?
The usefulness of laboratory results for answering these questions requires analytical validation—that is, how well an assay will measure a molecular event: its range, accuracy, precision, bias, and reproducibility. It also requires clinical validation—that is, its strength of association with the condition of interest: What can it be used for, and does it have actual value in health care? And the key question, said Dr. Eberhard: “Does it offer more than what we have now?”
As to who will pay for the technology, that remains to be seen, said
Donna Messner, Vice President and Senior Research Director, Center for Medical Technology Policy, a Baltimore company that looks at quality and relevance of clinical research.
“Molecular diagnostic tests have the potential to transform oncology practice, but integration of biomarkers into practice has been inefficient so far because evidence of clinical utility is inadequate, studies of clinical validity have been incomplete or flawed, there is no shared evidentiary framework, and clear and predictable methodologic standards are lacking.”
She added that there has been explosive growth in the number, complexity, and costs of tests in the past 20 years. For example, genetic testing is now available for more than 2,000 conditions, and more than 125,000 variants have been discovered in thousands of genes. “But the consequences of wrong information and/or decisions can be disastrous.”
What’s more, payers are demanding ever-closer scrutiny as tests proliferate. Coverage policies vary widely among payers because they serve different patient populations, they have differing financial and organizational models, they may not have reviewed the same evidence for each test, and corporate cultures differ.
For instance, some companies think that a test is medically necessary if it has a direct effect on clinical care. Others believe that the disease in question must be preventable or treatable, and still others require that the test results in a change in the intensity of surveillance and/or treatment. Some companies want to see improvement in outcomes when a test is used, and almost all will ask whether another, extant clinical tool is available for the same purpose.
Other reasons that insurers balk at covering genomic tests include too few published studies demonstrating clinical utility, the often-minor role of genetics in complex diseases, and the availability of alternative effective screening methods.
Even without the coverage issues, there are still clinical problems in precision medicine, said Lillian Siu, MD, Professor, University of Toronto, Princess Margaret Cancer Centre Drug Development Program. “It is difficult to keep up with a fast-growing body of knowledge, ensure that patients understand test results, find treatments (either approved drugs or appropriate clinical trials) to match the mutations found, and realize value generated through these agents.” ■
Disclosure: Dr. Levy is a consultant and a scientific advisor for Personalis and a consultant for GenomOncology. Drs. Litwack, Eberhard, Holdhoff, and Siu reported no potential conflicts of interest.
Breast Cancer Management in Review
Breast Cancer Management in Review
Part 2. Metastatic Disease and Survivorship Issues
By Jame Abraham, MD, FACP
April 25, 2015, Volume 6, Issue 7
—Jame Abraham, MD, FACP
With the field of breast oncology as complex as ever, a brief update of the latest findings impacting breast cancer treatment seems timely. To that end, I have assembled highlights from a collection of newsworthy studies featured over the past year and into early 2015.
Part 1 of this review, which appeared in the April 10, 2015, issue of The ASCO Post, focused on genetics and adjuvant therapies in breast cancer. In Part 2 of this two-part series, I will focus on newer therapeutic options for metastatic disease (fulvestrant [Faslodex], palbociclib [Ibrance], pertuzumab [Perjeta], and pictilisib) as well as several survivorship issues (fertility preservation, diet, and exercise).
Therapeutic Options for Metastatic Disease
Recent progress in drug development and the understanding of tumor biology has resulted in a variety of new treatment options for metastatic breast cancer. The following key trials demonstrate that although metastatic breast cancer remains incurable, patient survival in this setting continues to be extended.
PALOMA-1/TRIO-18 Trial
On February 3, 2015, palbociclib, an oral, highly selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in combination with letrozole for the initial endocrine-based treatment of postmenopausal women with estrogen receptor–positive, HER2-negative metastatic breast cancer (see Table 1). The supporting data for this approval came from the randomized phase II PALOMA-1/TRIO-18 trial, which included 165 women.1
Key Findings: The median progression-free survival was 20.2 months (95% confidence interval [CI] = 13.8–27.5) for the combination-treatment group and 10.2 months (95% CI = 5.7–12.6) for the letrozole-only group (hazard ratio [HR] = 0.488, 95% CI = 0.319–0.748, one-sided P = .0004). As for toxicity, more cases of grade 3/4 neutropenia (54% vs 1%), leukopenia (19% vs 0%), and fatigue (4% vs 1%) were reported with the addition of palbociclib.
Clinical Perspective: The FDA approval of palbociclib is significant for two reasons. To begin with, this is the first CDK inhibitor approved for breast cancer treatment. Second, and most important, based on PALOMA-1/TRIO-18, palbociclib is a highly active drug for patients with estrogen receptor–positive breast cancer. Ongoing and completed trials will establish and further define the role of palbociclib in breast cancer treatment.
FIRST Study
The randomized, phase II FIRST study compared 500 mg of fulvestrant with anastrozole in 205 patients with advanced hormone receptor–positive breast cancer.2 These women had not received prior endocrine therapy for their advanced disease.
Key Findings: The median overall survival was longer in those given fulvestrant than in those given anastrozole (54.1 vs 48.4 months; HR = 0.70, 95% CI = 0.50–0.98, P = .041). The frequency of serious adverse events was similar between the two groups (between 21% and 24%).
Clinical Perspective: According to the investigators, the FIRST study is the second trial to show an overall survival advantage for fulvestrant (500 mg) over another endocrine therapy. If the phase III FALCON study confirms these findings, Robertson and colleagues believe that fulvestrant should be considered for approval as a first-line agent in the treatment of advanced breast cancer.2
CLEOPATRA Study
Pertuzumab in combination with trastuzumab (Herceptin) and docetaxel was approved for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. This approval was based on the CLEOPATRA study, which reported improvement in progression-free survival in more than 800 women.3
Key Findings: The results of the final overall survival analysis from the CLEOPATRA study were reported at the 2014 ESMO Congress4 and published recently in The New England Journal of Medicine.5 First-line treatment with the three-drug combination significantly improved overall survival in these women compared with trastuzumab, docetaxel, and placebo (56.5 vs 40.8 months). This 15.7-month difference was a statistically significant improvement in overall survival in favor of the pertuzumab arm (HR = 0.68, 95% CI = 0.56–0.84, P = .0002).
Clinical Perspective: “The median overall survival of 56.5 months is unprecedented in first-line, and this substantial improvement confirms the pertuzumab-containing regimen as standard of care in this setting,” stated Sandra Swain, MD, Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center, Washington, DC, in a press release.
OPPORTUNE Study
Schmid and colleagues presented the first report of a preoperative window of opportunity study evaluating the PI3K inhibitor pictilisib in combination with anastrozole in the treatment of women with estrogen receptor–positive, HER2-negative operable breast cancer at the 2014 San Antonio Breast Cancer Symposium.6 In the OPPORTUNE study, 73 postmenopausal patients were randomly assigned to receive 2-week preoperative treatment; two-thirds were given anastrozole and pictilisib, and the other third, anastrozole alone.
Key Findings: In this patient population, the antiproliferative response to anastrozole was increased with the addition of pictilisib over anastrozole alone. According to a preplanned subgroup analysis, there also seemed to be an interaction in response to the two-drug treatment with molecular subtype and Ki67 level. Furthermore, patients who had luminal B tumors had a higher Ki67 response with anastrozole and pictilisib than with anastrozole alone (83% vs 38%), according to subset analyses. As for patients who had luminal A tumors, the Ki67 response appeared to be similar for both treatment groups.
Clinical Perspective: Preoperative studies such as the OPPORTUNE trial have emerged as a strategy to evaluate novel treatments in women with estrogen receptor–positive breast cancer.6 Such studies may potentially help to characterize the optimal target population for such treatments.
Survivorship Issues
Although improved diagnostics and therapeutics have led to longer lives for a greater number of breast cancer survivors, issues such as fertility, diet, and exercise and their roles in survival and quality of life for these patients are still being clarified. The following studies addressed some of these issues.
POEMS-SWOG S0230
The randomized phase III POEMS-SWOG S0230 trial evaluated whether premature ovarian failure could be reduced by the administration of a luteinizing hormone–releasing hormone analog (goserelin [Zoladex]) with chemotherapy in women with early-stage, hormone receptor–negative breast cancer.7,8 A total of 257 patients (younger than age 50) with stages I to IIIA disease received standard cyclophosphamide-containing chemotherapy with or without monthly goserelin.
Key Findings: Moore and colleagues presented their data on the 218 patients evaluated thus far during a Plenary Session at the 2014 ASCO Annual Meeting7 and recently published their findings in The New England Journal of Medicine.8 They found more success in attempting and achieving pregnancy with the addition of goserelin, with premature ovarian failure rates of 22% with standard chemotherapy and 8% with the addition of goserelin. In addition, there were 13 pregnancies among those who received standard chemotherapy and 22 pregnancies among those who received goserelin (odds ratio = 2.22, 95% CI = 1.00–4.92, P = .05).
Clinical Perspective: Not only were there fewer cases of premature ovarian failure and more pregnancies with the addition of goserelin to standard chemotherapy, an exploratory analysis suggested potential improvement in both disease-free and overall survival as well.7 This is clearly a practice-changing study with significant clinical implications.
Women’s Intervention Nutrition Study
The final survival analysis of this trial was presented at the 2014 San Antonio Breast Cancer Symposium.9 Of the more than 2,400 women between the ages of 48 and 79 years with early-stage breast cancer who took part in the trial, 975 patients received dietary intervention (targeting fat intake reduction [target 15% calories from fat] while maintaining nutritional adequacy) along with their standard cancer therapy, and the others did not. The dietary intervention consisted of eight biweekly individual counseling sessions by centrally trained registered dietitians, with subsequent every-3-month dietitian contacts.
Key Findings: After a median follow-up of 15 years, the lifestyle dietary intervention was associated with weight loss but not a significant increase in overall survival in women with resected breast cancer who received conventional cancer therapy.9 However, exploratory analyses suggested a favorable lifestyle influence on survival in the hormone receptor–negative subgroup and during active intervention.
Arthralgia Treatment
The final study centers on the impact of exercise vs usual care for aromatase inhibitor–induced arthralgia in previously inactive breast cancer survivors.10 Irwin and colleagues conducted this yearlong randomized trial, which included 121 breast cancer survivors who received an aromatase inhibitor and reported arthralgia. Half of these women received usual care, and the others underwent aerobic exercise sessions (up to 90 minutes per week with no strength training).
Key Findings: The worst joint pain scores decreased by 1.6 points (29%) at 12 months among the exercising women, compared with a 0.2-point increase (3%) among those receiving usual care (P < .001). In addition, pain scores on other standard indices and questionnaires decreased at 12 months in women randomly assigned to exercise.
Clinical Perspective: We clearly know that diet and lifestyle play a key role in breast cancer incidence, survival, and quality of life. Although we are awaiting confirmatory data, all breast cancer survivors should be counseled about the importance of diet and exercise. ■
Disclosure: Dr. Abraham reported no potential conflicts of interest
Part 2. Metastatic Disease and Survivorship Issues
By Jame Abraham, MD, FACP
April 25, 2015, Volume 6, Issue 7
—Jame Abraham, MD, FACP
With the field of breast oncology as complex as ever, a brief update of the latest findings impacting breast cancer treatment seems timely. To that end, I have assembled highlights from a collection of newsworthy studies featured over the past year and into early 2015.
Part 1 of this review, which appeared in the April 10, 2015, issue of The ASCO Post, focused on genetics and adjuvant therapies in breast cancer. In Part 2 of this two-part series, I will focus on newer therapeutic options for metastatic disease (fulvestrant [Faslodex], palbociclib [Ibrance], pertuzumab [Perjeta], and pictilisib) as well as several survivorship issues (fertility preservation, diet, and exercise).
Therapeutic Options for Metastatic Disease
Recent progress in drug development and the understanding of tumor biology has resulted in a variety of new treatment options for metastatic breast cancer. The following key trials demonstrate that although metastatic breast cancer remains incurable, patient survival in this setting continues to be extended.
PALOMA-1/TRIO-18 Trial
On February 3, 2015, palbociclib, an oral, highly selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in combination with letrozole for the initial endocrine-based treatment of postmenopausal women with estrogen receptor–positive, HER2-negative metastatic breast cancer (see Table 1). The supporting data for this approval came from the randomized phase II PALOMA-1/TRIO-18 trial, which included 165 women.1
Key Findings: The median progression-free survival was 20.2 months (95% confidence interval [CI] = 13.8–27.5) for the combination-treatment group and 10.2 months (95% CI = 5.7–12.6) for the letrozole-only group (hazard ratio [HR] = 0.488, 95% CI = 0.319–0.748, one-sided P = .0004). As for toxicity, more cases of grade 3/4 neutropenia (54% vs 1%), leukopenia (19% vs 0%), and fatigue (4% vs 1%) were reported with the addition of palbociclib.
Clinical Perspective: The FDA approval of palbociclib is significant for two reasons. To begin with, this is the first CDK inhibitor approved for breast cancer treatment. Second, and most important, based on PALOMA-1/TRIO-18, palbociclib is a highly active drug for patients with estrogen receptor–positive breast cancer. Ongoing and completed trials will establish and further define the role of palbociclib in breast cancer treatment.
FIRST Study
The randomized, phase II FIRST study compared 500 mg of fulvestrant with anastrozole in 205 patients with advanced hormone receptor–positive breast cancer.2 These women had not received prior endocrine therapy for their advanced disease.
Key Findings: The median overall survival was longer in those given fulvestrant than in those given anastrozole (54.1 vs 48.4 months; HR = 0.70, 95% CI = 0.50–0.98, P = .041). The frequency of serious adverse events was similar between the two groups (between 21% and 24%).
Clinical Perspective: According to the investigators, the FIRST study is the second trial to show an overall survival advantage for fulvestrant (500 mg) over another endocrine therapy. If the phase III FALCON study confirms these findings, Robertson and colleagues believe that fulvestrant should be considered for approval as a first-line agent in the treatment of advanced breast cancer.2
CLEOPATRA Study
Pertuzumab in combination with trastuzumab (Herceptin) and docetaxel was approved for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. This approval was based on the CLEOPATRA study, which reported improvement in progression-free survival in more than 800 women.3
Key Findings: The results of the final overall survival analysis from the CLEOPATRA study were reported at the 2014 ESMO Congress4 and published recently in The New England Journal of Medicine.5 First-line treatment with the three-drug combination significantly improved overall survival in these women compared with trastuzumab, docetaxel, and placebo (56.5 vs 40.8 months). This 15.7-month difference was a statistically significant improvement in overall survival in favor of the pertuzumab arm (HR = 0.68, 95% CI = 0.56–0.84, P = .0002).
Clinical Perspective: “The median overall survival of 56.5 months is unprecedented in first-line, and this substantial improvement confirms the pertuzumab-containing regimen as standard of care in this setting,” stated Sandra Swain, MD, Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center, Washington, DC, in a press release.
OPPORTUNE Study
Schmid and colleagues presented the first report of a preoperative window of opportunity study evaluating the PI3K inhibitor pictilisib in combination with anastrozole in the treatment of women with estrogen receptor–positive, HER2-negative operable breast cancer at the 2014 San Antonio Breast Cancer Symposium.6 In the OPPORTUNE study, 73 postmenopausal patients were randomly assigned to receive 2-week preoperative treatment; two-thirds were given anastrozole and pictilisib, and the other third, anastrozole alone.
Key Findings: In this patient population, the antiproliferative response to anastrozole was increased with the addition of pictilisib over anastrozole alone. According to a preplanned subgroup analysis, there also seemed to be an interaction in response to the two-drug treatment with molecular subtype and Ki67 level. Furthermore, patients who had luminal B tumors had a higher Ki67 response with anastrozole and pictilisib than with anastrozole alone (83% vs 38%), according to subset analyses. As for patients who had luminal A tumors, the Ki67 response appeared to be similar for both treatment groups.
Clinical Perspective: Preoperative studies such as the OPPORTUNE trial have emerged as a strategy to evaluate novel treatments in women with estrogen receptor–positive breast cancer.6 Such studies may potentially help to characterize the optimal target population for such treatments.
Survivorship Issues
Although improved diagnostics and therapeutics have led to longer lives for a greater number of breast cancer survivors, issues such as fertility, diet, and exercise and their roles in survival and quality of life for these patients are still being clarified. The following studies addressed some of these issues.
POEMS-SWOG S0230
The randomized phase III POEMS-SWOG S0230 trial evaluated whether premature ovarian failure could be reduced by the administration of a luteinizing hormone–releasing hormone analog (goserelin [Zoladex]) with chemotherapy in women with early-stage, hormone receptor–negative breast cancer.7,8 A total of 257 patients (younger than age 50) with stages I to IIIA disease received standard cyclophosphamide-containing chemotherapy with or without monthly goserelin.
Key Findings: Moore and colleagues presented their data on the 218 patients evaluated thus far during a Plenary Session at the 2014 ASCO Annual Meeting7 and recently published their findings in The New England Journal of Medicine.8 They found more success in attempting and achieving pregnancy with the addition of goserelin, with premature ovarian failure rates of 22% with standard chemotherapy and 8% with the addition of goserelin. In addition, there were 13 pregnancies among those who received standard chemotherapy and 22 pregnancies among those who received goserelin (odds ratio = 2.22, 95% CI = 1.00–4.92, P = .05).
Clinical Perspective: Not only were there fewer cases of premature ovarian failure and more pregnancies with the addition of goserelin to standard chemotherapy, an exploratory analysis suggested potential improvement in both disease-free and overall survival as well.7 This is clearly a practice-changing study with significant clinical implications.
Women’s Intervention Nutrition Study
The final survival analysis of this trial was presented at the 2014 San Antonio Breast Cancer Symposium.9 Of the more than 2,400 women between the ages of 48 and 79 years with early-stage breast cancer who took part in the trial, 975 patients received dietary intervention (targeting fat intake reduction [target 15% calories from fat] while maintaining nutritional adequacy) along with their standard cancer therapy, and the others did not. The dietary intervention consisted of eight biweekly individual counseling sessions by centrally trained registered dietitians, with subsequent every-3-month dietitian contacts.
Key Findings: After a median follow-up of 15 years, the lifestyle dietary intervention was associated with weight loss but not a significant increase in overall survival in women with resected breast cancer who received conventional cancer therapy.9 However, exploratory analyses suggested a favorable lifestyle influence on survival in the hormone receptor–negative subgroup and during active intervention.
Arthralgia Treatment
The final study centers on the impact of exercise vs usual care for aromatase inhibitor–induced arthralgia in previously inactive breast cancer survivors.10 Irwin and colleagues conducted this yearlong randomized trial, which included 121 breast cancer survivors who received an aromatase inhibitor and reported arthralgia. Half of these women received usual care, and the others underwent aerobic exercise sessions (up to 90 minutes per week with no strength training).
Key Findings: The worst joint pain scores decreased by 1.6 points (29%) at 12 months among the exercising women, compared with a 0.2-point increase (3%) among those receiving usual care (P < .001). In addition, pain scores on other standard indices and questionnaires decreased at 12 months in women randomly assigned to exercise.
Clinical Perspective: We clearly know that diet and lifestyle play a key role in breast cancer incidence, survival, and quality of life. Although we are awaiting confirmatory data, all breast cancer survivors should be counseled about the importance of diet and exercise. ■
Disclosure: Dr. Abraham reported no potential conflicts of interest
FDA Drug Approvals 2014
FDA Drug Approvals 2014
By The ASCO Post
January 25, 2015, Volume 6, Issue 1
•Nivolumab (Opdivo), a monoclonal antibody, was approved for treatment of metastatic melanoma. Approved December 22, 2014.
•Olaparib (Lynparza), a poly (ADP-ribose) polymerase (PARP) inhibitor, was approved for treatment of BRCA-mutated advanced ovarian cancer. Approved December 19, 2014.
•Lanreotide (Somatuline) depot injection, a somatostatin analog, was approved for treatment of gastroenteropancreatic neuroendocrine tumors. Approved December 16, 2014.
•Ramucirumab (Cyramza) injection, a recombinant monoclonal antibody, was approved for treatment (in combination with docetaxel) of metastatic non–small cell lung cancer. Approved December 12, 2014.
•Ruxolitinib (Jakafi), a Janus-associated kinase (JAK1 and JAK2) inhibitor, was approved for the treatment of polycythemia vera. Approved December 4, 2014.
•Blinatumomab (Blincyto), a bispecfic CD-19 directed CD3 T-Cell engager (BiTE®), was granted accelerated approval for the treatment of relapsed or refractory acute lymphoblastic leukemia. Accelerated approval granted December 3, 2014.
•Bevacizumab (Avastin), a vascular endothelial growth factor–specific angiogenesis inhibitor, was approved for treatment (in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan) of ovarian, fallopian tube, or primary peritoneal cancer. Approved November 14, 2014.
•Ramucirumab (Cyramza), a recombinant monoclonal antibody, was approved for treatment (in combination with paclixatel) of advanced gastric or gastroesophageal junction adenocarcinoma. Approved November 5, 2014.
•Pembrolizumab (Keytruda), a PD-1–blocking antibody, was granted accelerated approval for the treatment of unresectable or metastatic melanoma. Accelerated approval granted September 4, 2014.
•Bevacizumab (Avastin), a vascular endothelial growth factor–specific angiogenesis inhibitor, was approved for treatment (in combination with paclitaxel/cisplatin or paclitaxel/topotecan) of cervical cancer. Approved August 14, 2014.
•Idelalisib (Zydelig) tablets, a kinase inhibitor, was approved for the treatment of relapsed chronic lymphocytic leukemia. Approved July 23, 2014.
•Belinostat (Beleodaq), a histone deacetylase inhibitor, was granted accelerated approval for treatment of relapse or refractory peripheral T-cell lymphoma. Accelerated approval granted July 3, 2014.
•Ceritinib (Zykadia), a kinase inhibitor, was granted accelerated approval for treatment of anaplastic lymphoma kinase (ALK)-positive, non–small cell lung cancer. Accelerated approval granted April 29, 2014.
•Mercaptopurine (Purixan) oral suspension, a nucleoside metabolic inhibitor, was approved for treatment of acute lymphoblastic leukemia (ALL). Approved April 28, 2014.
•Siltuximab (Sylvant) injection, an interleukin-6 (IL-6) antagonist, was approved for treatment of multicentric Castleman’s disease. Approved April 23, 2014.
•Ofatumumab (Arzerra) injection, a CD20-directed cytolytic monoclonal antibody, was approved for treatment of chronic lymphocytic leukemia (CLL). Approved April 17, 2014.
•Ibrutinib (Imbruvica), a kinase inhibitor, was granted accelerated approval for treatment of chronic lymphocytic leukemia (CLL). Accelerated approval granted February 12, 2014.
•Trametinib (Mekinist) and dabrafenib (Tafinlar), two kinase inhibitors, were granted accelerated approval for use in combination, for treatment of unresectable or metastatic melanoma. Accelerated approval granted January 10, 2014. ■
By The ASCO Post
January 25, 2015, Volume 6, Issue 1
•Nivolumab (Opdivo), a monoclonal antibody, was approved for treatment of metastatic melanoma. Approved December 22, 2014.
•Olaparib (Lynparza), a poly (ADP-ribose) polymerase (PARP) inhibitor, was approved for treatment of BRCA-mutated advanced ovarian cancer. Approved December 19, 2014.
•Lanreotide (Somatuline) depot injection, a somatostatin analog, was approved for treatment of gastroenteropancreatic neuroendocrine tumors. Approved December 16, 2014.
•Ramucirumab (Cyramza) injection, a recombinant monoclonal antibody, was approved for treatment (in combination with docetaxel) of metastatic non–small cell lung cancer. Approved December 12, 2014.
•Ruxolitinib (Jakafi), a Janus-associated kinase (JAK1 and JAK2) inhibitor, was approved for the treatment of polycythemia vera. Approved December 4, 2014.
•Blinatumomab (Blincyto), a bispecfic CD-19 directed CD3 T-Cell engager (BiTE®), was granted accelerated approval for the treatment of relapsed or refractory acute lymphoblastic leukemia. Accelerated approval granted December 3, 2014.
•Bevacizumab (Avastin), a vascular endothelial growth factor–specific angiogenesis inhibitor, was approved for treatment (in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan) of ovarian, fallopian tube, or primary peritoneal cancer. Approved November 14, 2014.
•Ramucirumab (Cyramza), a recombinant monoclonal antibody, was approved for treatment (in combination with paclixatel) of advanced gastric or gastroesophageal junction adenocarcinoma. Approved November 5, 2014.
•Pembrolizumab (Keytruda), a PD-1–blocking antibody, was granted accelerated approval for the treatment of unresectable or metastatic melanoma. Accelerated approval granted September 4, 2014.
•Bevacizumab (Avastin), a vascular endothelial growth factor–specific angiogenesis inhibitor, was approved for treatment (in combination with paclitaxel/cisplatin or paclitaxel/topotecan) of cervical cancer. Approved August 14, 2014.
•Idelalisib (Zydelig) tablets, a kinase inhibitor, was approved for the treatment of relapsed chronic lymphocytic leukemia. Approved July 23, 2014.
•Belinostat (Beleodaq), a histone deacetylase inhibitor, was granted accelerated approval for treatment of relapse or refractory peripheral T-cell lymphoma. Accelerated approval granted July 3, 2014.
•Ceritinib (Zykadia), a kinase inhibitor, was granted accelerated approval for treatment of anaplastic lymphoma kinase (ALK)-positive, non–small cell lung cancer. Accelerated approval granted April 29, 2014.
•Mercaptopurine (Purixan) oral suspension, a nucleoside metabolic inhibitor, was approved for treatment of acute lymphoblastic leukemia (ALL). Approved April 28, 2014.
•Siltuximab (Sylvant) injection, an interleukin-6 (IL-6) antagonist, was approved for treatment of multicentric Castleman’s disease. Approved April 23, 2014.
•Ofatumumab (Arzerra) injection, a CD20-directed cytolytic monoclonal antibody, was approved for treatment of chronic lymphocytic leukemia (CLL). Approved April 17, 2014.
•Ibrutinib (Imbruvica), a kinase inhibitor, was granted accelerated approval for treatment of chronic lymphocytic leukemia (CLL). Accelerated approval granted February 12, 2014.
•Trametinib (Mekinist) and dabrafenib (Tafinlar), two kinase inhibitors, were granted accelerated approval for use in combination, for treatment of unresectable or metastatic melanoma. Accelerated approval granted January 10, 2014. ■
miércoles, 20 de mayo de 2015
DNA Sequencing and New Drugs
Reuters Health Information
How DNA Sequencing Is Transforming the Hunt for New Drugs
By Julie Steenhuysen
May 13, 2015
CHICAGO (Reuters) - Drug manufacturers have begun amassing enormous troves of human DNA in hopes of significantly shortening the time it takes to identify new drug candidates, a move some say is transforming the development of medicines.
The efforts will help researchers identify rare genetic mutations by scanning large databases of volunteers who agree to have their DNA sequenced and to provide access to detailed medical records.
It is made possible by the dramatically lower cost of genetic sequencing - it took government-funded scientists $3 billion and 13 years to sequence the first human genome by 2003. As of last year, the cost was closer to $1,500 per genome, down from $20,000 five years ago.
Regeneron Pharmaceuticals Inc, which signed a deal with Pennsylvania's Geisinger Health System in January 2014 to sequence partial genomes of some 250,000 volunteers, is already claiming discoveries based on the new approach. Company executives told Reuters they have used data from the first 35,000 volunteers to confirm the promise of 250 genes on a list of targets for drugs aimed at common medical conditions, including high levels of cholesterol and triglycerides.
Regeneron says it has also identified "several dozen" new gene targets, including a novel gene that plays a role in obesity.
Pfizer Inc, Roche Holding AG and Biogen Inc are working on similar projects that use DNA and patient health data to find new drug targets or predict the effects of drugs.
Their investments have been inspired by early successes in cancer with drugs such as Pfizer's lung cancer treatment Xalkori (crizotinib), which was approved in 2011 and targets mutations in tumors driving the disease. More recently, Vertex Pharmaceuticals has changed the treatment of cystic fibrosis with Kalydeco (ivacaftor), which targets the disease's underlying genetic cause.
"All of a sudden, it all opened up," as companies recognize the potential for drugs targeting genetic glitches, Dr. Eric Topol, a genomics expert at the Scripps Translational Science Institute. "It's starting to really become a new preferred model for drug development."
In the past, discovering such genes was a painstaking process, often involving years of research into isolated populations. In 1991, for example, researchers discovered a rare mutation in a gene called Angptl3 that caused very low levels of artery-clogging cholesterol and triglycerides among families in the remote Italian village of Campodimele.
It took nearly two more decades and several groups of scientists to fully understand the potential cardiovascular benefits linked to mutations in that gene.
Since last autumn, the Regeneron Genetics Center has sequenced the DNA of more than 35,000 Geisinger patients and is on track to sequence 100,000 by year end. Already, the company has identified 100 people carrying similar cholesterol-affecting mutations to those first observed in Campodimele and elsewhere.
"You no longer have to find that one rare family in Italy, because it's just in the database," said Dr. George Yancopoulos, chief scientific officer of Regeneron.
PRECISION MEDICINE
Identifying target genes is just a first step, though, and does not guarantee that a drug can be developed on a genetic lead, or that it will ultimately be safe and effective enough to be used.
Experts also differ on approach. Regeneron is sequencing exomes, the protein-making genes that comprise 1 to 2% of the genome, a search that costs roughly $700 per person. Others favor looking at the whole genome, which costs the $1,500 per person.
Craig Venter, one of the first scientists to sequence the human genome, believes the whole genome approach will be more meaningful over time.
"I'd rather have a gold mine with a deep vein of gold and modern industrial equipment to mine it rather than sitting there with a pan in a stream looking for gold," he said. "Both will find gold. It's a question of how much you find."
Even so, the early returns from new "genomic" medicines have attracted attention from the White House. In January, President Barack Obama said he would seek $130 million from Congress to gather genetic data from 1 million volunteers as part of a "precision medicine" initiative.
Regeneron is lobbying for the Geisinger database to become a cornerstone of that effort, and proposes creating a consortium of drugmakers to fund it. In return, Yancopoulos said, the company hopes to recoup some of its investment.
Dr. Francis Collins, director of the National Institutes of Health, which is in charge of the precision medicine project, identified Regeneron among a short list of potential contributors to the 1 million-strong DNA study. Others on the list include Kaiser Permanente, Mayo Clinic, and the Marshfield Clinic in Wisconsin. A decision is expected by early fall.
For drug companies, the lure of a big payoff is strong. Regeneron and its partner Sanofi are expected to soon win regulatory approval for a cholesterol-lowering drug that works by blocking the PCSK9 gene. Amgen and Pfizer have developed similar treatments.
Individuals born with non-functioning versions of PCSK9 have very low cholesterol. The new drugs mimic that effect and are considered a poster child for treatments that take advantage of glitches in the genome that prove beneficial to the rare individuals who carry them. Wall Street analysts project Regeneron/Sanofi's PCSK9 drug will generate revenues of $4.4 billion by 2019.
MINING THE DATA
Amgen bolstered its search for gene targets by buying Decode Genetics in late 2012 for $415 million, giving it a database of complete genetic sequences of 2,636 Icelanders. The community shares a relatively homogenous genetic profile due to its geographic isolation, allowing researchers to identify gene variations more easily.
In March, Amgen reported the discovery of a new mutation that increases the risk of Alzheimer's and confirmed the role of two mutations involved in diabetes and atrial fibrillation.
This past January, Roche's Genentech unit tapped Venter's Human Longevity Inc for a large sequencing project.
Genetic testing company 23andMe announced deals this year with Genentech and Pfizer. Genentech will have access to 3,000 individuals in 23andMe's community of Parkinson's patients, and Pfizer will expand an existing collaboration with the company to study the genetics of lupus.
That same month, Biogen formed a $30 million research alliance to support the formation of a sequencing center at Columbia University.
"All of the companies are feeling like, 'Oh my gosh. We have to do something substantial in genomics - yesterday,'" said Dr. David Goldstein, director of Columbia's Institute for Genomic Medicine.
At the heart of Regeneron's model is finding rare mutations that disable normal gene function. So far, it has identified people with at least one such "loss-of-function" gene that correlates with nearly all 250 genes on the company's list of drug targets.
That includes essentially every gene previously linked to triglyceride regulation and several novel candidates, Yancopoulos said. They have done the same for cholesterol and coronary artery disease.
Regeneron has also partnered with academic centers studying families with extreme genetic disorders, collaborations that already have led to the discovery of a couple of dozen new candidate genes, said Dr. Aris Baras, who runs Regeneron's genetics center.
In one case, they are using the Geisinger database to study a rare gene they believe causes severe obesity in young children. The team has found milder mutations in the overall population that may cause an average 10-pound weight gain in adults. That would validate the role that such genes play in regulating body weight and suggests that, "if you had a drug it could have a profound effect," Yancopoulos said.
"This is why everybody is excited about it," he said.
How DNA Sequencing Is Transforming the Hunt for New Drugs
By Julie Steenhuysen
May 13, 2015
CHICAGO (Reuters) - Drug manufacturers have begun amassing enormous troves of human DNA in hopes of significantly shortening the time it takes to identify new drug candidates, a move some say is transforming the development of medicines.
The efforts will help researchers identify rare genetic mutations by scanning large databases of volunteers who agree to have their DNA sequenced and to provide access to detailed medical records.
It is made possible by the dramatically lower cost of genetic sequencing - it took government-funded scientists $3 billion and 13 years to sequence the first human genome by 2003. As of last year, the cost was closer to $1,500 per genome, down from $20,000 five years ago.
Regeneron Pharmaceuticals Inc, which signed a deal with Pennsylvania's Geisinger Health System in January 2014 to sequence partial genomes of some 250,000 volunteers, is already claiming discoveries based on the new approach. Company executives told Reuters they have used data from the first 35,000 volunteers to confirm the promise of 250 genes on a list of targets for drugs aimed at common medical conditions, including high levels of cholesterol and triglycerides.
Regeneron says it has also identified "several dozen" new gene targets, including a novel gene that plays a role in obesity.
Pfizer Inc, Roche Holding AG and Biogen Inc are working on similar projects that use DNA and patient health data to find new drug targets or predict the effects of drugs.
Their investments have been inspired by early successes in cancer with drugs such as Pfizer's lung cancer treatment Xalkori (crizotinib), which was approved in 2011 and targets mutations in tumors driving the disease. More recently, Vertex Pharmaceuticals has changed the treatment of cystic fibrosis with Kalydeco (ivacaftor), which targets the disease's underlying genetic cause.
"All of a sudden, it all opened up," as companies recognize the potential for drugs targeting genetic glitches, Dr. Eric Topol, a genomics expert at the Scripps Translational Science Institute. "It's starting to really become a new preferred model for drug development."
In the past, discovering such genes was a painstaking process, often involving years of research into isolated populations. In 1991, for example, researchers discovered a rare mutation in a gene called Angptl3 that caused very low levels of artery-clogging cholesterol and triglycerides among families in the remote Italian village of Campodimele.
It took nearly two more decades and several groups of scientists to fully understand the potential cardiovascular benefits linked to mutations in that gene.
Since last autumn, the Regeneron Genetics Center has sequenced the DNA of more than 35,000 Geisinger patients and is on track to sequence 100,000 by year end. Already, the company has identified 100 people carrying similar cholesterol-affecting mutations to those first observed in Campodimele and elsewhere.
"You no longer have to find that one rare family in Italy, because it's just in the database," said Dr. George Yancopoulos, chief scientific officer of Regeneron.
PRECISION MEDICINE
Identifying target genes is just a first step, though, and does not guarantee that a drug can be developed on a genetic lead, or that it will ultimately be safe and effective enough to be used.
Experts also differ on approach. Regeneron is sequencing exomes, the protein-making genes that comprise 1 to 2% of the genome, a search that costs roughly $700 per person. Others favor looking at the whole genome, which costs the $1,500 per person.
Craig Venter, one of the first scientists to sequence the human genome, believes the whole genome approach will be more meaningful over time.
"I'd rather have a gold mine with a deep vein of gold and modern industrial equipment to mine it rather than sitting there with a pan in a stream looking for gold," he said. "Both will find gold. It's a question of how much you find."
Even so, the early returns from new "genomic" medicines have attracted attention from the White House. In January, President Barack Obama said he would seek $130 million from Congress to gather genetic data from 1 million volunteers as part of a "precision medicine" initiative.
Regeneron is lobbying for the Geisinger database to become a cornerstone of that effort, and proposes creating a consortium of drugmakers to fund it. In return, Yancopoulos said, the company hopes to recoup some of its investment.
Dr. Francis Collins, director of the National Institutes of Health, which is in charge of the precision medicine project, identified Regeneron among a short list of potential contributors to the 1 million-strong DNA study. Others on the list include Kaiser Permanente, Mayo Clinic, and the Marshfield Clinic in Wisconsin. A decision is expected by early fall.
For drug companies, the lure of a big payoff is strong. Regeneron and its partner Sanofi are expected to soon win regulatory approval for a cholesterol-lowering drug that works by blocking the PCSK9 gene. Amgen and Pfizer have developed similar treatments.
Individuals born with non-functioning versions of PCSK9 have very low cholesterol. The new drugs mimic that effect and are considered a poster child for treatments that take advantage of glitches in the genome that prove beneficial to the rare individuals who carry them. Wall Street analysts project Regeneron/Sanofi's PCSK9 drug will generate revenues of $4.4 billion by 2019.
MINING THE DATA
Amgen bolstered its search for gene targets by buying Decode Genetics in late 2012 for $415 million, giving it a database of complete genetic sequences of 2,636 Icelanders. The community shares a relatively homogenous genetic profile due to its geographic isolation, allowing researchers to identify gene variations more easily.
In March, Amgen reported the discovery of a new mutation that increases the risk of Alzheimer's and confirmed the role of two mutations involved in diabetes and atrial fibrillation.
This past January, Roche's Genentech unit tapped Venter's Human Longevity Inc for a large sequencing project.
Genetic testing company 23andMe announced deals this year with Genentech and Pfizer. Genentech will have access to 3,000 individuals in 23andMe's community of Parkinson's patients, and Pfizer will expand an existing collaboration with the company to study the genetics of lupus.
That same month, Biogen formed a $30 million research alliance to support the formation of a sequencing center at Columbia University.
"All of the companies are feeling like, 'Oh my gosh. We have to do something substantial in genomics - yesterday,'" said Dr. David Goldstein, director of Columbia's Institute for Genomic Medicine.
At the heart of Regeneron's model is finding rare mutations that disable normal gene function. So far, it has identified people with at least one such "loss-of-function" gene that correlates with nearly all 250 genes on the company's list of drug targets.
That includes essentially every gene previously linked to triglyceride regulation and several novel candidates, Yancopoulos said. They have done the same for cholesterol and coronary artery disease.
Regeneron has also partnered with academic centers studying families with extreme genetic disorders, collaborations that already have led to the discovery of a couple of dozen new candidate genes, said Dr. Aris Baras, who runs Regeneron's genetics center.
In one case, they are using the Geisinger database to study a rare gene they believe causes severe obesity in young children. The team has found milder mutations in the overall population that may cause an average 10-pound weight gain in adults. That would validate the role that such genes play in regulating body weight and suggests that, "if you had a drug it could have a profound effect," Yancopoulos said.
"This is why everybody is excited about it," he said.
martes, 19 de mayo de 2015
Sunscreen Use
Medscape Medical News US Sunscreen Use Abysmally Low, Especially Among Men
Janis C. Kelly
May 19, 2015
Adults in the United States seldom used sunscreen as recommended, tended to use it only on the face, and often did not know whether their sunscreen provided broad-spectrum ultraviolet protection, according to survey results published online May 19 in the Journal of the American Academy of Dermatology.
In fact, less than 15% of men and 30% of women used sunscreen as recommended, and 42% of men reported never using sunscreen. "Men may view sunscreen as nonmasculine, messy, or inconvenient, and sunscreen advertisements target women more often than men," write Dawn M. Holman, MPH, and colleagues from the Centers for Disease Control and Prevention (CDC). "Men may rely on protective clothing and shade more than sunscreen, and these alternatives could be encouraged. However, there may still be times when sunscreen is necessary for adequate protection, and more research is needed to develop effective sun-safety interventions targeting men." Interestingly, men living in the Northeast were more likely to regularly use sunscreen on the face than those living in the Midwest or South.
The authors used cross-sectional data from the 2013 Summer ConsumerStyles survey to examine sunscreen use in 4033 adults. Key findings included:
•43.8% of men and 27.0% of women reported that they never use sunscreen on their faces;
•42.1% of men and 26.8% of women reported they never use sunscreen on other exposed skin;
•42.6% of women reported that they regularly use sunscreen on the face, but only 34.4% reported that they regularly use it on other exposed skin;
•only 16.0% of Hispanic men reported using sunscreen on the face, and only 11.9% reported using sunscreen on other exposed skin;
•among Hispanic women, 36.3% reported using sunscreen on the face and 25.7% reported using sunscreen on other exposed skin; and
•almost 40%% of sunscreen users are unsure whether they use a broad-spectrum formula.
Because exposure to ultraviolet radiation is viewed as the most preventable risk factor for all types of skin cancer, including melanoma, these data have major public health implications. Mark Lebwohl, MD, president of the American Academy of Dermatology, said in a news release, "Anyone can get skin cancer, so everyone should take steps to protect themselves from the sun. The Academy recommends everyone choose a sunscreen with a label that states it is broad-spectrum, has a Sun Protection Factor (SPF) of 30 or higher, and is water-resistant.
"Broad-spectrum sunscreen protects against both [ultraviolet A and ultraviolet B] rays, both of which can cause cancer. Recent sunscreen regulations implemented by the U.S. Food and Drug Administration make it easier for consumers to see on the sunscreen label whether the product is broad-spectrum."
The study authors note that their results are consistent with previous data showing that sunscreen use is low among non-Hispanic blacks and those who tend not to sunburn. They write, "These groups may have a lower perceived susceptibility to sun damage and need guidance on balancing the risks and benefits of sun exposure, given the variation in susceptibility even within racial/ethnic groups."
Lead author Dawn M. Holman, MPH, commented in a press release, "Using sunscreen can reduce your risk of skin cancer and early skin aging, but it shouldn't be your only line of defense against the sun. It's best to combine sunscreen with other forms of sun protection. Communities can help with strategies like providing shade in outdoor areas, which can make it easier for individuals to stay sun-safe while enjoying the outdoors."
The authors have disclosed no relevant financial relationships.
J Am Acad Dermatol. Published online May 19, 2015.
Janis C. Kelly
May 19, 2015
Adults in the United States seldom used sunscreen as recommended, tended to use it only on the face, and often did not know whether their sunscreen provided broad-spectrum ultraviolet protection, according to survey results published online May 19 in the Journal of the American Academy of Dermatology.
In fact, less than 15% of men and 30% of women used sunscreen as recommended, and 42% of men reported never using sunscreen. "Men may view sunscreen as nonmasculine, messy, or inconvenient, and sunscreen advertisements target women more often than men," write Dawn M. Holman, MPH, and colleagues from the Centers for Disease Control and Prevention (CDC). "Men may rely on protective clothing and shade more than sunscreen, and these alternatives could be encouraged. However, there may still be times when sunscreen is necessary for adequate protection, and more research is needed to develop effective sun-safety interventions targeting men." Interestingly, men living in the Northeast were more likely to regularly use sunscreen on the face than those living in the Midwest or South.
The authors used cross-sectional data from the 2013 Summer ConsumerStyles survey to examine sunscreen use in 4033 adults. Key findings included:
•43.8% of men and 27.0% of women reported that they never use sunscreen on their faces;
•42.1% of men and 26.8% of women reported they never use sunscreen on other exposed skin;
•42.6% of women reported that they regularly use sunscreen on the face, but only 34.4% reported that they regularly use it on other exposed skin;
•only 16.0% of Hispanic men reported using sunscreen on the face, and only 11.9% reported using sunscreen on other exposed skin;
•among Hispanic women, 36.3% reported using sunscreen on the face and 25.7% reported using sunscreen on other exposed skin; and
•almost 40%% of sunscreen users are unsure whether they use a broad-spectrum formula.
Because exposure to ultraviolet radiation is viewed as the most preventable risk factor for all types of skin cancer, including melanoma, these data have major public health implications. Mark Lebwohl, MD, president of the American Academy of Dermatology, said in a news release, "Anyone can get skin cancer, so everyone should take steps to protect themselves from the sun. The Academy recommends everyone choose a sunscreen with a label that states it is broad-spectrum, has a Sun Protection Factor (SPF) of 30 or higher, and is water-resistant.
"Broad-spectrum sunscreen protects against both [ultraviolet A and ultraviolet B] rays, both of which can cause cancer. Recent sunscreen regulations implemented by the U.S. Food and Drug Administration make it easier for consumers to see on the sunscreen label whether the product is broad-spectrum."
The study authors note that their results are consistent with previous data showing that sunscreen use is low among non-Hispanic blacks and those who tend not to sunburn. They write, "These groups may have a lower perceived susceptibility to sun damage and need guidance on balancing the risks and benefits of sun exposure, given the variation in susceptibility even within racial/ethnic groups."
Lead author Dawn M. Holman, MPH, commented in a press release, "Using sunscreen can reduce your risk of skin cancer and early skin aging, but it shouldn't be your only line of defense against the sun. It's best to combine sunscreen with other forms of sun protection. Communities can help with strategies like providing shade in outdoor areas, which can make it easier for individuals to stay sun-safe while enjoying the outdoors."
The authors have disclosed no relevant financial relationships.
J Am Acad Dermatol. Published online May 19, 2015.
I Refuse to Capitulate to Cancer By Paul Kalanithi, MD,
I Refuse to Capitulate to Cancer
By Paul Kalanithi, MD, as was told to Jo Cavallo
April 10, 2015, Volume 6, Issue 6
I’ve been fortunate to overcome the immediate challenge of having advanced lung cancer and wondering how much time I have left. Now the question is, how do I proceed toward realizing my hopes and ambitions in a responsible and productive way?
—Paul Kalanithi, MD
Editor’s note: We regret to announce that Paul Kalanithi, MD, passed away on March 9, 2015. Dr. Kalanithi was Chief Resident in Neurological Surgery at Stanford University when he shared his story, reprinted here, with The ASCO Post just over 1 year ago, in March 2014. Click here for a memorial tribute to Dr. Kalanithi. We extend our deepest sympathies to Dr. Kalanithi’s family.
Early last year, just as I returned to my residency in neurologic surgery at Stanford University after completing 2 years of my postdoctoral fellowship in a laboratory developing optogenetic techniques, I started losing weight—dropping from 180 lb to 160 lb in just 6 months—and I was having fairly significant back pain. The symptoms didn’t sound any alarm bells at first. After all, I had gone from a sedentary job in the laboratory where I was eating three or four meals a day—and had put on a fair amount of weight—to working 90 hours a week at the hospital and grabbing food in between seeing patients and performing surgeries, which also put a lot of stress on my back.
Nevertheless, when the symptoms persisted, I saw my primary care physician. She ordered some x-rays to rule out isthmic spondylolisthesis as a cause of the back pain, and when they came back negative, she suggested that I have physical therapy to strengthen my back muscles and take ibuprofen for the pain, which helped. Still, I had a nagging suspicion that things were not quite right.
By May, my symptoms had exploded into spontaneous fevers, night sweats, and chest and back pain so severe, they kept me awake at night and frightened me. My weight, which had stabilized, started dropping again and I developed a slight cough. I knew something was seriously wrong, and I started considering cancers that commonly occur in young people, including testicular cancer, but I didn’t feel any masses, so that seemed unlikely. Next, I saw my dermatologist to check for melanoma, but I had no suspicious skin lesions.
Finally, I went back to my primary care physician for a chest x-ray, which showed indistinct lesions on my lungs. I went to the hospital, was admitted, and had a CT scan performed. As I watched the images come on the screen, I could clearly see masses of lesions matting my lungs and deforming my spine. Although I’m not a thoracic oncologist, having reviewed dozens of patients’ scans for colleagues to determine if surgery offered any hope, I knew immediately what I was seeing: metastatic cancer. When I put the results of the scans together with my lab values, which showed anemia and other system abnormalities, I knew things looked grim. I thought to myself, I have a matter of months to live.
Seeking Survival Statistics
After being in medical training for 11 years—and poised to launch an excellent career in neurosurgery and neuroscience—the news that I had stage IV non–small cell EGFR-positive lung cancer was devastating. When I saw my oncologist, I asked her what my Kaplan-Meier survival estimate was. She flatly refused to tell me. Instead, she appropriately laid out my treatment options.
What was interesting to me is that when she talked about my options, she suggested that I could go back to work someday. Even though my oncologist wouldn’t give me statistics on my prognosis, I knew from my own research that large general studies showed that between 70% and 80% of patients with lung cancer died within 2 years of their diagnosis. Of course, most of those patients were older and heavy smokers. What was the study result in nonsmoking, 36-year-old neurosurgeons?
Having No Regrets
I was prescribed erlotinib (Tarceva) and, fortunately, I’m having a really good response to the drug. The majority of the spots on my lungs have disappeared, and the primary lung nodule has shrunk. I’ve put back all the weight I lost, and last November I returned to work full-time.
Some days I feel that maybe I should be in a less demanding, less stressful job, but doing that would be a capitulation to cancer. Yes, life is harder now. I’m a little more tired than I used to be, and everything takes a bit more effort, but I can still operate every day, sometimes for more than 12 hours a day.
As I continue to get stronger, I’m beginning to feel that it’s possible I will have a very long career, although I still realize I may not. At least I know what’s important to me. You have to ask yourself, which do you want more: to have a career and life that you love, knowing that they can come crashing down if you get sick again, or not to do those things and feel regret? I choose the former.
Appreciating the Stresses of Living
At the moment, my life is at the maximum point of uncertainty. I need to get my career trajectory fully back on course, and my wife is pregnant with our first child. So life is really exciting—and stressful. But these are the stresses of living, not of dying. The fact that I get to deal with all of the worries of having a highly demanding career and a new family is a blessing.
Being both a doctor and a patient has been an interesting experience. I’ve gotten occasional advice from well-meaning colleagues who say that coming back to neurosurgery is crazy. Some of their advice is quite useful because their feedback helps me assess whether I’m making the right decisions or in complete denial of the seriousness of my medical situation. But the flip side of their advice is that it can persuade you to limit your goals, and I’d rather not let cancer do that.
I’ve been fortunate to overcome the immediate challenge of having advanced lung cancer and wondering how much time I have left. Now the question is, how do I proceed toward realizing my hopes and ambitions in a responsible and productive way? The answer may mean building backup plans into the equation in case the cancer becomes uncontrollable and aggressive.
In the meantime, I’m pursuing the things that drive me. The fact of death is unsettling. Yet there is no other way to live. ■
By Paul Kalanithi, MD, as was told to Jo Cavallo
April 10, 2015, Volume 6, Issue 6
I’ve been fortunate to overcome the immediate challenge of having advanced lung cancer and wondering how much time I have left. Now the question is, how do I proceed toward realizing my hopes and ambitions in a responsible and productive way?
—Paul Kalanithi, MD
Editor’s note: We regret to announce that Paul Kalanithi, MD, passed away on March 9, 2015. Dr. Kalanithi was Chief Resident in Neurological Surgery at Stanford University when he shared his story, reprinted here, with The ASCO Post just over 1 year ago, in March 2014. Click here for a memorial tribute to Dr. Kalanithi. We extend our deepest sympathies to Dr. Kalanithi’s family.
Early last year, just as I returned to my residency in neurologic surgery at Stanford University after completing 2 years of my postdoctoral fellowship in a laboratory developing optogenetic techniques, I started losing weight—dropping from 180 lb to 160 lb in just 6 months—and I was having fairly significant back pain. The symptoms didn’t sound any alarm bells at first. After all, I had gone from a sedentary job in the laboratory where I was eating three or four meals a day—and had put on a fair amount of weight—to working 90 hours a week at the hospital and grabbing food in between seeing patients and performing surgeries, which also put a lot of stress on my back.
Nevertheless, when the symptoms persisted, I saw my primary care physician. She ordered some x-rays to rule out isthmic spondylolisthesis as a cause of the back pain, and when they came back negative, she suggested that I have physical therapy to strengthen my back muscles and take ibuprofen for the pain, which helped. Still, I had a nagging suspicion that things were not quite right.
By May, my symptoms had exploded into spontaneous fevers, night sweats, and chest and back pain so severe, they kept me awake at night and frightened me. My weight, which had stabilized, started dropping again and I developed a slight cough. I knew something was seriously wrong, and I started considering cancers that commonly occur in young people, including testicular cancer, but I didn’t feel any masses, so that seemed unlikely. Next, I saw my dermatologist to check for melanoma, but I had no suspicious skin lesions.
Finally, I went back to my primary care physician for a chest x-ray, which showed indistinct lesions on my lungs. I went to the hospital, was admitted, and had a CT scan performed. As I watched the images come on the screen, I could clearly see masses of lesions matting my lungs and deforming my spine. Although I’m not a thoracic oncologist, having reviewed dozens of patients’ scans for colleagues to determine if surgery offered any hope, I knew immediately what I was seeing: metastatic cancer. When I put the results of the scans together with my lab values, which showed anemia and other system abnormalities, I knew things looked grim. I thought to myself, I have a matter of months to live.
Seeking Survival Statistics
After being in medical training for 11 years—and poised to launch an excellent career in neurosurgery and neuroscience—the news that I had stage IV non–small cell EGFR-positive lung cancer was devastating. When I saw my oncologist, I asked her what my Kaplan-Meier survival estimate was. She flatly refused to tell me. Instead, she appropriately laid out my treatment options.
What was interesting to me is that when she talked about my options, she suggested that I could go back to work someday. Even though my oncologist wouldn’t give me statistics on my prognosis, I knew from my own research that large general studies showed that between 70% and 80% of patients with lung cancer died within 2 years of their diagnosis. Of course, most of those patients were older and heavy smokers. What was the study result in nonsmoking, 36-year-old neurosurgeons?
Having No Regrets
I was prescribed erlotinib (Tarceva) and, fortunately, I’m having a really good response to the drug. The majority of the spots on my lungs have disappeared, and the primary lung nodule has shrunk. I’ve put back all the weight I lost, and last November I returned to work full-time.
Some days I feel that maybe I should be in a less demanding, less stressful job, but doing that would be a capitulation to cancer. Yes, life is harder now. I’m a little more tired than I used to be, and everything takes a bit more effort, but I can still operate every day, sometimes for more than 12 hours a day.
As I continue to get stronger, I’m beginning to feel that it’s possible I will have a very long career, although I still realize I may not. At least I know what’s important to me. You have to ask yourself, which do you want more: to have a career and life that you love, knowing that they can come crashing down if you get sick again, or not to do those things and feel regret? I choose the former.
Appreciating the Stresses of Living
At the moment, my life is at the maximum point of uncertainty. I need to get my career trajectory fully back on course, and my wife is pregnant with our first child. So life is really exciting—and stressful. But these are the stresses of living, not of dying. The fact that I get to deal with all of the worries of having a highly demanding career and a new family is a blessing.
Being both a doctor and a patient has been an interesting experience. I’ve gotten occasional advice from well-meaning colleagues who say that coming back to neurosurgery is crazy. Some of their advice is quite useful because their feedback helps me assess whether I’m making the right decisions or in complete denial of the seriousness of my medical situation. But the flip side of their advice is that it can persuade you to limit your goals, and I’d rather not let cancer do that.
I’ve been fortunate to overcome the immediate challenge of having advanced lung cancer and wondering how much time I have left. Now the question is, how do I proceed toward realizing my hopes and ambitions in a responsible and productive way? The answer may mean building backup plans into the equation in case the cancer becomes uncontrollable and aggressive.
In the meantime, I’m pursuing the things that drive me. The fact of death is unsettling. Yet there is no other way to live. ■
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