High-Risk Prostate Cancer and DNA Damage And Repair Gene Profiling

DNA Damage And Repair Gene Profiling Predicts High-Risk Prostate Cancer
Genetic profiling may indicate a patient’s risk of metastatic prostate cancer after surgery

Date: 08 Jan 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Prostate Cancer / Translational Research / Surgery and/or Radiotherapy of Cancer

medwireNews: A gene profiling study suggests that characterising DNA damage and repair (DDR) pathway genes could help identify prostate cancer patients at high risk of developing metastases after radical prostatectomy.

“As a biomarker of disease progression, DDR pathway profiling may be used to select patients for earlier treatment intensification with approaches such as adjuvant radiation or systemic therapy and may represent an avenue toward improved personalization of therapy for prostate cancer patients”, say Felix Feng, from University of Michigan Medical Center in Ann Arbor, USA, and co-workers.

The researchers profiled 1090 men, aged an average of 65.3 years at the time of prostate cancer diagnosis and surgery, for nine DDR pathways using 17 gene sets. Gene Set Enrichment Analysis was conducted using microarray gene expression from prostatectomy samples in patients with a median of 10.3 years of follow-up.

As reported in JAMA Oncology, there were “distinct clusters” of DDR pathways. These clusters had only a weak correlation with patient age, Gleason score and prostate-specific antigen level, but 13 of the 17 DDR sets showed a strong correlation with androgen receptor pathway markers.

Initial analysis suggested that seven of the nine DDR pathways were significantly associated with metastasis-free survival and multivariate analysis showed that four of the DDR pathways, as well as Gleason score and seminal vesicle invasion, were significantly associated with metastasis-free survival.

A prognostic signature created from the DDR pathway profiles in a training cohort of 545 patients was then applied to the remaining men divided into three validation cohorts of 232, 130 and 183 patients.

A high-risk versus low-risk signature significantly correlated with the pooled likelihood of biochemical recurrence-free survival (hazard ratio [HR]=1.89), metastasis-free survival (HR=1.88) and overall survival (HR=1.90), and these relationships were independent of clinicopathological characteristics.

The DDR pathway signature’s performance was significantly stronger in men aged less than 70 years than those aged 70 years or older (HR=1.67 vs 0.77), indicating that “the DDR pathways play a different role in younger vs older patients, and that this may [be] responsible for the differential outcomes after radiotherapy”, the team comments.

By contrast, patient ethnicity did not significantly correlate with the likelihood of a low- or high-risk signature.

Noting that the genes assessed in the DDR pathways are “rarely affected by mutation”, the researchers conclude: “These findings demonstrate that DDR pathway profiling is a promising tool in the management of prostate cancer, and we have built a nomogram that would ease its use.”

Reference

Evans JR, Zhao SG, Chang L, et al. Patient-level DNA damage and repair pathway profiles and prognosis after prostatectomy for high-risk prostate cancer. JAMA Oncol 2016; Advance online publication 7 January.doi:10.1001/jamaoncol.2015.4955

ColoRectalCancer and the Molecular Subtypes

CRC Molecular Subtypes Linked to Clinical Patterns, Prognosis
Most colorectal cancer patients fall into one of four subgroups characterised by molecular patterns and clinical behaviour

Date: 13 Oct 2015
Author: Lynda Williams, Senior medwireNews Reporter
Topic: Colon Cancer / Rectal Cancer / Translational Research

medwireNews: Research suggests that colorectal cancer (CRC) patients could be classified according to one of four consensus molecular subtypes (CMSs), each associated with a clinical profile.

“We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions”, say Justin Guinney, from Sage Bionetworks in Seattle, Washington, USA, and fellow CRC Subtyping Consortium investigators.

The team explains that six different CRC classification systems were applied to 18 gene expression data sets for a total of 4151 patients, allowing a network-based approach to identification of recurring patterns.

Four CMSs emerged, with 14% of patients classified as CMS1 (microsatellite instability [MSI] immune), 37% as CMS2 (canonical), 13% as CMS3 (metabolic) and 23% as CMS4 (mesenchymal). A further 7% of patients were classified as having a mixture of two subtypes, and the remainder had indeterminate samples.

Samples taken from the CMS2 and CMS4 groups had high chromosomal instability, as defined by number of somatic copy number alterations (SCNAs), while CMS1 and CMS3 had low SCNA, the researchers report in Nature Medicine.

Patients in the CMS1 group had CRC samples characterised by hypermutation and widespread hypermethylation, as well as overexpression of proteins involved in DNA damage repair. CMS1 also included the majority of tumours showing MSI, although some CMS3 tumours also showed MSI.

BRAF mutations were common in CMS1 and there was “nearly universal” activation of the receptor tyrosine kinase and mitogen-activated protein kinase pathway in CMS1 and CMS3, but the researchers emphasise that none of the CMSs were defined by a single gene mutation or SCNA.

“This supports the notion that tumors harboring commonly assumed driver events in CRC still vary markedly in their biology and highlights the very poor genotype-phenotype correlations in this disease”, they comment.

The CMSs also showed distinct patterns of gene expression: CMS1 samples showed upregulation of genes associated with immune infiltration and evasion, while CMS2 samples had increased expression of genes associated with epithelial differentiation and CRC carcinogenesis. CMS3 showed gene expression associated with metabolic alterations, while CMS4 tumours had gene expression patterns linked to epithelial-to-mesenchymal transition processes including angiogenesis.

Moreover, the CMSs showed distinct clinical and prognostic characteristics, such that CMS1 samples were associated with female patients and right-sided tumours with a high histopathological grade, CMS2 tumours tended to be left-sided and CMS4 tumours were more likely than other subtypes to be diagnosed at stage III or IV.

Indeed, in multivariate analysis, patients with CMS4 tumours had significantly poorer overall and relapse-free survival than other patients, whereas CMS2 patients had better survival after relapse.

In a comment to the press, co-author Anguraj Sadanandam, from the Institute of Cancer Research in London, UK, said the results “could allow doctors to pick out those patients with more aggressive disease and treat them accordingly.”

“Ultimately, it could lead to development of new molecular diagnostic tests to diagnose patients by their particular type of bowel cancer, and give them the most effective treatments for that type”, he added.
Reference

Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015; Advance online publication 12 October. doi:10.1038/nm.3967

ASCO and ACS Issue New Guideline on Breast Cancer Survivorship Care

ASCO and ACS Issue New Guideline on Breast Cancer Survivorship Care
FOR IMMEDIATE RELEASE:
December 7, 2015
Contact:

Lada Krilov
571-483-1377
Lada.Krilov@asco.org

ALEXANDRIA, Va. – The American Society of Clinical Oncology (ASCO) and the American Cancer Society (ACS) today issued a joint clinical practice guideline on the care of female adult breast cancer survivors. The guideline includes recommendations on surveillance for breast cancer recurrence, screening for second primary cancers, management of long-term and late effects, health promotion, care coordination and practice implications.

“ASCO is pleased to collaborate with the American Cancer Society on this first joint ACS-ASCO guideline,” said ASCO President Julie M. Vose, MD, MBA, FASCO. “We look forward to continuing our work together to improve the quality of cancer care for the millions of people affected by cancer.”

The guideline is intended to provide recommendations to primary care physicians, as well as other clinicians who care for breast cancer survivors. The recommendations are consistent with and complementary to ASCO’s breast cancer follow-up care guideline and ASCO’s symptom-focused survivorship guidelines.

“The new guideline addresses the issues facing women breast cancer survivors as they transition from treatment to survivorship,” said Carolyn D. Runowicz, MD, FASCO chair of the ASCO/ACS Expert Workgroup that developed the guideline. “The recommendations should result in high quality survivorship care, with a focus on improving their quality of life and health outcomes.”

The guideline recommendations were developed by a multidisciplinary expert workgroup, with expertise in primary care, gynecology, surgical oncology, medical oncology, radiation oncology and nursing. In addition, a cancer survivor was included to provide a patient perspective. The workgroup conducted a systematic review of literature published through April 2015 and identified 237 relevant articles.

“I believe that this broad set of recommendations will provide for optimal health outcomes for the increasing number of breast cancer survivors,” said Gary H. Lyman, MD, MPH, FASCO, FRCP, ASCO’s representative on the ASCO/ACS Expert Panel that developed the guideline. “This joint guideline initiative will also serve as a framework for future fruitful collaborations between ACS and ASCO across the spectrum of cancer care and survivorship.”

Key guideline recommendations:

Patients should undergo regular surveillance for breast cancer recurrence (including cancer-related history and physical examinations), and be screened for new primary breast cancer.
Routine laboratory test or imaging tests to evaluate for breast cancer recurrence are not recommended in asymptomatic patients.
Primary care physicians should counsel patients about the importance of maintaining a healthy lifestyle, monitor for post-treatment symptoms and for adherence to hormone (endocrine) therapy.

The guideline, American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline, was published today in both CA: A Cancer Journal for Clinicians and Journal of Clinical Oncology.

Information providing insight on these recommendations for patients is available at www.cancer.net/recommendations. The guideline is available at www.asco.org/guidelines/breastsurvivorship, along with supplementary materials.

Related ASCO guidelines include:

Breast Cancer Follow-Up and Management After Primary Treatment: American Society of Clinical Oncology Clinical Practice Guideline Update
Screening, Assessment, and Management of Fatigue in Adult Survivors of Cancer: An American Society of Clinical Oncology Clinical Practice Guideline Adaptation
Screening, Assessment, and Care of Anxiety and Depressive Symptoms in Adults With Cancer: An American Society of Clinical Oncology Guideline Adaptation
Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

ASCO encourages feedback on its guidelines from oncologists, practitioners and patients through the ASCO Guidelines Wiki at www.asco.org/guidelineswiki.

Emerging Agents in Colorectal Cancer

NYU Expert Examines Emerging Agents in Colorectal Cancer
Gina Columbus @ginacolumbusonc
Published Online: Thursday, December 31, 2015
Jennifer Wu, MD

Jennifer Wu, MD
With the FDA approval of a novel therapy and the discovery of a possible biomarker to predict which patients are likely to respond to a PD-1 inhibitor, 2015 proved to be a positive year for the treatment paradigm of colorectal cancer (CRC).

The oral nucleoside TAS-102 (Lonsurf) was approved by the FDA in September for the treatment of patients with metastatic disease who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biologic product, and an anti-EGFR monoclonal antibody, if RAS wild-type. This provides a second single-agent option for patients, as regorafenib (Stivarga) was approved in 2012 for patients with metastatic disease who had prior therapy.

The TAS-102 approval was based on results from the phase III RECOURSE trial, which examined 800 patients with refractory metastatic CRC.1 In the study, the overall survival (OS) for those who received TAS-102 was 7.1 months compared with 5.3 months with placebo (HR, 0.68; P <.0001). The median progression-free survival (PFS) in the TAS-102 arm was 2 months versus 1.7 months with placebo (HR, 0.48; P <.0001). Earlier this year, at the 2015 ASCO Annual Meeting, data showed that individuals with CRC who have high levels of deficiency in DNA mismatch repair (MMR) have a higher production of neo-antigens and are potential candidates for immunotherapy.2 In the study, patients with MMR deficiencies who received pembrolizumab (Keytruda) had an objective response rate of 62% compared with 0% in patients with MMR-proficient tumors. These findings suggest that MMR could be a biomarker for PD-1 inhibition. In an interview with OncLive, Jennifer Wu, MD, an assistant professor of Medicine in the Department of Medicine at Perlmutter Cancer Center and NYU Langone Medical Center, sheds light on TAS-102, as well as some emerging agents likely to play a role in the treatment of patients with CRC. OncLive: What are some of the most promising emerging agents in CRC right now?

Wu: Currently, there is a focus on two single agents. One is regorafenib, which is a non-chemotherapeutic agent that showed OS benefits in refractory CRC. The other one was actually approved in September—TAS-102—and, as a single agent, it also showed an OS benefit.

Both of these are oral agents and they have shown a pretty impressive survival benefit in similar patient populations, except that TAS-102 includes patients who had received prior regorafenib. The agents each have their own side effect profile.

I think those are very good choices for our patients now. We have two options, and the choice of one versus the other depends on patient preference, prior patience experience, or prior chemotherapy. We can choose one or the other. Sometimes, it is even possible to do it sequentially.

Secondly, we now have EGFR inhibitors for RAS and RAF wild-type patients. We have realized that it’s not adequate to just inhibit BRAF. In contrast to melanoma, we have EGFR feedback activation in CRC. If we just inhibit a single-agent BRAF inhibitor, it doesn’t really work.

Therefore, there are ongoing studies that combine both BRAF and EGFR inhibitors with pretty good results, although it is preliminary data. There are also data indicating that, by combining all 3 BRAF, MEK and EGFR inhibitors, patients had either stable disease or a response rate of 80% in the refractory setting.

There is also the fact that when patients are treated with therapy, they acquire resistance. Acquired resistance actually increases in patients with HER2 amplification, so there has been a study combining EGFR and HER2 agents in patients who have received 5 prior lines of therapy, and the response rate was 35%. That is pretty impressive.

There are also some agents being combined with chemotherapy agents, such as a SYK inhibitor and an Hsp90 inhibitor. Although they are small studies, the OS is 16 months, and that is very exciting.

Stem cell inhibitors are also being investigated in CRC. What can you share about this?

This is the most exciting one to me. We understand that there are stem cells for all kinds of cancers, and there are a couple stem cell inhibitors that are ongoing with CRC treatment right now.

One of them inhibits a transcription factor in the stem cell pathway called Nanog. In patients who were positive for this biomarker, their PFS was approximately 16 weeks in fifth-line therapy versus 6 weeks in patients without the stem cell marker. It is a small study, but perhaps we now have a biomarker about stem cells.

Another study examined a stem cell inhibitor that inhibited STAT3 and β-catenin pathway when combined with an EGFR inhibitor in the second- or third-line setting. One group includes patients who have never been treated with an EGFR inhibitor before; the other group is made up of patients treated with EGFR inhibitors, but now in combination with the stem cell inhibitor.

- See more at: http://global.onclive.com/web-exclusives/nyu-expert-examines-emerging-agents-in-colorectal-cancer/1#sthash.nspDmFdG.dpuf

In both groups, the control rate is approximately 40%. However, the patients who were treated before seemed to do better—both in disease control rate and PFS. That gave us an idea that, perhaps, stem cell inhibition is the way to go, especially for patients who have been previously treated with chemotherapy. I’m sure we are going to hear more about all of these above agents at upcoming conferences.

The FDA has approved TAS-102 as a single agent. Is there interest in seeing what effects it could have in combination with other agents?

We know that it was tested with oxaliplatin in preclinical models, and we also know that there was an abstract presented earlier this year where TAS-102 was combined with bevacizumab in refractory CRC, and it did have pretty high response rates, as well. I think that TAS-102 will be on the way to have novel combinations in the future, maybe not just with chemotherapy, but maybe more exciting stuff, such as stem cell inhibitors. It’s an open question.

There were also exciting results presented at the 2015 ASCO Annual Meeting regarding clinical activity with immunotherapy in patients with MMR-deficient tumors. Can you comment on these findings?

This is almost like a whole new door for us. If we have a DNA defect, the MMR enzyme comes in, corrects it, and DNA continues to replicate. It’s the same thing with cancer cells. When you have a deficiency in such an enzyme, the cancer cells cannot repair themselves very well. If we have an agent that sort of stops this enzyme from working even better, then we can stop the cancer cells from proliferating.

For patients who have MMR, their proliferation is not high because they keep having errors every time they replicate. The mutation load for such cancer cells is very high, so we know that the mutation rate here is 1500. In normal CRC cells, it is about 40. In immunotherapy in particular, this worked in patients who had higher mutational loads. Therefore, the MMR deficiency in CRC is a category where we believe immunotherapy would have some effect. In the study, all patients who had MMR-deficient genes had a response. It doesn’t matter if it’s CRC or non-CRC.

Now, we are in an era where immunotherapy allows us to focus not on organ-specific disease, but on molecular biology. It’s very provocative. The response rates are extremely high, and also the PFS rate has not even been reached in patients with MMR deficiency. I think that immunotherapy will be something very exciting, at least for this subgroup.

What other ongoing clinical trials are you anticipating the results of?

There are multiple ongoing studies. We know the EGFR pathway goes down to RAF, RAS, and MEK. However, there is another pathway involving PI3K, AKT, and mTOR. There are definitely trials ongoing in PI3K, either for wild-type or mutant patients, where we see combinations of EGFR inhibitors with chemotherapy or with mTOR inhibitors. There is also a lot of excitement with PI3K inhibitors. We are in this era where colon cancer is no longer one disease. It’s based on the molecular biology where we have specific agents for those patients. - See more at:

http://global.onclive.com/web-exclusives/nyu-expert-examines-emerging-agents-in-colorectal-cancer/2#sthash.1t2H3Dsd.dpuf