Molecular classification system for colorectal cancer

The International Consensus of Intrinsic Subtypes of Colorectal Cancer
The most robust molecular classification system currently available for colorectal cancer

Date: 29 Oct 2015
Topic: Genitourinary cancers / Translational research

The Colorectal Cancer Subtyping Consortium was formed to assess the presence or absence of core subtype patterns among existing gene expression–based colorectal cancer subtyping algorithms. The researchers also wanted to characterise the key biological features of the core subtypes, integrate and confront all other available data sources (mutation, copy number, methylation, microRNA and proteomics) and assess whether the subtype assignment correlated with patient outcome. Furthermore, their aim was to establish an important paradigm for collaborative, community-based cancer subtyping that will facilitate the translation of molecular subtypes into the clinic, not only for colorectal cancer, but for other malignancies as well.

The colorectal cancer subtypes are:

CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation;
CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation;
CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and
CMS4 (mesenchymal, 23%), prominent transforming growth factor–β activation, stromal invasion and angiogenesis.

Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity.
Clinical and prognostic associations of the consensus molecular subtypes

The consortium also found important associations between the CMS groups and clinical variables. CMS1 tumours were frequently diagnosed in females with right-sided lesions and presented with higher histopathological grade.

Conversely, CMS2 tumours were mainly left-sided and, whereas CMS4 tumours tended to be diagnosed at more advanced stages (III and IV).

To determine whether the CMS groups differed in outcome, the researchers performed a Cox proportional hazards analysis on the combined data sets and separately in the subset of patients enrolled in a clinical trial with uniform follow-up (PETACC-3 clinical trial).

Irrespective of patient cohort, CMS4 tumours resulted in worse overall survival and worse relapse-free survival in both univariate and multivariate analyses, after adjustment for clinico-pathological features, MSI status and presence of BRAF or KRAS mutations.

The researchers also found superior survival rates after relapse in CMS2 patients, with a larger proportion of long-term survivors in this subset.

Notably, the CMS1 population had a very poor survival rate after relapse, in agreement with recent studies showing worse prognosis of patients with MSI and BRAF-mutated colorectal cancers that recur.

These differences in prognosis with unsupervised gene expression signatures confirm the clinical relevance of the intrinsic biological processes implicated in each CMS.

From a biological perspective, the consortium researchers were able to refine the number and interpretation of the 'non-MSI' subtypes, which represent nearly 85% of the primary colorectal cancer samples. They also described strong molecular associations, particularly for samples lacking a mesenchymal phenotype. From a clinical perspective, in colorectal cancer, as for many other cancer types, it remains unclear what features will provide the most relevant subclassification tool.

In colorectal cancer, few biomarkers (including RAS and BRAF mutations and MSI and CIMP status) have been translated to patient care. It is important to emphasize that although the CMS groups are enriched for some genomic and epigenomic markers, their associations described do not allow categorisation of gene expression subtypes, thus reinforcing the notion that transcriptional signatures allow refinement of disease subclassification beyond what can be achieved by currently validated biomarkers.

For example, although tumours with wild-type RAS are considered to be a homogeneous entity for the purpose of making therapeutic decisions in the setting of advanced cancer, they were found across distinct CMS groups with profound biological differences that are expected to translate into heterogeneous drug responses.

Thanks to the collaborative bioinformatics work on the largest collection of colorectal cancer cohorts with molecular annotation to date, and building upon previous efforts by the independent researchers, the analyses by members of the consortium resulted in a consensus molecular classification system that allows the categorisation of most tumours into one of four robust subtypes.

Marked differences in the intrinsic biological underpinnings of each subtype support the new taxonomy of this disease. The Consortium researchers believe that this new taxonomy will facilitate future research in the colorectal cancer field and should be adopted by the community for colorectal cancer stratification.
Reference

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

Processed meat and colorectal cancer: a review

Nutr Cancer. Author manuscript; available in PMC 2009 Mar 27.
Published in final edited form as:
Nutr Cancer. 2008; 60(2): 131–144.
doi: 10.1080/01635580701684872
PMCID: PMC2661797
HALMS: HALMS334544
Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence
Raphaëlle L. Santarelli,* Fabrice Pierre, and Denis E. Corpet

Abstract

Processed meat intake may be involved in the etiology of colorectal cancer, a major cause of death in affluent countries.

The epidemiologic studies published to date conclude that the excess risk in the highest category of processed meat-eaters is comprised between 20 and 50% compared with non-eaters.

In addition, the excess risk per gram of intake is clearly higher than that of fresh red meat. Several hypotheses, which are mainly based on studies carried out on red meat, may explain why processed meat intake is linked to cancer risk.

Those that have been tested experimentally are
(i) that high-fat diets could promote carcinogenesis via insulin resistance or fecal bile acids;
(ii) that cooking meat at a high temperature forms carcinogenic heterocyclic amines and polycyclic aromatic hydrocarbons;
(iii) that carcinogenic N-nitroso compounds are formed in meat and endogenously;
(iv) that heme iron in red meat can promote carcinogenesis because it increases cell proliferation in the mucosa, through lipoperoxidation and/or cytotoxicity of fecal water.

Nitrosation might increase the toxicity of heme in cured products. Solving this puzzle is a challenge that would permit to reduce cancer load by changing the processes rather than by banning processed meat.

Introduction

Colorectal cancer (CRC) is a major cause of cancer death in affluent countries, notably the United States and Western Europe.
Diet would strongly influence CRC risk, and changes in foods habits might reduce up to 70% of this cancer burden (1–3).
Epidemiologic studies suggest that meat intake is associated with CRC risk, although the association is not significant in most studies. Published in 1997, the World Cancer Research Fund authoritative expert report states: “evidence shows that red meat probably increases risk and processed meat possibly increases risk of CRC” (2).

Since 2000, three meta-analyses showed that total meat intake is not related to risk, but that red meat intake is a significant risk factor. In addition, as reported below, the association of CRC risk with processed red meat may be stronger than that with fresh red meat (4–6).

Several hypotheses could explain how processed meat could increase CRC risk, and experimental studies have been carried out accordingly. The major hypotheses that have been tested experimentally are
(i) that high-fat or high-protein diets could promote carcinogenesis;
(ii) that cooking meat at high temperature forms mutagenic and carcinogenic heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs);
(iii) that potentially carcinogenic N-nitroso compounds (NOCs) are formed in food and/or endogenously by nitrosation of amines and amides;
(iv) that heme iron in red meat can promote carcinogenesis because it increases cell proliferation in the colonic mucosa, through lipoperoxidation and/or cytotoxicity of fecal water.
Few experiments have been directly carried out on processed meats but the studies undertaken on red meats make it possible to propose the hypotheses cited above. There are no clearly demonstrated biologic mechanisms that could explain the risk difference between processed and unprocessed meat.

The aims of the present paper are
(i) to describe briefly the processed meat products

(ii) to review the epidemiologic evidence that processed meat increases CRC risk,

(iii) to review the experimental studies on the mechanisms explaining the effect of processed meat on colorectal carcinogenesis.

Processed Meat

Processed meat is made mostly from pork or beef meat that are preserved by methods other than freezing, and that undergo a treatment to improve the quality of cuts of carcasses, to increase preservation, and to change flavor.
There is a huge variety of processed meat products and it is not easy to sort them by categories, but parameters involved in the making of these foods are curing (adding salt and other additives), drying, smoking, cooking and packaging.
Processed meat includes bacon, ham (raw, smoked or cooked), heated sausages like hot-dogs (frankfurters), raw sausages (like salami), bologna, blood sausage (UK: black pudding), liver pâté (or liverwurst) and other pâtés and spread meat, luncheon meat and other cold cuts, canned meat, and corned beef (7, 8).
This list is not comprehensive, and many other specific products are made all over the world, using traditional recipes. Curing and smoking, two specific processes for meat, are described below as they might generate potential hazards.

Curing is the addition of a combination of salt, sugar and either nitrate or nitrite: salt improves the taste of meat and preserves it by stopping bacterial growth, because it diffuses inside the muscle and reduces the water activity.

Nitrite inhibits the germination of Clostridium botulinum spores, and gives the meat the desirable cured color by combining with heme iron. Nitrosylmyoglobin is responsible for the red color of raw cured meat. Cooking denatures globin which detaches from the heme, yielding a pink mononitrosylheme complex, the color of cooked cured meat (9, 10).

When saltpeter/nitrate is used, a previous step is needed so that bacteria reduce nitrate to nitrite. In many countries, the maximum permitted concentration of nitrite in processed meat is 200 ppm, and it is 150 ppm in the European Union. Curing can be done with dry salt, in a brine tank, or by injection:

Dry salting is the old way of meat curing. Cuts of meat are placed on heaps of salt and rubbed with salt or with a mix of salt, sugar and saltpeter (11).
This treatment is simple, but long, and its efficacy depends on the diffusion of salt into the meat.
A low temperature must be maintained until the center of the meat piece is salted enough to prevent internal spoilage.

Tank curing is faster than dry salting: meat pieces are placed in brine, water saturated with salt that may also contain sugar and nitrite.

Methods have been developed to accelerate the rate of diffusion of curing agents into meat either by the use of the arterial system by needle injections, or with multi-needle system.
Moreover, new additives have been used in brine to improve the color formation and stability with reducing agents like sodium ascorbate or erythorbate.

Smoking is the process of exposing meat to the smoke from incomplete wood pyrolysis. This gives meat a brown color, changes its flavor and helps its preservation because smoke contains phenols, aldehydes, acetic acid and other carboxylic acids. Wood pyrolysis may generate carcinogenic polycyclic aromatic hydrocarbon (PAH), and the process is hard to control.
A more controlled process is obtained by immersing meat pieces into a “smoke solution”, which gives smoke flavor without PAH contamination, and improves meat preservation because it contains acetic acid.

Among the many existing processed meat products, we chose to describe ham and sausages that contribute most to the overall processed meat intake (12). Ham is obtained by curing the upper quarter (thigh and sirloin) of a pig, and may be boiled (Jambon de Paris), dried (country ham), and/or smoked.
Sausages are prepared with chopped meat (pork usually, or a mix of pork and beef), lard, salt, and other additives (e.g., wine, saltpeter, garlic, herbs, spices). This preparation is usually packed in a casing (historically the intestines of the animal, though now often collagenic, cellulosic or polymeric).
Sausages may be dried (salami-type), cooked (hot-dog type), and/or smoked.
Blood sausage (UK black pudding) is prepared with blood (usually from pork), lard or suet, and a plant-based filling (bread, barley, onions), in three equal parts, with salt and spice. This preparation is packed in a pork bowel, and cooked until it becomes thick.

Processed meat intake makes one half to one fifth of total red meat intake. For instance, in 1999 French adults ate 38 and 63 g/d processed and fresh red meat, respectively (13).

In Europe, the intake of processed meat was 27 g/d [11–48] in women (median and range of 23 EPIC centers from ten European countries), and 48 g/d [19–88] in men (12). Fresh red meat intake was 36 g [25–52] in women, and 60 g/d [40–120] in European men (7). In the American CPSII Nutrition Cohort (median age 63 years) the median intake of processed and fresh red meat was estimated as 10 and 40 g/d, respectively (14).

In a Bethesda case-control study (median age 58 years) the mean intake of processed and red meat was 12 and 36 g/d (15, 16). These values may be underestimated, since they are based on food-frequency questionnaire data, and because subjects were older than the general population. Indeed, Norat et al. estimated that red meat intake in North America is 72 g/d per caput (5).

Epidemiologic Studies

International ecological studies show that countries where people eat more red meat are also countries where the risk of CRC is high (17). Analytical studies suggest that this association is also seen at the individual level, but the link is significant in only one study out of three (18).

Three meta-analyses have been published since 2000, and their quantitative risk estimate for fresh red meat and processed meat intake are summarized below and in Table 1.

Excess risk of CRC associated with the intake of fresh red meat and of processed meat in three dose-response meta-analyses of analytical studies Sandhu et al. (2001) made a meta-analysis gathering 13 cohort studies, selected from 17 studies, according to pre-established quality criteria (4).

All cohorts’ studies with relative risks between meat/processed meat intake and colon/colorectal cancer incidence or mortality were included up to 1999. Prospective studies that did not report the level of exposure (red meat/processed meat consumption) were excluded.

Norat et al. (2002) study derives 18 case-control and 6 cohort studies, selected from 48 (5). All studies published up to 1999, and providing association between total meat, red meat or processed meat intake and colon, rectal and colorectal incidence or mortality, were included.

Sandhu’s and Norat’s meta-analyses were not independent, since eleven studies were common to both articles.
Last, Larsson et al. published in 2006 a meta-analysis of 18 prospective studies, selected from 23, gathering a total of more than one million subjects. Norat’s and Larsson’s studies were quite independent, since only 15% of Norat’s subjects were counted again in Larsson’s study (6).

These three meta-analyses take all previous studies into account, and bring global and consistent conclusions on the effect of different types of meat: total meat, red meat, processed meat. Briefly:


Total intake of meat (including white and red meat from all sources) is not associated with CRC risk in Norat’s and in Larsson’s analyses. Sandhu’s study shows a significant moderate risk associated with total meat intake, but the authors did not include white meat (poultry) in total meat.

A high intake of red meat (usually including beef, veal, lamb, mutton, pork, and offal) is associated with a moderate and significant increased risk of CRC in the three studies:

In Sandhu’s study (4), the average relative risk (RR) of CRC for a 100 g portion of red meat is 1.17. The 95% confidence interval (CI) is 1.05–1.31. Processed meat was not included in red meat, we think, in this study (4).

In Norat’s study (5), CRC RR = 1.35 (CI: 1.21–1.51) for the highest quartile of consumption of red meat (including processed meat). A minor difference is observed between results from case-control and cohort studies (RR=1.36 and 1.27 respectively). The intake of 120 g/d of fresh (unprocessed) red meat is associated with a significant risk, but of lower magnitude than when processed meat is included (+ 19% compared with + 35%) (5).

In Larsson’s study (6), CRC RR = 1.28 (CI: 1.15–1.42) for the highest category of consumption of red meat (including processed meat). Fresh red meat intake (unprocessed meat) was reported in nine studies out of fifteen, and the associated RR was 1.22, a significant value. The risk excess associated with intake of 120 g/d of red meat was + 28%. Larsson’s article does not report the quantitative effect of fresh red meat, and no precision is given on the categories (6).

Processed meat intake (usually including sausages, meats burgers, ham, bacon, salami, nitrite-treated meat and meat products) is associated with CRC risk in all reports: Global RR are 1.49 (CI: 1.22–1.81), 1.31 (CI: 1.13–1.51) and 1.20 (CI: 1.11–1.31) in the three meta-analyses (4–6). In Norat’s analysis, a minor difference is observed between results from case-control and cohort studies (RR=1.29 and 1.39 respectively).

Thus the estimated excess risk associated with fresh red meat intake was 17%, 19% and 22%, and the risk associated with processed meat was 49%, 31% and 20%, in the three reviews, respectively.

The estimates of risk for fresh red meat are within a narrow range, but estimates of risk for processed meat are more dispersed. However, all RRs are significant, and none is larger than 1.5, which shows the consistency of the meta-analyses. As shown in Table 1, doses-response meta-analyses suggest that one gram of processed meat is eleven-times, six-times or twice more “promoting” than one gram of fresh red meat in the three meta-analyses, respectively (4–6).

It is not easy to explain why the processed/fresh meat ratio is higher in Sandhu’s study than in Larsson’s study. However, the three studies indicate that processed meat intake is associated with a higher CRC risk than the intake of other types of meat.

Four cohort study articles dealing with processed meat intake and CRC have been published after Larsson’s 2006 review (one new cohort, and three re-analyses, Table 2), and seven case-control studies shown in Table 3 were published after Norat’s 2002 review. Let us examine below if they strengthen or weaken the above-reported meta-analyses results.

Prospective studies published between 2003 and 2006, on the association between processed meat intake and colorectal cancer risk.

Case-control studies published between 2003 and 2007, on the relationship between processed meat intake and colorectal cancer risk.

A cohort of 30,000 men and women in Japan was studied by Oba et al. (2006), with 231 CRC cases.
Processed meats were ham, sausage, bacon, and yakibuta (Chinese roasted pork). In men, there was a positive association between CRC and the highest tertile of processed meat consumption (RR=1.98, CI: 1.24–3.16). No association was seen in women (RR=0.85, CI: 0.5–1.43) (19).
Three other articles made use of already published cohort studies, but they analyzed prospective data by dietary patterns, instead of type of foods. Fung et al. (2003) used data from the Nurses’ Health Study (20). The highest quintile of women eating a “western pattern”, defined by a high intake of red and processed meats, sweets and desserts, French fries, and refined grains, had a marginally significant increase in colon cancer risk, consistent with meta-analyses result (RR= 1.46, CI: 0.97–2.19).
No association was found with rectal cancer (20). Dixon et al. (2004) analyzed three prospective studies: the Alpha-Tocopherol Beta-Carotene Study (ATBC), the Netherlands Cohort (NLC), and the Swedish Mammography Cohort (SMC) (21).

Exploratory factor analysis identified a dietary pattern that includes processed meat in the three cohorts: the Processed meat, Pork, and Potatoes pattern. This pattern was associated with an increased risk of colon cancer in the SMC women (RR=1.62, CI: 1.12–2.34), and of rectal cancer in the ATBC men (RR=2.21, CI: 1.07–4.57), but not in the NLC study (RRs=0.9) (21). Kesse et al. (2006) studied food patterns in a French cohort of women, already reported in the EPIC study.

The “Western” diet pattern included: processed meat, potatoes, pizzas and pies, sandwiches, sweets, cakes, cheese, cereal products, eggs, and butter. The three other diets were: “Healthy” diet (vegetables, fruit, yogurt, sea products, and olive oil, “Drinker” diet (sandwiches, snacks, processed meat, and alcoholic beverages) and “Meat eaters” diet (meat, poultry, and margarine). “The” Western pattern increased adenoma risk, but not CRC risk (RR= 1.39, CI: 1.00–1.94 and RR = 1.09, CI: 0.60–2.00 respectively). “The” Drinker and the Meat eaters diets increased the adenoma risk and the CRC risk (see RRs on Table 3) (22).

To sum up these recent prospective studies, they bring some support to the conclusions of Larsson’s metaanalysis that processed meat intake is associated with increased risk, and the RR is in the range 1.5–2. However, the link was not found in all sub-groups (male/female, colon/rectum), and the risk associated with dietary patterns cannot be attributed to processed meat alone.


Seven case-control studies dealing with processed meat have been published after Norat’s meta-analysis. All studies report OR above 1.15, but only three studies out of six found a significant association between processed meat intake and CRC risk.

In Shangai, China, Chiu et al. (2003) found that a high intake of preserved foods (whether animal or plant source) was associated with an increased risk of colon cancer (OR= 2.0, CI: 1.5–2.9 in men, and OR=2.7, CI: 1.9–3.8 in women). Preserved vegetables was more strongly associated with cancer risk than preserved animal foods (23).

In the U.S.A., Chiu and Gapstur (2004) investigated the effect of dietary changes during adult life. They showed that risk was higher for people who did not reduce their consumption of red meat and processed meat after the age of 30 years, and risk was particularly high for pork chops/ham steaks eaters (OR= 3.7, CI: 1.6–8.7) (24).

In Canada, Nkondjock et al. established dietary patterns, as reported above for cohorts. The “pork and processed meat” pattern, characterized by a high consumption of processed meat, pork, and white bread, increased colon cancer risk nearly significantly (RR=1.6, CI: 0.9–2.8) (25).In Utah and Northern California, Murtaugh et al. (2004) found no association between processed meat intake and the risk of rectal cancer (RR=1.2, CI: 0.85–1.7) (26).

In Japan, Kimura et al. found that processed meat intake (and red meat intake) was not related to CRC risk (OR=1.15, CI: 0.83–1.60) (27). A Maryland case-control study of colorectal adenoma found a two-fold increased risk in the highest, compared to the lowest, quartile of processed meat intake (95% CI = 1.0–4.0). This OR was mostly explained by nitrate/nitrite intake, and marginally attenuated by MeIQx intake (a heterocyclic amine formed by cooking).

In addition, ham steak/pork chops, hot dogs/other sausages, and liverwurst intake each were associated with a two-fold risk of adenoma, while bacon, breakfast sausages, ham, bologna, salami, and other luncheon meats intake were not associated with the risk (16).

Lastly, In Canada, Hu et al. (28) found that consumption of processed meat increase risk of both proximal and distal colon cancer in men and women (all four OR were between 1.4 and 1.6, all CI:1.0–2.0, 2.2 or 2.4). Bacon intake was particularly associated with risk of colon cancer (proximal and distal) in women.

The estimation of cancer risk associated with meat may be influenced by other dietary factors, as shown clearly in the “dietary pattern” studies cited above (20–22). In those studies, the intake of processed meat was associated with intake of French fries (or potatoes), sweets, cakes, desserts, snacks and alcoholic beverages: These high glycemic index diets, and alcohol intake, may be risk factors for colorectal cancer.

In addition, high-meat diets have been negatively associated with food groups rich in antioxidants and fiber, components which have been associated with a reduced risk of colorectal cancer (4).

Thus, the effect of processed meat consumption on the risk of colorectal cancer may be confounded by other foods, as discussed further in the “Indirect mechanisms” section below. However, red meat intake is more consistently associated with risk than any other dietary factor, except the total energy intake (3, 29).

In summary,

the results of these meta-analyses support the hypothesis that high consumption of red and processed meat may increase the risk of CRC. The few studies published after the metaanalyses also support the evidence, although individual studies are seldom significant. In addition, the risk associated with consumption of one gram of processed meat was two to ten times higher than the risk associated with one gram of fresh red meat. It is thus likely that processed meat contains some components that are more potent than fresh red meat components.

Processed Meat and Cancer AICR

Processed Meat and Cancer

This article appears in the August 7, 2014 issue of AICR's eNews.

Lunch meats bacon, ham, cold cuts – we get more questions about processed meats than any other type of food. It’s not surprising since the headlines can change with every new study. So we put together some answers to your most-asked questions.

What Are Processed Meats?

AICR/WCRF’s expert report and its updates define processed meat as “meat preserved by smoking, curing or salting, or addition of chemical preservatives.” Ham, bacon, sausages, hot dogs and yes, deli meats, are all considered processed meat.

How Does Processed Meat Affect Cancer Risk?

The latest analysis of the global research found that eating even small amounts of cold cuts or other processed meats on a regular basis increases the risk of colorectal cancer.

The report by AICR/WCRF also found that eating high amounts of red meat – over 18 ounces a week (501 gr.)– linked to increased risk of colorectal cancer.

In addition to its link to colorectal cancer, processed meat may also increase risk of heart disease.

How Much Processed Meat Is Safe to Eat?

Processed Meats

Sausage
Bacon
Deli meats
Hot dogs
Ham
Pepperoni
Salami
Corned beef

Research suggests that regularly eating even small amounts of cold cuts, bacon, sausage and hot dogs increase colorectal cancer risk, which is why AICR recommends avoiding these foods, except for special occasions.

The risk continues to rise as processed meat consumption increases. Studies show that compared to eating no processed meat, eating 3.5 ounces every day – a large hot dog – increases colorectal cancer risk by 36%.

Why Does Processed Meat Increase Cancer Risk?

It’s not yet clear exactly why processed meats increase risk for colorectal cancer. Researchers are currently exploring a few possible mechanisms, including:

Nitrates/Nitrites: These are added to processed meats to preserve color and prevent spoilage. In lab studies, these compounds form cancer-causing compounds, carcinogens.
Smoking: Smoked meats contain PAHs (Polycyclic Aromatic Hydrocarbons), substances that are formed at high-heat and considered carcinogenic.
Cooking at high temperatures: Meats cooked at high temperatures can also contain PAHs and heterocyclic amines (HCAs), which can damage DNA.
Heme iron: The heme iron found in red meat may damage the lining of the colon.

What about nitrate/nitrite-free turkey or other deli meats?

These products are relatively new. At this point, more research is needed to distinguish between nitrate/nitrite-free processed meats and the typical hot dogs and luncheon meats with added nitrates and nitrites. Sausage and other processed meat made from turkey or chicken is still smoked, salted, or cured so it is also included among the processed meats to carefully limit.

How to Reduce Overall Risk

When it comes to nutrition and cancer, it’s the healthy choices you make every day that matter most. The occasional hot dog at a baseball game or ham on a holiday is unlikely to increase cancer risk. To decrease your overall risk, try some of these simple swaps:

Replace packaged deli meats with fresh chicken or fish
Instead of bacon, chorizo or salami, try spicy vegetarian sausages.
Replace sausage in chili and sauces with beans like kidney beans, chickpeas and lentils.
Try out different sources of protein like eggs, cottage cheese and hummus.
Use herbs and spices like garlic, fennel seed and chili flakes to add flavor to your dish.

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This article appears in the August 7, 2014 issue of AICR's eNews

IMRT for Locally Advanced NSCLC

Medscape Medical News from the

American Society for Radiation Oncology (ASTRO) 57th Annual Meeting

Medscape Medical News > Conference News
'No Brainer': IMRT for Locally Advanced NSCLC

Zosia Chustecka
October 23, 2015


SAN ANTONIO — New results from one of the largest clinical trials ever carried out in non-small cell lung cancer (NSCLC) could "fundamentally change the way we deliver radiation therapy" for locally advanced disease, says Stephen Chun, MD, from the Department of Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston.

Dr Chun was speaking here at the American Society for Radiation Oncology (ASTRO) 57th Annual Meeting. The new findings show that intensity-modulated radiotherapy (IMRT) was associated with fewer adverse events, including severe pneumonitis, than was standard three-dimensional (3D) conformal radiotherapy (CRT), he said.

"IMRT should be routinely considered for locally advanced NSCLC patients," Dr Chun concluded.

"We predict that the new findings will change practice practices," he commented at a press briefing, explaining that insurance companies do not yet cover IMRT use in lung cancer, although it is covered for prostate, head and neck, and brain cancer. "Their argument has been lack of data," he said, adding that IMRT is more expensive because it is more complex as a result of configuring. He hopes that insurance companies will now be convinced by the new data.

The data come from the RTOG 0617 trial, a phase 3 study that has already shown that higher-dose radiotherapy was not better than low-dose (results presented in 2013). Now, Dr Chun and colleagues have conducted a secondary analysis of the data, focusing on the two different forms of radiotherapy used, in a total of 482 patients.

In this trial, the choice of radiotherapy was left to the physician's discretion; about 47% of patients received IMRT and the rest had standard CRT, Dr Chun told Medscape Medical News.

Because this aspect of the trial not randomized, the IMRT group had larger and more advanced-stage tumors (stage 3B tumors in 38.6% vs 30.3% of patients in the CRT group). Despite this, the patients in the IMRT group had fewer problems.

Patients in the IMRT group had a significantly lower occurrence of severe pneumonitis (defined as lung inflammation that required oxygen, steroids, or mechanical ventilation and/or led to death). The rate was 3.5% compared with 7.9% in the CRT group (P = .046).

Dr Chun noted that the protective effect of IMRT for pneumonitis persisted in multivariate analysis (hazard ratio [HR], 0.44; P=.0653) and was particularly pronounced in large tumors that were bigger than the median size of 460 mL (HR, 0.22; P = .02).

IMRT also significantly reduced radiation doses delivered to the heart, which was highly associated with patient survival. Larger heart radiation volume (V40) was associated with worse overall survival (HR, 1.013; P < .001), and the heart V40 was significantly lower in patients treated with IMRT, Dr Chun noted. In addition, patients treated with IMRT were more likely to complete high-dose consolidative chemotherapy than patients treated with CRT (37% vs 29%; P = .05). "By reducing severe and life-threatening pneumonitis, IMRT can improve patients' quality of life, reduce hospital/intensive care unit admissions, and decrease supplemental oxygen use," Dr Chun said in a statement. "In our study, it seemed that IMRT might also facilitate patients being able to tolerate higher doses of consolidative chemotherapy, which are standard after radiation."

Approached for comment on the study, Henning Willers, MD, PhD, radiation oncologist at the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, welcomed the new data, which support what he has been seeing in clinical practice. The difference with IMRT is clear in patients "so much that in my mind it's a no-brainer that IMRT is better," he told Medscape Medical News. As well as the reduction in severe pneumonitis reported by the trialists, he says that in practice he has seen a dramatic reduction in severe esophagitis: "It is completely eliminated with IMRT," he said, whereas with CRT about 11% to 20% of patients develop grade 3 esophagitis and require feeding tubes.

Insurance companies have opposed covering IMRT for lung cancer, especially Blue Cross and Blue Shield, because of the lack of data to support it, he said. These new data come from a prospective, well-designed clinical trial, he said. Although the choice of radiotherapy was not randomized, and so there may be some institutional bias there, the results clearly show that IMRT is associated with fewer adverse events.

This may be the best data that will be available, he added. Dr Willers said that he cannot see another trial that would randomize between IMRT and CRT being conducted now because clinicians would be unwilling to put their patients in the CRT group, having seen in practice the improved toxicity with IMRT.

The RTOG 0617 study was supported by grants from the National Cancer Institute (NCI) and Bristol-Myers Squibb and Eli Lilly and Company.

American Society for Radiation Oncology (ASTRO) 57th Annual Meeting. Abstract 2 presented October 18, 2015.

Exceptional Responders in Oncology

Medscape Internal Medicine > George Lundberg: At Large at Medscape
COMMENTARY
Exceptional Responders in Oncology: A Response Worth Sharing

George D. Lundberg, MD
Disclosures | October 22, 2015


Those of us active in the field were defining, developing, and maturing evidence-based medicine (EBM) in the late 1980s and all through the 1990s and 2000s. I credit Dr David Eddy[1] with having first published the term in the Journal of the American Medical Association [now called JAMA] and Dr David Sackett[2] with doing the lion's share of early development and promotion.

EBM considers large, randomized, controlled, preferably double-blinded, clinical trials—with big enough numbers to boast statistical power—to be the "Holy Grail," the sine qua non, the absolute essential for establishing medical research information as close to "truth" as you can get.

Of course, the results of such clinical trials were often in conflict with the results of other similar trials. Thus, the field of meta-analysis came to be, to endeavor to get even closer to truth. But there were always those pesky outliers.

Then came some results from the Human Genome Project.[3] We learned—almost in disbelief, and to our group consternation—that often, especially with cancer but also with common cardiovascular and other diseases, the essential "apples-with-apples" comparisons that were so laboriously sought were flawed. When viewed genomically, cancers with like names were, as often as not, mixtures of apples with oranges, and with grapefruit. And maybe even pomegranates. Oh my!

Medians and means were still medians and means. But clinical trials that were considered "failed" statistically may well have been successful for some patients, even those far removed from the mean or median—those outliers.

Now we know that cancer in fact often is many, varied genomic, proteomic, metabolomic diseases wrapped into what was once considered, by location, morphology, and patterns, to be a single cancer diagnosis. That anatomical diagnosis—non-small cell lung cancer, or pancreatic adenocarcinoma, or malignant glioma—must now be divided into types, and those into subtypes, and those into sub-subtypes.

Alexander Pope said, "The proper study of mankind is man."[4] I would further say, "The proper study of me is me," and "The proper study of my cancer would be my cancer."

Most cancer treatment in the United States is not provided in comprehensive cancer centers or within controlled clinical trials. Most cancer patients are treated by practicing, community clinical oncologists. These treatment results are not part of studies, and thus often are not captured and shared with the broader medical community.

Cancer patients may experience "exceptional responses" to therapies. Many cancer researchers are now thinking that some of these cases might be of serious intellectual and scientific value, over and above the obvious clinical value for individual patients.

Cancer Commons, a not-for-profit organization based in Palo Alto, California, is endeavoring to change that by collecting and sharing such valuable therapeutic, experiential information so that others can learn from it. Other possible similar examples of clinical therapeutic responses could then be grouped and compared. (Full disclosure: I was a founder of the organization in 2011. I remain an unpaid advisor and strongly believe in its mission.)

In order to encourage the collection and sharing of information about "exceptional responders," thereby heightening awareness and increasing the opportunity for study, another Palo Alto entity, the Cureus journal of medicine, has teamed up with Cancer Commons to promote the literary competition known as "Exceptional Responders in Oncology". (Disclosure: I am an unpaid executive advisor to Cureus and strong advocate for post-publication peer review).

Please submit your case reports of "exceptional responders" (positive or negative) to Cureus between October 22 and November 23, 2015. All published case reports will be judged by reader/reviewer "crowdsourced" post-publication peer review. There is a monetary prize of $3000 for the winning author(s).

This is an exercise intended to actually find exceptional responders—the further study of whom might unlock some cancer mysteries—as well as to call widespread attention to the importance of the concept of practicing physicians now being able to easily share their important clinical observations with their fellow physicians via true open-access publishing.

Give it a try. Help us improve the world of cancer care.

That's my opinion. I'm Dr George Lundberg, At Large for Medscape.

U.S. FDA Approves YONDELIS® (trabectedin) for the treatment of Liposarcoma or Leiomyosarcoma

U.S. FDA Approves YONDELIS® (trabectedin) for the Treatment of Patients with Unresectable or Metastatic Liposarcoma or Leiomyosarcoma, Two Common Subtypes of Soft Tissue Sarcoma

Approval based on largest Phase 3 study conducted to date in this patient population

HORSHAM, Pa., Oct. 23, 2015 /PRNewswire/ -- Janssen Biotech, Inc. today announced the U.S. Food and Drug Administration (FDA) has approved YONDELIS® (trabectedin) for the treatment of patients with unresectable (unable to be removed with surgery) or metastatic liposarcoma (LPS) or leiomyosarcoma (LMS) who received a prior anthracycline-containing regimen. The approval was based on recently published clinical efficacy and safety data from the Phase 3, randomized, open-label, controlled study (ET743-SAR-3007), which evaluated YONDELIS versus the chemotherapy agent dacarbazine, in patients with unresectable or metastatic LPS or LMS previously treated with an anthracycline and at least one additional chemotherapy regimen.[1]

While approved for both LPS and LMS, YONDELIS is the first treatment to be specifically approved for LPS in the U.S.

"Our academic teams are dedicated to finding new treatments with scientific merit and the promise to improve outcomes for patients with sarcomas. Today's announcement marks a meaningful event built upon years of research, offering new hope for people living with two of the most prevalent subtypes of this serious disease – liposarcoma and leiomyosarcoma – where there are limited available alternatives," said George D. Demetri, M.D.,+ Director of the Ludwig Center at Harvard and Director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute, and principal investigator of the Phase 3 registration trial. "In the clinical trial, YONDELIS significantly increased progression-free survival compared to dacarbazine; this is an important endpoint for these patients, in whom rapid worsening of the disease can lead to worse symptoms and life-threatening situations."

The pivotal Phase 3 study enrolled over 500 patients and demonstrated an improvement in progression free survival (PFS) for patients treated with YONDELIS. The median PFS among the YONDELIS treatment group was 4.2 months (n=345; 95% confidence interval (CI): 3.0 - 4.8 months), while the median PFS in the dacarbazine treatment group was 1.5 months (n=173; 95% CI: 1.5 - 2.6 months), representing a 45% reduction in the risk of disease progression or death with YONDELIS (HR=0.55; 95% CI: 0.44 - 0.70; p<0.001). The final analysis of overall survival (OS) demonstrated a median OS of 13.7 months for the YONDELIS arm and 13.1 months in dacarbazine arm, which was not significant (HR=0.93; 95% CI: 0.75, 1.15; p=0.49). LPS and LMS are subtypes of soft tissue sarcoma (STS) and represent more than 35% of all STS cases.[2] LMS is an aggressive type of STS where smooth muscle cells become cancerous. LMS typically occurs in the uterus, abdominal cavity or blood vessels but can also arise in any part of the body.[3],[4] LPS is comprised of several subtypes and develops in fat cells that become cancerous in any part of the body.[5],[6] Since YONDELIS was first approved in Europe in 2007, approximately 50,000 patients in close to 80 countries have benefited from this therapy across all indications. "The U.S. approval for YONDELIS exemplifies our commitment to improving the health of people living with cancer and addressing unmet needs," said Roland Knoblauch, M.D., Ph.D., Clinical Leader, YONDELIS, Janssen Research & Development, LLC. "We are proud that our Phase 3 study is the largest ever conducted in this patient population and we're delighted that patients in the U.S. can now benefit from the treatment."

The safety profile of YONDELIS in the Phase 3 study was consistent with previous clinical studies. The most serious risks associated with YONDELIS are neutropenic sepsis (severe infections due to decreased white blood cells), rhabdomyolysis (severe muscle problems), cardiomyopathy (heart muscle problems, including heart failure), hepatotoxicity (liver problems, including liver failure), anaphylaxis, and extravasation (leakage of YONDELIS out of the vein during infusion) leading to tissue necrosis (tissue cell damage or death) and embryofetal toxicity. Among the 378 patients who received at least one dose of YONDELIS in the randomized trial, the most common (>20%) adverse reactions were nausea (75%), fatigue (69%), vomiting (46%), constipation (37%), decreased appetite (37%), diarrhea (35%), peripheral edema (28%), dyspnea (25%) and headache (25%). The most common (>5%) Grade 3-4 laboratory abnormalities were neutropenia (43%), increased alanine transaminase (ALT) (31%), thrombocytopenia (21%), anemia (19%), increased aspartate aminotransferase (AST) (17%) and increased creatine phosphokinase (6.4%).

The recommended dose of YONDELIS is 1.5 mg/m2 administered as an intravenous infusion over 24 hours through a central venous line every 21 days (3 weeks) until disease progression or unacceptable toxicity in patients with normal bilirubin and AST or ALT, less than or equal to 2.5 times the upper limit of normal.

Melanoma Therapy Injected Directly Into Lesions

International Approvals > Medscape Medical News
EU Likes Melanoma Therapy Injected Directly Into Lesions

Zosia Chustecka
Disclosures | October 23, 2015


A new treatment for melanoma that is injected directly into the lesion has been recommended for approval in Europe.

The product, talimogene laherparepvec (Imlygic, Amgen), described as the first oncolytic immunotherapy, is destined for use in adults with unresectable melanoma that is regionally or distantly metastatic (stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral disease, according to the European Medicines Agency (EMA).

This product has also recently been recommended for approval in the United States, where it will be marketed as T-VEC. A US Food and Drug Administration decision is due by October 27.

Talimogene laherparepvec is a first-in-class advanced therapy medicinal product (ATMP), derived from a virus that has been genetically engineered to infect and kill cancer cells. The recommendation for approval was based on an assessment carried out by the Committee for Advanced Therapies (CAT), the European agency's expert committee for ATMPs.

The EMA explains that the product is derived from a herpes simplex virus-1 that has been genetically engineered to infect and replicate within cancer cells and to produce the protein granulocyte macrophage colony-stimulating factor (GM-CSF). It is thought to work in two ways. It enters the tumor cell and uses the cell's energy stores to replicate, eventually overwhelming the cell and causing it to die. By producing the protein GM-CSF, it also stimulates the patient's immune system to recognize and destroy tumor cells. Once an infected tumor cell dies, copies of the virus are released into the patient's bloodstream to infect more tumor cells. Although the product can also enter healthy cells, it is not able to replicate in these healthy cells and so it does not kill them, the agency points out.

The recommendation for approval is based on efficacy data that come from one randomized controlled trial (known as OPTiM) in adults with unresectable regionally or distantly metastatic melanoma. The study enrolled 436 patients, with 295 patients treated with talimogene laherparepvec compared with 141 patients treated with GM-CSF.

Analysis of the subset of patients in the study whose disease had not spread to the lung or other internal organs (249 patients with stage IIIB, IIIC, and IVM1a disease) showed a benefit in patients treated with talimogene laherparepvec, with a durable response rate of 25% vs 1% with GM-CSF alone, according to the EMA.

A durable response was defined as disappearance of the tumors or at least 50% reduction of tumors lasting at least 6 months, until patients' health declined or they required subsequent therapy, the agency noted.

An exploratory analysis in these patients suggested improvements in survival in patients treated with talimogene laherparepvec, the agency noted, but it points out that "this is not yet fully clear." It addition, there are no comparative data with other approved therapies for melanoma, which have already been shown to improve overall survival.

Overall, the expert committee considered that the product is relatively well-tolerated in patients with cancer and concluded that the medicine's benefits outweigh its risks, the agency stated.

The OPTiM study was published in May in the Journal of Clinical Oncology (2015;33:2780-2788), as reported at the time. The data in the publication are a little different to what the EMA cites in its press release, as in the publication, the durable response rate with the product was reported as 16.3% vs 2.1% with GM-CSF. In addition, it reports complete responses in 10.8% of patients on the product, compared with <1.0% on GM-CSF. "Durable responses to T-VEC were seen across all disease stages tested, including in patients within each subset of stage IV disease," said the authors, led by Howard L. Kaufman, MD, FACS, from the Rutgers Cancer Institute of New Jersey in New Brunswick. Noting that T-VEC could potentially delay or prevent relapses or preclude progression to later disease stages, they add that it "represents a novel potential new treatment option for patients with injectable metastatic melanoma and limited visceral disease." Dr. Kaufman told Medscape Medical News at the time: "Despite all the advances in the field of melanoma, many patients do not respond to treatment."

"Some patients are not able to tolerate some of the drugs for a variety of reasons, and so any agent that has some activity is important," he added.

"Interestingly, I think one of the more important things in the data is that nearly 11% of the patients had a complete response.... We don't often see that in melanoma studies. I think that's very significant," he commented.

Doctors Aren't Doing Enough to Get Patients to Exercise

Medscape Orthopedics
Sideline Consult
Doctors Aren't Doing Enough to Get Patients to Exercise

Bert R. Mandelbaum, MD, DHL (Hon)


A Sports Doctor's Most Important Job

Like most physicians in the United States, sports medicine specialists get paid for fixing problems, not for preventing them. Patients come to us with a torn anterior cruciate ligament (ACL) injury or ulnar collateral ligament. We operate or prescribe therapy and coach them through rehabilitation. After performing these services, we get paid our fees.

But I believe that we all have a higher calling. Our most important job is to motivate our patients to take control of their fitness—and to get their family members to join them. And in the long run, what's best for our patients is best for us as well.

The idea that doctors should prescribe exercise goes back to the dawn of medicine. In the Greek pantheon, Panacea and Hygeia, the goddesses of intervention and prevention, were held in equal esteem as daughters of Aesculapius, the god of medicine. Even before Hippocrates, Herodicus, a fifth-century BCE Athenian physician, recommended treating patients with exercise.

What these forefathers of medicine understood, and what too many of us have forgotten, is that human beings are hardwired to be athletes. Homo sapiens evolved to go out and hunt and gather. That history is embedded in our genes. If we don't exercise, our bodies don't function well. And lack of exercise is contributing to most of the common diseases we now face.


The Leading Cause of Preventable Death

As Steven N. Blair, PhD, a professor of exercise science, epidemiology, and biostatistics at the Arnold School of Public Health at the University of South Carolina, has noted, inactivity has surpassed obesity and smoking as the leading cause of preventable death in the world.[1]

A rational healthcare system would provide incentives for physicians to encourage exercise. The potential impact of getting just a few people to exercise more can be huge. Diabetes costs the US healthcare system $245 billion per year.[2] Stroke adds another $34 billion.[3] Sarcopenia adds $19 billion.[4] All could be mitigated with exercise programs.

But the fact that we don't work in a rational system doesn't relieve us of the responsibility to lead, inspire, and motivate.


Three Vital Roles for Physicians

Physicians can reassume this vital role in three ways. First, we can serve as role models. We must show our patients that it's possible to stay fit despite the pressure of our demanding work. We should all set aside at least a few hours each week for our personal fitness.

Second, we can speak to our patients one-on-one. I'm always impressed by how ready my patients are to receive the encouragement to exercise, even those who haven't been active in many years. Just because someone is 150 pounds overweight, let's not believe that that's their desired situation. They're looking for a spiritual and emotional solution to their problem.

Likewise, when talking to some of our elderly patients, it may be tempting to conclude that their years of activity are behind them. But the research shows that exercise can have an important impact at any age. Master athletes have fitness levels equivalent to the average for people 20 years younger.[5]

People who play sports late in life also experience improvements in body composition and lipid profiles. They improve in almost every category, especially their quality of life.[5] In a study in Denmark, 45-year-old sedentary women who took up soccer significantly increased their bone density.[6]

I challenge people to just go out for a mild walk some early morning and see how they feel at the end. Virtually 100% of the time, they come back and say, "I feel great." We've got endorphins that make us feel good just by doing simple exercise. And it doesn't cost anything. Lately I've been coaching patients to use smartphone apps that help them track their calories. This allows them to compare a variety of activities and choose the type that suits them best.

Third, we can seek opportunities to speak to larger groups. We can approach schools, YMCAs, senior centers, and civic groups and offer to speak about aspects of fitness and injury prevention.

When I'm talking to large groups, I say, "My role here is to motivate and inspire you. I'd like all the athletes to stand up."

Typically, about 50% stand up. Then I say, "How many did high school sports, hike, or garden?"

Before you know it, we get everyone standing up. I say, "That's right. We are all athletes. It's the only way we are supposed to be as human beings."

Participating in sports is in our genes. Each of us wanders off course, whether because of babies or jobs. But once we discover what's inside us, we can get back on track.

Aside from a few research grants, I have never been paid to think in terms of prevention. But that's always been a focus of my work. It's why I helped create warm-up programs to prevent ACL injury. It's why I wrote The Win Within: Capturing Your Victorious Spirit.[7]

You're not likely to get reimbursed directly for this kind of work. But taking a public role can raise the profile of your practice and build your patient base.

And you can save more lives with inspiration than you ever will with a scalpel.

Vitamins and Supplements for Athletes?

Medscape Orthopedics
Sideline Consult
Vitamins and Supplements for Athletes? Only in Special Cases

Bert R. Mandelbaum, MD, DHL (Hon)
Disclosures | October 21, 2015


Supplements Send Thousands to the ED

Sports medicine physicians get questions all the time about nutritional supplements and performance-enhancing drugs. We hear from professional athletes looking for an edge that could transform their careers and from amateurs who don't have to submit to drug tests. And with the news reported this month that supplements send 23,000 Americans to emergency departments every year, those questions are taking on a new urgency.[1]

The supplement business is lucrative; it took in about $32 billion in 2013.[2] Too often the companies behind these pills are selling hype and false hope. People hear marketing fluff on TV and can't sort it out.

So how can we help athletes make the right choices?


Risks of Vitamins and Supplements

It would be dishonest to start by saying that no drug is going to help your performance. Anabolic steroids can make you bigger and stronger.[3] Caffeine and creatinine can provide some temporary zip and zest.[3] A handful of other substances have shown a handful of other benefits.[3]

But all of these substances come with real risks. Steroids can raise the risk for cardiovascular disease and male infertility.[3] I have seen several deaths that I can attribute to some combinations. Caffeine at high levels can impair concentration and cause gastrointestinal upset.[3] Creatinine can cause muscle cramps and weight gain.[3]

And dangers lurk in unexpected places. One of the problem substances I see the most is cannabis. Athletes are around marijuana a lot. Some don't realize it is banned by the US Anti-Doping Agency, and not just at the lowest levels.[4]

Even some everyday foods can cause athletes to run into trouble. In some countries, like Mexico, even beef may be tainted by clembuterol, an anabolic steroid.[5]

The National Collegiate Athletic Association (NCAA) sanctions athletes for a serum caffeine level above 15 mcg/mL.[6] It would take about 15 cups of coffee to get there, but it happens.[6]

Otherwise innocuous vitamins are often bottled with dangerous contaminants or banned drugs. If you are taking care of athletes, it is your role to help educate them to understand that almost 25% of all supplements may be tainted with some banned substance.[7]


Nothing Replaces a Balanced Diet

One point I make in these conversations is that vitamins are extraneous for most people who eat a balanced diet. A good example is eicosapentaenoic acid (EPA), an omega-3 fatty acid. In the late 1970s, researchers studied Inuit who were eating only fish and had little incidence of cardiac disease.[8]

Some people extrapolated from this finding that folks in the United States who were eating Big Macs could avoid heart disease by swallowing fish oil supplements without changing their diet. Forty years later, no one has proved this.[8] The story of vitamin E is similar.[9] Over and over, we have isolated one molecule from a healthy diet of whole foods and expected it to work miracles. And over and over, we've been disappointed.

Some athletes hope that their supplements can compensate for the unhealthy foods they eat. But in the case of antioxidants, that doesn't seem to work. Researchers have measured free radicals and watched the levels shoot up when their subjects drank a pint of vodka. With antioxidants, you can deflect that a little, but the effect is not robust enough to counteract the negative effects.[10]

What is a balanced diet? The American College of Sports Medicine and the Academy of Nutrition and Dietetics guidelines are helpful. For those who want more specific recommendations, I always say that the Mediterranean diet is by far the best way to go. It features fish, fruits, nuts, and vegetables and not much beef and animal fat. And it's been shown in prospective trials to extend life.[11]

I recommend adding or subtracting carbohydrates, proteins, and fats based on which of these macronutrients an individual needs. The needs of the couch potato are very different from those of the triathlete. And the needs of the 16-year-old on a high school track team are different from those of a 70-year-old master runner.
A Few Exceptions

However, there are specific situations where I do recommend supplements. For example, when athletes are exercising so hard that they lose a lot of electrolytes, it may be hard for them to compensate for these deficits with diet alone, especially in very hot and humid climates.[12] In these cases, I think it's a good thing to take multivitamins and particularly magnesium, calcium, and zinc.

A growing number of people are vitamin-D deficient, and this has been associated with stress injuries and even cancer. I also sometimes recommend vitamin D, calcium, and sometimes iron for competitive female athletes. As athletic women grow older, their need for calcium goes up, especially when their hormones are naturally cycling down.[13]

Athletes who truly need supplements should look for products that are independently certified to contain the ingredients listed on the label and not contaminants or substances banned for athletic competition. One organization that provides such certification is NSF International, through its Certified for Sport program.[14]

Amateur athletes don't have to contend with drug tests. They're in a position to consider some substances that, from a therapeutic perspective, are normally off-limits to the professional or elite athlete. For example, male master athletes may want to consider testosterone supplements if they are coping with androgen deficiency, which can reduce their muscle mass and strength.[15]

Female master athletes may benefit from estrogen replacement because they run an increased risk for injury to the joints with reduced estrogen levels.[16] Each of these judgments and decisions should always be made in concert with a physician, as there are significant risks, as well potential benefits, in both cases. Take the initiative. Broach this subject with your patients who are athletic.
Risky Even When Indicated

Recently we have observed that testosterone supplementation can increase the risk for thrombosis.[15] Estrogen replacement can increase the risk for breast cancer and heart disease.[16] If athletes are truly deficient in a hormone, then discuss the pros and cons of supplementation with them before writing a prescription.

None of this is exciting or dramatic. In fact, it pretty much boils down to moderation and common sense. But as sports medicine professionals, that's sometimes all we have to sell.

Safety Profile of HPV Vaccines

EMA Commences Review to Further Clarify Safety Profile of HPV Vaccines. ESMO

The review will focus on rare reports of complex regional pain syndrome and postural orthostatic tachycardia syndrome

Date: 19 Oct 2015
Topic: Epidemiology/Etiology/Cancer Prevention

The European Medicines Agency (EMA) has started a review of human papillomavirus (HPV) vaccines to further clarify aspects of their safety profile. These vaccines have been used in around 72 million people worldwide and their use is expected to prevent many cases of cervical cancer and various other cancers and conditions caused by HPV. The review does not question that the benefits of HPV vaccines outweigh their risks.

Cervical cancer is the 4th most common cause of cancer death in women worldwide, with tens of thousands of deaths in Europe each year despite the existence of screening programmes to identify the cancer early.

As for all licensed medicines the safety of these vaccines is monitored by the Agency’s Pharmacovigilance Risk Assessment Committee (PRAC). The current review will look at available data with a focus on rare reports of two conditions: complex regional pain syndrome (CRPS, a chronic pain condition affecting the limbs) and postural orthostatic tachycardia syndrome (POTS, a condition where the heart rate increases abnormally after sitting or standing up, causing symptoms such as dizziness and fainting, as well as headache, chest pain and weakness).

Reports of these conditions in young women who have received an HPV vaccine have been previously considered during routine safety monitoring by the PRAC but a causal link between them and the vaccines was not established. Both conditions can occur in non-vaccinated individuals and it is considered important to further review if the number of cases reported with HPV vaccine is greater than would be expected.

In its review the PRAC will consider the latest scientific knowledge, including any research that could help clarify the frequency of CRPS and POTS following vaccination or identify any causal link. Based on this review, the Committee will decide whether to recommend any changes to product information to better inform patients and healthcare professionals.

While the review is ongoing there is no change in recommendations for the use of the vaccine.

FDA Expands Nivolumab Lung Cancer Approval

FDA Expands Nivolumab Lung Cancer Approval
Jason M. Broderick @jasoncology
Published Online: Friday, October 9, 2015
Dr. Richard Pazdur

Richard Pazdur, MD
Acting 3 months ahead of schedule, the FDA approved nivolumab (Opdivo) for patients with nonsquamous non–small cell lung cancer (NSCLC) who progress on or following platinum-based chemotherapy, or EGFR- or ALK-targeted agents in patients harboring those mutations.

The approval is based on data from the phase III CheckMate-057 trial, in which second-line nivolumab reduced the risk of death by 27% versus docetaxel in patients with nonsquamous NSCLC, including a 60% risk reduction among patients with the highest levels of PD-L1 expression.

“There is still a lot to learn about the PD-1/PD-L1 pathway and its effects in lung cancer, as well as other tumor types,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “While Opdivo showed an overall survival benefit in certain non–small cell lung cancer patients, it appears that higher expression of PD-L1 in a patient’s tumor predicts those most likely to benefit.”

Nivolumab was previously approved in March 2015 for patients with squamous cell NSCLC who have progressed on or after platinum-based chemotherapy. A diagnostic for PD-L1, the IHC 28-8 pharmDx test, was approved along with nivolumab, to help guide treatment decisions for patients with both histologies of NSCLC. The test is a "complementary," not a "companion," diagnostic, meaning its use is not mandated prior to administering nivolumab, according to Bristol-Myers Squibb, the developer of the drug.

The phase III open-label CheckMate-057 trial randomized 582 patients with advanced nonsquamous NSCLC after the failure of platinum-based doublet chemotherapy to nivolumab at 3 mg/kg IV every 2 weeks (n = 292) or docetaxel at 75 mg/m2 intravenously every 3 weeks (n = 290). The treatments were administered until disease progression or unacceptable toxicity.

Patients received a median of 6 and 4 doses in the nivolumab and docetaxel arms, respectively. Patients had an ECOG performance status of 0 or 1. The median patient age was 61 years in the nivolumab arm and 64 years in the docetaxel cohort.

Prior maintenance with bevacizumab, pemetrexed, or erlotinib was allowed, as was TKI therapy for known EGFR mutations or ALK translocation. Forty-percent and 38% of patients in the nivolumab and docetaxel arms, respectively, had received prior maintenance therapy. In the nivolumab arm, 15% of patients were EGFR-positive and 4% were ALK-positive, with comparable rates of 13% and 3%, respectively, in the docetaxel group.

Overall survival (OS) was the primary endpoint, with secondary objectives focused on progression-free survival (PFS), objective response rate (ORR) per RECIST v1.1, efficacy by PD-L1 expression, and safety.

The study was stopped early after an independent monitoring panel determined the primary endpoint of improved OS had been reached. Eligible patients were allowed to continue treatment or cross over to the nivolumab arm in an open-label extension of the study.

Data from an interim analysis presented at the 2015 ASCO Annual Meeting showed a median OS of 12.2 months with nivolumab versus 9.4 months with docetaxel (HR, 0.73; 96% CI, 0.59-0.89; P = .00155), with a 1-year OS of 50.5% versus 39.0%, respectively.1



Updated long-term OS data for CheckMate-057 were recently presented at the 2015 European Cancer Congress2 and simultaneously published in The New England Journal of Medicine. At a minimum follow-up of 17.2 months, the OS rate with nivolumab was 39% compared with 23% for docetaxel. There remained a 2.8-month OS benefit with nivolumab versus docetaxel (HR, 0.72; 95% CI, 0.60-0.88; P <.001). ORR was 19% with the PD-1 inhibitor compared with 12% with chemotherapy (Odds Ratio = 1.72; 95% CI, 1.1-2.6; P = .0246). Complete and partial response rates were 1% and 18% in the nivolumab arm and <1% and 12% in the docetaxel group, respectively. The stable disease rate was 25% and 42% with PD-1 inhibition and chemotherapy, respectively. Median time to response was 2.1 months with nivolumab versus 2.6 months with docetaxel. Median duration of response was 17.2 months versus 5.6 months in the nivolumab and control arms, respectively. Fifty-two percent of the nivolumab responses are still ongoing compared with 14% of the docetaxel responses. Median PFS was comparable between the cohorts at 2.3 months in the nivolumab arm compared with 4.2 months in the docetaxel group (HR, 0.92; 95% CI, 0.77-1.11; P = .393). One-year PFS favored nivolumab at 18.5% versus 8.1% for the control arm. The researchers measured PD-L1 levels in pretreatment tumor biopsies with the Dako automated IHC assay. Higher PD-L1 expression was associated with improved survival outcomes among the 78% of patients for whom PD-L1 status was detectable. In PD-L1–positive patients (PD-L1 expression on ≥1% of tumor cells), median OS was improved by 41% among 123 individuals treated with nivolumab versus 123 patients who received docetaxel (median OS = 17.2 months vs 9.0 months; HR , 0.59). The OS benefit continued to rise as PD-L1 levels increased. The reduction in the risk of death was 57% (median OS = 18.2 months) and 60% (median OS = 19.4 months) for patients expressing PD-L1 on ≥5% and ≥10% of their tumor cells, respectively. The researchers did not observe a similar OS benefit among patients with low or undetectable PD-L1 levels. Median OS was 10.4, 9.7, and 9.9 months among patients with PD-L1 expression levels <1%, <5%, and <10%, respectively. “Non-small cell lung cancer is a difficult to treat disease with high mortality, and patients with squamous and non-squamous NSCLC often respond differently to treatment,” Roy Herbst, MD, PhD, chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, said in a statement. “Opdivo is becoming an important treatment option for more patients with previously treated metastatic NSCLC, and is a welcome addition to our therapy of this disease.”



Nivolumab was well tolerated and had a better safety profile than docetaxel. Among patients evaluable for safety, all-grade adverse event (AE) rates were 69% versus 88% in the nivolumab versus docetaxel arms, respectively. The most common all-grade AEs with nivolumab versus docetaxel were fatigue (16% vs 29%), nausea (12% vs 26%), decreased appetite (11 vs 16%), asthenia (10 vs 18), and diarrhea (8% vs 23%).



Grade 3-5 adverse events were reported in 10.5% of the nivolumab arm compared with 53.7% of the docetaxel cohort. The most common grade 3/4 AEs with nivolumab were fatigue, nausea, and diarrhea, at 1% each. Twenty-seven percent of patients in the docetaxel arm had grade 3/4 neutropenia versus 0 in the nivolumab arm.



Toxicity-related discontinuations occurred in 4.9% of patients receiving nivolumab compared with 14.9% of those treated with chemotherapy. Systemic therapy was administered to 42.1% and 49.7% of patients who discontinued nivolumab and docetaxel, respectively. No treatment-related deaths occurred in the nivolumab group compared with 1 in the docetaxel arm.



With the approval, nivolumab joins pembrolizumab as the second PD-1 inhibitor approved for second-line NSCLC across all histologies. Pembrolizumab was recently approved for patients with NSCLC who progressed on or after platinum-containing chemotherapy or EGFR-or ALK-targeted agents in patients harboring those mutations.


However, unlike nivolumab, pembrolizumab is only approved for patients with PD-L1–positive tumors, as determined by the PD-L1 IHC 22C3 pharmDx companion diagnostic that was simultaneously approved with the drug.
- See more at: http://www.onclive.com/web-exclusives/fda-expands-nivolumab-lung-cancer-approval#sthash.2iX4Quhw.dpuf

Cancer Research in the Next Decade

ASCO Reports
A Blueprint for Cancer Research in the Next Decade


Tremendous progress has been achieved over the 50 years since the American Society of Clinical Oncology was founded. Investment in cancer research has increased dramatically, spurring major increases in survival and a revolution in our biological understanding of cancer. Many of these advances are highlighted in the Cancer Progress Timeline.

But there is still an urgent need to accelerate the pace of clinical cancer research, the engine that drives progress against the disease. Nearly 500,000 people die from cancer in the United States each year, and the disease is projected to become the nation's leading killer in the years ahead. Worldwide, the burden of cancer is growing quickly.


A New Era of Clinical Research

Cancer science is undergoing revolutionary change. Thanks to a rapidly growing understanding of the biology of cancer, treatments can increasingly be targeted to the molecular "on-off" switches that drive uncontrolled growth of cancer cells. Cancer is increasingly defined – and treatments developed – according to molecular characteristics, not only location in the body. At the same time, new technologies – from fields such as nanotechnology, medical imaging and health information technology (HIT) – are leading to entirely new ways to develop therapies.

If the promise of these advances is fully realized, cancer patients will benefit from treatments that are more personalized, more efficient and more effective.


The Challenge: A System Unprepared for the Molecular Era

Our nation's clinical and translational research system is not fully equipped to deliver on the potential brought by recent scientific and technological advances:

Current drug development approaches are not equipped to capitalize on our new knowledge. Researchers have a limited understanding of which molecular pathways are most important to target and a lack of diagnostics to identify patients with these key molecular markers. Financial and regulatory barriers hinder companies' and researchers' ability to collaborate on new approaches.

Clinical trials – involving rigorous studies that test the safety and efficacy of new therapies in people – have not kept pace with personalized cancer medicine. Current trial designs lack the flexibility to provide quick answers about treatments tailored to specific groups of patients who are defined by their molecular characteristics. At the same time, clinical research efforts have been weakened by a labyrinth of regulatory requirements and years of under-funding.

The promise of health information technology is only beginning to be realized. Limited, uncoordinated and inconsistent use of HIT tools to date, including electronic health records and other, more advanced technologies, has inhibited efforts to accelerate research and improve patient care.


A Vision and Recommendations for the Future

In November 2011, ASCO released Accelerating Progress Against Cancer: ASCO's Blueprint for Transforming Clinical and Translational Cancer Research, presenting a vision for the next decade, in which cancer research and patient care become significantly more targeted, efficient and effective. The Blueprint includes real-world recommendations to policymakers and the cancer community in three key areas:

Establish a new approach to therapeutic development, driven by our more thorough understanding of cancer biology and the advent of new technologies.
Identify and prioritize the molecular targets that have the greatest promise to extend patients' lives.
Incentivize collaboration that encourages researchers to pursue high-priority targeted therapies and diagnostics in combination.
Ensure more aggressive and timely development of biomarkers and diagnostic tests to guide treatment decisions and speed research.
Design smarter, faster clinical trials to provide evidence for effective treatments targeted to patients most likely to benefit.
Prioritize trials with the greatest potential benefits for patients, or that address clear unmet needs. Also, shift away from trials that promise only marginal improvements in care.
Develop common standards for flexible trial designs that allow researchers to demonstrate results with smaller populations, selected based on the molecular characteristics of their disease.
Revitalize the National Cancer Institute's Clinical Trials Cooperative Group Program (see sidebar), including full implementation of the Institute of Medicine 2010 report, A National Clinical Trials System for the 21st Century.
Harness advances in health information technology to seamlessly integrate clinical research and patient care.
Use health information tools, including electronic health records and "rapid learning" systems like ASCO’s CancerLinQ, to enable the experiences of all patients to inform our understanding of the effectiveness and safety of treatments, and to help us focus on the most important research questions.
Standardize electronic health records, harmonizing data fields and ensuring secure patient and provider access to information at any time.
Develop industry standards for working with, storing and capturing information from biospecimens (tissue and blood samples), which are essential to identifying and evaluating new therapeutic targets.
Ensure that advances protect patient privacy, while enabling information sharing and intellectual property protections to support HIT innovation.

Exercise and Survival in Cancer

Medscape Medical News > Oncology
Does Exercise Improve Survival in Cancer?

Roxanne Nelson, RN, BSN
October 15, 2015

When it comes to cancer, a growing body of evidence supports the premise that regular physical activity may play a protective role and decrease the risk for many types of the disease. Exercise may also temper the adverse effects of treatment and help in recovery and rehabilitation when cancer therapy has ended.

But for all of its benefits, does exercise affect cancer outcomes? Do patients who regularly engage in physical activity have a better shot at survival, and do they lower their risk for disease recurrence?

The answer to that question remains up in the air. The jury is definitely still out, with no definitive agreement among the cancer community, as highlighted in a recent "Cross Talk" article published in Cancer World.

The New Chemo?

The role of regular physical activity as a way of reducing cancer risk has been embraced by many experts in the cancer community, as well as organizations such as International Agency for Research on Cancer. The 12-point official guide from the European Union on how to lower your cancer risk puts physical activity in the number 4 slot: "Be physically active in everyday life. Limit the time you spend sitting."

But as the Cancer World article points out, the benefits of exercise are more controversial for those who already have cancer. While no one is disputing that exercise can be beneficial, there is disagreement as to the strength of current evidence regarding exercise and its role in survival.

One advocate highlighted in the article is Thierry Bouillet, MD, an oncologist at Avicenne Hospital in Paris, France, who feels that physical activity should be prescribed to women with early breast cancer, along with their regular therapeutic regimen.

The premise for this is based in part on the results of an analysis published in April, from the scientific commission of the National Federation Sport and Cancer CAMI in France. This review of 8 studies looked at how physical activity affected survival in patients with localized breast cancer (Crit Rev Oncol Hematol. 2015;94:74-86). Led by Dr Bouillet, the authors reported that "a physical activity higher than 8–9 metabolic equivalent task (MET)-hour per week was associated with a 50% reduction in mortality from both cancer and all causes."

This translated into a benefit of 4% to 6% in terms of 5-year and 10-year survival, the "same benefit as chemotherapy," Dr Bouillet told Cancer World.

The studies in the review were observational, but Dr Bouillet still felt that they built a "credible picture" because they were large and accounted for important confounders. He also pointed to randomized controlled trials that suggest exercise helps patients feel and function better, as well as help their social and psychological functioning. Taken together, these factors may affect survival.

The CAMI federation began in 1998, with Dr Bouillet as one of the founding members. It now has almost 60 partner institutions across France that run courses in a variety of different physical activities, everything from the martial arts to modern dance, and the programs are adapted for people with different types of chronic medical conditions. According to the article, the programs are now increasingly being offered by hospitals, such as the Institut Gustave Roussy in Villejuif, France, which now holds dance and karate classes.

The principle of prescribing physical activity that is adapted to the patient's "pathology, physical abilities and medical risk" was also recently introduced as an amendment into a new piece of health legislation in France, the "Loi de la Santé." The amendment sets the framework for providing this type of service, including the responsibilities for training physicians in prescribing adequate physical activity.

Cancer World also points to a controversial summary statement that was published in association with the amendment, which refers specifically to breast cancer treatment. While it discusses the more proven benefits of physical activity for counteracting fatigue, it mentions the effect in reducing recurrences and increasing survival chances by more than 50%.
But on the other side of the fence, the feeling is that evidence to promote exercise as a means of improving the odds of survival and preventing recurrence is just not there.

As Cancer World points out, earlier this year the consensus panel of the St Gallen International Breast Cancer Conference found that there was insufficient evidence to include physical activity in adjuvant therapy clinical guidelines for treating patients with early-stage disease. The panel did, however, endorse prescribing both physical activity and weight loss for their general health benefits.

One expert who advocates the need for better evidence is Pam Goodwin, MD, a medical oncologist at the University of Toronto's Mount Sinai Hospital in Canada, who has conducted a great deal of research on lifestyle factors associated with breast cancer.

Dr Goodwin argues that the evidence for an effect of greater physical activity on cancer outcomes in early breast cancer is "simply not strong enough to tell patients their breast cancer outcomes will be improved if they become more active or lose weight."

"The St Gallen adjuvant therapy guidelines focus on breast cancer specific survival and reduction in risk of recurrence," she told Cancer World. "It wasn't that I or anybody else was opposed to having breast cancer patients who are interested in being physically active be active — there's no problem with that. The issue is that we don't have the evidence to tell them that it will improve their breast cancer outcomes."

Dr Goodwin also doesn't put much faith in large series of observational studies because the results often don't pan out. She uses the example of hormone replacement therapy, for which observational studies showed that the benefits outweighed the risks. But when randomized studies were done, they showed an increase in breast cancer risk and "a lot of the added benefits we thought existed didn't."

Julie Gaillot, from the French National Cancer Institute INCa, says that there is still uncertainty about the effect on survival. As for the amendment to the Loi de la Santé, she stated that INCa was not consulted and that, on the basis of current evidence, it is incorrect to suggest that physical activity can lead to a 50% reduction in mortality risk.

But Gaillot backs the general principle that physicians should be encouraging patients to be more active and that a change of mentality is needed. "It's hard for doctors to introduce physical activity because they are not trained and educated about the benefits of exercise for people who are ill, whether it's cancer or other chronic illnesses, or in the general population," she told Cancer World.

INCa has the responsibility to provide advice to the public, she noted, but will provide only information that is based on validated evidence. This primarily means evidence that comes from randomized controlled trials on the benefits on fatigue, quality of life, body composition, and fitness — and not just about participation in sports but more generally adopting a less sedentary lifestyle. At the current time, they will not be endorsing any specific benefit on cancer survival because more solid evidence is needed.

More solid data may be on the way, as Cancer World notes that several randomized controlled trials that are ongoing or about to start will scrutinize the effect of physical activity and weight loss on cancer prognosis.

One is the CHALLENGE trial, led by the National Cancer Institute of Canada, which is investigating the effect of exercise on recurrence in colon cancer. Another that is about to be launched will investigate the effect of weight loss on breast cancer outcomes. That study will be led by Jennifer Ligibel at the Dana-Farber Cancer Institute in Boston. While these studies will take time to show results, the hope is that they will generate more reliable evidence.

More Support for Further Evidence

Medscape Medical News also spoke with two experts about this issue, and both agree that more evidence is needed as far as a survival benefit.

"I would take the same position as Pam Goodwin," said Kerry S. Courneya, PhD, professor and Canada Research Chair in Physical Activity and Cancer, University of Alberta, Edmonton, Canada.

"There is good evidence for benefits both during and after treatments for several symptoms and some aspects of quality of life," he noted, "but there is insufficient evidence that exercise will improve cancer outcomes."

Anne McTiernan, MD, PhD, from the Fred Hutchinson Cancer Research Center, Seattle, Washington, agrees with the St Gallen recommendations.

"Many studies have shown that cancer survivors who are physically active have improved prognosis," Dr McTiernan told Medscape Medical News. "However, the observational data from which these results come cannot control for potential confounding factors, such as presence of undetected micrometastases, which can cause fatigue and impact exercise levels."

Mediterranean Diet and Breast Cancer

From Medscape Education Clinical Briefs
Can a Mediterranean Diet Avert Breast Cancer?

News Author: Nick Mulcahy
CME Author: Laurie Barclay, MD




Clinical Context

Since 2008, the global incidence of breast cancer has risen by more than 20%, and it is the leading cause of cancer in women. Although findings from some observational studies suggest that the Mediterranean diet (MeDiet) may lower breast cancer risk, there have been no previous findings from randomized trials.

The goal of this secondary analysis of the randomized PREDIMED (Prevención con Dieta Mediterránea) trial by Martínez-González and colleagues was to compare the impact of 2 interventions of the MeDiet vs advice to follow a low-fat diet (control) on breast cancer incidence. Original findings from the PREDIMED trial showed that following the MeDiet -- which features vegetables, fruits, fish, and olive oil -- was associated with a lower risk for cardiovascular disease.


Study Synopsis and Perspective

The MeDiet appears to protect against more than just cardiovascular disease -- it might also prevent breast cancer, according to results from the randomized controlled PREDIMED trial.

The diet is characterized by an abundance of plant foods, fish, and olive oil and has been repeatedly shown to be cardioprotective in major clinical trials.

The PREDIMED study, conducted from 2003 to 2009, is one of those trials. It was stopped early because of the cardiovascular benefit seen with a MeDiet, compared with a low-fat diet.

The researchers now report on breast cancer incidence -- a secondary outcome. And the news is promising.

"The results of the PREDIMED trial suggest a beneficial effect of a MeDiet supplemented with extra-virgin olive oil in the primary prevention of breast cancer," write the study authors, led by Miguel A. Martínez-González, MD, from the Instituto de Salud Carlos III in Madrid, Spain.

Importantly, this randomized trial is the first to see the effect of a long-term dietary intervention on breast cancer incidence.

Of the 4282 postmenopausal women involved in the 3-group trial, there were 35 confirmed incident cases of breast cancer. Median follow-up was 4.8 years.

The observed rates for breast cancer (per 1000 person-years) were 1.1 for those assigned to the MeDiet supplemented with extra-virgin olive oil, 1.8 for those assigned to the MeDiet supplemented with nuts, and 2.9 for those assigned a low-fat diet.

The risk for malignant breast cancer was 62% lower in women randomly assigned to the MeDiet supplemented with extra-virgin olive oil than in those randomly assigned to the low-fat diet (hazard ratio, 0.38; P = .02).

The MeDiet supplemented with nuts was also associated with a lower risk, but it was not statistically significant.

"The number of observed cases of breast cancer is small, but the results are statistically significant," summarized Dr Martínez-González in an interview with Medscape Medical News.

This nutritional intervention study is the first to evaluate the effect of the MeDiet on breast cancer, say the researchers.

The study findings were published online September 14 in JAMA Internal Medicine.

Mitchell H. Katz, MD, one of the journal's editors, reports that the study design caught their eye. "We were immediately impressed that it was a randomized clinical trial of diet," he writes in an accompanying editorial.

The study has a "high-quality structure," according to Dr Katz, who is director of the Los Angeles County Department of Health Services, Los Angeles, California.

Dr Katz and the PREDIMED team acknowledge that the study has multiple limitations. For example, the women were not all screened for breast cancer with mammography, and they were all white and postmenopausal. Furthermore, to be enrolled in the trial, the women had to be at high risk for cardiovascular disease.

The researchers caution that longer-term, larger trials with more cases of breast cancer are needed. However, this will be a tall order, given the associated time and expense, Dr Martínez-González explained.

In the meantime, he is advising his female patients that a MeDiet might be protective against invasive breast cancer.


More Study Details

Dieticians ran individual and group lessons on the MeDiet for study participants.

The women in the 2 MeDiet groups were given supplementary foods for free: either extra-virgin olive oil (1 L/week for the participant and her family) or mixed nuts (walnuts 15 g, hazelnuts 7.5 g, and almonds 7.5 g), depending on their assigned diet.

Initially, funding for the supplements came from the Instituto de Salud Carlos III, which is the equivalent of the National Institutes of Health. "At first, we went to the supermarket for supplies," said Dr Martínez-González.

But across time, the organizers received bulk shipments of products donated by olive oil producers in Spain and nut producers in California and Spain.

The supplements were supplied to participants to ensure a high consumption of the key components of a traditional MeDiet and to promote a better overall adherence to the intervention.

Participants completed questionnaires annually to provide information on adherence to diet, food intake, and lifestyle in general.

Other prospective cohort studies have evaluated the association between adherence to a MeDiet and breast cancer risk, but none have been randomized controlled trials, the researchers report.

Furthermore, a meta-analysis of case-control studies concluded that the consumption of olive oil, including extra-virgin and other common types, was inversely associated with breast cancer incidence (Lipids Health Dis. 2011;10:127).

However, at least 1 major study, the European Prospective Investigation Into Cancer and Nutrition study, did not find any such association (Int J Cancer. 2012;131:2465-2469).

The PREDIMED researchers explain that all types of olive oil provide a high supply of monounsaturated fatty acids, mainly oleic acid, as well as squalene. Extra virgin, which is a thinner, more viscous oil, also contains various biologically active compounds, such as the polyphenols oleocanthal, oleuropein, hydroxytyrosol, and lignans.

"In vitro studies have suggested that oleic acid has an antiproliferative effect by affecting the expression of human oncogenes," they write.

The potential beneficial effect of the MeDiet is likely explained by several mechanisms, including a reduction in DNA oxidative damage, the team says.

The PREDIMED trial was supported by Instituto de Salud Carlos III, the US National Institutes of Health, and other agencies. The supplemental foods were donated by Patrimonio Comunal Olivarero and Hojiblanca (olive oil), the California Walnut Commission (walnuts), Borges SA (almonds), and La Morella Nuts (hazelnuts). Some of the study authors have disclosed relevant financial relationships with the food industry, including the International Nut and Dried Fruit Foundation and the California Walnut Commission, and with pharmaceutical companies. Dr Katz has disclosed no relevant financial relationships.

JAMA Intern Med. Published online September 14, 2015.


Study Highlights

At primary healthcare centers in Spain from 2003 to 2009, a total of 4282 women 60 to 80 years old and at high risk for cardiovascular disease were invited by their primary care clinicians to participate in the single-blind PREDIMED trial.
Participants were randomly assigned 1:1:1 to receive a MeDiet supplemented with extra-virgin olive oil, a MeDiet supplemented with mixed nuts, or counseling on how to reduce dietary fat (control group).
Participants in the extra-virgin olive oil group received 1 L/week of oil to use for themselves and their families at no charge. Those in the mixed nuts group received 30 g/day of nuts, consisting of 15 g of walnuts, 7.5 g of hazelnuts, and 7.5 g of almonds.
For the 4152 women without a previous history of breast cancer, a prespecified secondary outcome was breast cancer incidence.
There were 35 confirmed incident cases of breast cancer during follow-up (median duration, 4.8 years).
Per 1000 person-years, there were 1.1 cases of breast cancer for the MeDiet with extra-virgin olive oil group, 1.8 for the MeDiet with nuts group, and 2.9 for the control group.
Compared with the control group, the MeDiet with extra-virgin olive oil group had a 68% reduction in breast cancer incidence (multivariable adjusted hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.13-0.79; P =.02).
For the MeDiet with nuts group, the HR was 0.59 (95% CI, 0.26-1.35), but this result was not statistically significant.
For each additional 5% of calories from extra-virgin olive oil, the HR for breast cancer was 0.72 (95% CI, 0.57-0.90), based on analyses with yearly cumulative updated dietary exposures.
On the basis of their findings, the investigators concluded that this randomized trial was the first to show an effect of a long-term dietary intervention on breast cancer incidence.
The findings suggest that a MeDiet supplemented with extra-virgin olive oil is beneficial in the primary prevention of breast cancer.
However, the investigators caution that their results need to be confirmed in longer-term and larger studies, because this study was a secondary analysis of a previous trial and there were few incident breast cancer cases.
Study limitations include failure to screen all women for breast cancer with mammography before study entry, and limited generalizability because participants were white, postmenopausal, and at high risk for cardiovascular disease.
In light of the long duration and high costs of longer-term, larger randomized trials, while awaiting confirmation, clinicians may wish to advise their female patients that a MeDiet may help protect against breast cancer.
Mechanisms underlying the potential benefit of the MeDiet may include a reduction in DNA oxidative damage.
Oleic acid contained in olive oil may affect the expression of human oncogenes to inhibit cancer cell growth and reproduction.

Clinical Implications

Findings from this secondary analysis of a previous trial suggest that a MeDiet supplemented with extra-virgin olive oil is beneficial in the primary prevention of breast cancer.
The results of this secondary analysis need to be confirmed in longer-term and larger studies. However, while awaiting these results, clinicians may wish to advise their female patients that a MeDiet may help protect against breast cancer.
Implications for the Healthcare Team: Members of the healthcare team should be aware that this evidence from randomized trial findings is the first to show an effect of a long-term dietary intervention on breast cancer incidence.