BREAST CANCER AT LEAST 1O DISEASES-THE DEATH OF "LUMINAL" SUBTYPE

A "new map" of breast cancer, which identifies 10 distinct disease subtypes based on gene activity, will revolutionize the diagnosis and treatment of this disease, say researchers.

The findings, published online April 18 in Nature, come from the largest global gene study of breast cancer tissue ever performed.

"This research is 'ground-breaking' indeed," said world-renowned breast cancer expert Martine Piccart, MD, PhD, from the Jules Bordet Institut in Brussels, Belgium. "The current classification of breast cancer is overly simplistic and results in suboptimal treatment selections for our patients," she told Medscape Medical News.

"I am not at all surprised that breast cancer is not 4 diseases but at least 10…and I do believe that this discovery will lead to the better management of patients…although this will probably take another 10 years," Dr. Piccart said.

Researchers in the United Kingdom and Canada analyzed nearly 2000 tumor samples taken from women diagnosed with breast cancer 5 to 10 years ago. They integrated tumor-sample copy numbers and gene expression with data on long-term clinical outcomes. They concluded that the samples could be divided into at least 10 distinct subtypes on the basis of common genetic features that correlate with survival.

The next step is validation in clinical trials, but the ultimate aim is to target treatment to the precise "genetic fingerprint" of each tumor type, said colead author Carlos Caldas, MD, FMedSci, from the Department of Oncology at Cambridge University, United Kingdom, and senior group leader at Cancer Research UK's Cambridge Research Institute.

"Our results will pave the way for doctors in the future to diagnose the type of breast cancer a woman has, the type of drugs that will work, and those that won't, in a much more precise way than is currently possible," he said.

"This landmark study will completely change the way we look at breast cancer," according to Cancer Research UK, which provided much of the funding for the study. The charity highlighted the study at a press conference held in London, United Kingdom.

Current Pathology Subtypes

Currently, breast cancer is classified by pathologists into 4 subtypes, Dr. Caldas explained. This is based on testing for the estrogen receptor (ER), which if positive indicates responsiveness to hormonal therapies, and for HER2, which if positive indicates responsiveness to trastuzumab (Herceptin).

By far the largest proportion of breast cancers (70%) are ER-positive/HER2-negative, about 7.5% are ER-positive/HER2-positive, and about 7.5% are ER-negative/HER2-positive. The remainder are the so-called triple-negative breast cancers (ER-negative/progesterone-receptor-negative/HER2-negative), which are aggressive, do not benefit from any targeted therapy, and are treated with chemotherapy, he said.

However, in the 70% of breast cancers that are classified as ER-positive/HER2-negative, there is a tremendous heterogeneity, Dr. Caldas explained, with some patients having a much better prognosis than others.

The researchers found that 7 of the 10 newly identified disease subtypes are in this category. There is a wide variation in prognosis by subtype; at 15 years, the best shows 80% survival and the worst shows less than 40% survival. "We are getting more separation in this largest subgroup of breast cancer. This is very important. We have been on a quest to find better markers in this group of patients," Dr. Caldas said at the press briefing.

The new classification identifies very robust HER2-positive tumors, whether they are ER-positive or ER-negative, he noted. "All previous molecular tests have failed to do this properly," he added. This might increase the number of patients classified as HER2-positive, who could benefit from treatment with trastuzumab, the researchers write.

Another of the new subtypes, known as cluster 10, coincides fairly closely with the triple-negative subtype, although not exactly, Dr. Caldas said.

The largest of the new subtypes identified, known as cluster 4, accounts for about 16% of the total and is "very interesting," he continued. This subtype has fewer copy number gains and losses, and shows a significant infiltration of inflammatory cells, suggesting an activation of the immune system. This subtype comprises patients with ER-positive, with ER-negative, and with triple-negative tumors, and "would be missed in any other classification system that relies on sequencing," he said.

The researchers also discovered several new genes. Some of these, such as kinases and phosphatases, are very attractive targets for new drug development, he said.

"We have produced a completely new way of looking at breast cancer," Dr. Caldas said. "It is very robust because of the number of samples that we looked at," he explained.

When asked by Medscape Medical News how this novel molecular stratification of breast cancer fits with other tests that are already available, such as Oncotype DX and MammaPrint, Dr. Caldas explained that the evidence suggests that neither of those tests add much to the subtypes that are identified by high-quality pathology. "The United Kingdom leads the world with regard to pathology, especially in breast cancer," he said. In this setting, neither Oncotype DX nor MammaPrint add much information, he said. In fact, the National Institute of Clinical Excellence deemed that both are not cost effective, he added.

Another expert told Medscape Medical News that this work is in its early stages. "This is very exciting work that will significantly advance the field of personalized medicine and could potentially have important therapeutic implications. However, I would caution that the findings are not ready for prime time yet, and need validation in prospective clinical studies before they can be incorporated into clinical practice," said Aditya Bardia, MD, MPH, from the Massachusetts General Hospital Cancer Center in Boston.

CHILDREN WITH ALL FAILING INDUCTION CHEMOTHERAPY

A "remarkable collaborative effort" has provided insight into a rare group of patients — children with acute lymphoblastic leukemia (ALL) who fail induction chemotherapy. Because they comprise only 2% to 3% of the total patient population, 14 centers on 3 continents pooled their data, in the largest study to date, to analyze outcomes.

The results, which appear in the April 12 issue of the New England Journal of Medicine,show a high degree of heterogeneity. The researchers offer a rather surprising conclusion that could lead to a change in clinical practice.

"In the past, when patients did not respond to induction therapy, we thought that they wouldn't respond to any other therapy, so we would go on to stem cell transplants," said corresponding author Ching-Hon Pui, MD, chair of the Department of Oncology at St. Jude Children's Research Hospital in Memphis, Tennessee. "But we have been pleasantly surprised by these results."

The results show that one subgroup of patients who fail induction therapy — children younger than 6 years who have B precursor leukemia (about 25% of the total) — respond better to further chemotherapy than to transplantation.

"I believe that the evidence is strong enough to use this new approach to therapy," Dr. Pui told Medscape Medical News.

"This may substantially affect current practice," writes Karen Rabin, MD, PhD, from the Texas Children's Cancer Center, Baylor College of Medicine, in Houston, in an accompanying editorial.

"Until now, children with ALL with induction failure have generally been considered to be an extremely high-risk group, and most pediatric oncologists have viewed stem cell transplantation as the best treatment option," Dr. Rabin told Medscape Medical News.

This study "demonstrates a range of outcomes among children with induction failure, and suggests that treatment with chemotherapy without stem cell transplantation may be appropriate in some cases," she said.

International Collaboration

"Induction failure is rare, occurring in only 2% to 3% of all patients, but it constitutes one of the most unfavorable outcomes in pediatric ALL," write the researchers, headed by Martin Schrappe, MD, from the Department of Pediatrics at the Christian-Albrechts University Kiel in Germany.

They collaborated with other centers in Europe, the United States, and Japan to collect sufficient data on this rare patient population.

In total, 14 centers collaborated and pooled data on 44,017 patients (age, 0 to 18 years) with newly diagnosed ALL who were treated from 1985 to 2000. From this group, the team identified 1014 patients (2.4%) who failed induction therapy.

Induction treatment is usually carried out with 3 or 4 drugs, Dr. Pui explained, including steroids, vincristine, asparaginase, and usually danorubicin.

The analysis found that overall, patients who failed induction therapy had poor outcomes, with a 10-year survival rate estimated to be only 32%.

In contrast, children who respond to induction therapy and then go on to transplant or continuation chemotherapy have a very high chance of cure — around 80% to 90% in developed countries, Dr. Pui told Medscape Medical News. At St. Jude, the 10-year survival for the overall ALL population (which includes induction failures) is now 91%, he said.

These results show that the patients who failed induction were a very heterogeneous group, some patients fared better than others, and outcomes depended on subsequent treatment.

The team found that pediatric ALL patients who have T cell leukemia and who fail induction therapy (about 38% of all the induction-failure patients in this study) appear to have a better outcome with allogeneic stem cell transplantation than with chemotherapy. Conversely, patients with precursor B-cell leukemia without other adverse features (about 25% of the total) appear to have a better outcome with chemotherapy.

Another 13% of patients who failed induction therapy had the Philadelphia chromosome. They were not included in this analysis because targeted drugs such as imatinib (Gleevec) have led to dramatic improvements in their outcome.

Subgroup With Best Outcome

The patients with the best outcomes were those with precursor B-cell leukemia who were either younger than 6 years or had high hyperdiploidy, the researchers report. This subgroup had a 10-year survival rate of 72% when treated with chemotherapy alone.

This is starting to approach the 80% to 90% cure rate for ALL overall, said Dr. Pui, and is strikingly better than the 32% rate seen for the total induction-failure population.

"Our analysis showed no benefit of allogeneic transplantation in patients younger than 6 years of age who had precursor B-cell ALL and induction failure and no high-risk cytogenetic features," the researchers write.

This observation has "considerable clinical implications, since transplantation is generally considered to be the standard of care for such patients," they add.

"Given this result, I would not automatically recommend transplantation for children 1 to 6 years of age with precursor B-cell leukemia and no other high-risk features, as we have done in the past," Dr. Pui explained. "I would give these patients consolidation treatment with high-dose methotrexate and mercaptopurine to evaluate the response. For patients who respond well to this treatment, I would continue with intensive chemotherapy, and would reserve transplantation for patients who do not respond well."

Dr. Schrappe added in a statement that "these results tell us that induction failure should no longer be considered an automatic indication for a transplant."

CRIZOTINIB MAY LOWER TESTOSTERONE LEVELS

Men experience a marked drop in their testosterone levels when taking a targeted therapy - crizotinib, to control anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC). That's according to a University of Colorado Cancer Center study published in the April issue of Cancer. Investigators looked at the hormone levels, after a 35-year-old man on the drug reported symptoms that are often attributed to low testosterone levels: fatigue and sexual disinterest.

Listening to the specific issue

Crizotinib tablets were licensed by the USA Food and Drug Administration in August 2011, because of its dramatic and long-lasting suppression of ALK positive NSCLC. ALK positive lung cancer was only recently described, so very few cancer centers have a lot of experience identifying and treating this subtype of the disease. University of Colorado Cancer Center was involved in the initial development of the drug and has treated one of the largest groups of ALK positive patients in the world.

The testosterone study included 19 men with NSCLC taking crizotinib and 19 men with lung cancer receiving other kinds of therapy. According to Dr Andrew Weickhardt, senior clinical fellow, and one of the study's co-authors, when the team started to track testosterone levels over time, they clearly saw a drop within days of starting on the drug, and while testosterone was low in only about 30% of men on other therapies, it was low in all of the men who were on crizotinib.

Spotting patterns and making advances that can improve how someone with lung cancer feels on a daily basis

As men may stay on crizotinib for months, or even years, the effects of low testosterone could be profound. Low testosterone can reduce bone density and muscle strength as well decrease sex drive and increase fatigue and depression. There are many factors associated with a cancer diagnosis that can lower testosterone, but according to endocrinologist, Dr Micol Rothman, co-author of the study, the levels in crizotinib-treated patients were so uniformly low and their direct relationship with starting the therapy meant there was no doubt the drug was contributing to it. Fortunately, this condition can be easily tested for and treated by testosterone supplements.

In recent weeks, several studies from the University of Colorado Cancer Center have advanced understanding about ALK positive NSCLC. One study published in Clinical Cancer Research, reveals that when ALK positive lung cancer eventually mutates to become resistant to crizotinib it does so in different ways. Either the cancer changes the ALK protein so that the crizotinib is ineffective against it or it develops another type of cancer molecule that makes the cancer less dependent on ALK. If the ALK protein changes, it may be vulnerable to a stronger ALK inhibitor. If it combines with another type of cancer molecule, a combination of drugs may be required.

The University of Colorado Cancer Center’s Thoracic Oncology Program is world renowned for its pioneering treatment of lung cancer. The program includes a multidisciplinary team of specialists and subspecialists working together to establish the best treatment plan for each patient. Advanced molecular profiling of a patient's tumor, combined with an extensive array of standard and experimental treatments available through clinical trials has lead to major advances in patient outcomes in the last few years. It is the lead site for the Lung Cancer Mutation Consortium, the collaboration of 14 of elite lung cancer programs in USA. The consortium is profiling ten different molecular abnormalities in lung cancer and pairing them with specific experimental treatments over the next few years.

ASPIRIN CAN REDUCE CANCER MORTALITY AND METASTASES RISK

Evidence from 3 new studies demonstrates that aspirin can reduce the risk for cancer-related mortality and can reduce or prevent the risk for distant metastasis.

Peter M. Rothwell, MD, PhD, professor of clinical neurology at the University of Oxford, United Kingdom, was lead author on all 3 studies.

In the first study, published online March 21 in the Lancet, comparing daily aspirin with no aspirin to prevent vascular events, aspirin use reduced the risk for nonvascular death in all 51 trials examined (1021 vs 1173 deaths; odds ratio [OR], 0.88; P = .003). When data from 34 trials were examined (n = 69,224; 89% of total cohort), there were fewer deaths from cancer in the aspirin than in the control group (562 vs 664 deaths; OR, 0.85; P = .008).

Dr. Rothwell and colleagues note that even though the decreased risk for major vascular events in these trials was initially offset by a higher risk for major bleeding, both of these effects diminished over time, leaving only the reduced risk for cancer after 3 years.

"In view of the very low rates of vascular events in recent and ongoing trials of aspirin in primary prevention, prevention of cancer could become the main justification for aspirin use in this setting," they write.

Compelling But No Recommendations Yet

In an accompanying editorial, Andrew T. Chan, MD, MPH, and Nancy R, Cook, ScD, both from Harvard Medical School in Boston, Massachusetts, note that although these results are compelling, they do have limitations.

These analyses exclude the largest randomized trials in primary prevention, the editorialists point out. The Women's Health Study (WHS) of 39,876 women treated with alternate-day aspirin 100 mg over 10 years and the Physicians' Health Study (PHS) of 22,071 men treated with alternate-day aspirin 325 mg over 5 years were not included in the current study because of possible differences in the biologic effect between alternate-day and daily aspirin intake. However, in these 2 studies, aspirin was not associated with a lower risk for colorectal cancer or overall cancer incidence or mortality.

Another limitation, say the editorialists, is that the researchers only used 6 randomized trials to analyze low-dose aspirin in the primary prevention of cancer.

In these 6 trials (n = 35,535), aspirin was shown to lower the incidence of cancer after 3 years in women (132 vs 176; OR, 0.75; P = .01), in men (192 vs 245; OR, 0.77; P = .008), and in both (324 vs 421; OR, 0.76; P = .0003).

A third limitation is that because the included studies were designed to examine cardiovascular end points, there was no information about cancer screening or surveillance.

Finally, some of the analyses were limited by the quality of available data; some estimates pooled individual-level data with published results.

But "caveats notwithstanding, Rothwell and colleagues show quite convincingly that aspirin seems to reduce cancer incidence and death across different subgroups and cancer sites, with an apparent delayed effect," they write. For most individuals, "the risk–benefit calculus of aspirin seems to favor aspirin's long-term anticancer benefit. These findings are consistent with observational findings and our understanding of the stepwise progression of carcinogenesis."

These data might not be the final word on aspirin, as far as making a population-based recommendation, the editorialists caution, because the WHS and PHS remain "significant counterbalancing trials that have not shown a cancer benefit with alternate-day aspirin up to 10 to 12 years."

Another factor to be considered is the adverse events from daily aspirin. Even though there is a "convincing case" that the vascular and anticancer benefits of aspirin outweigh the harms of major extracranial bleeding, less serious adverse effects on quality of life, such as less severe bleeding, are not accounted for in these analyses, Drs. Chan and Cook write.

Nonetheless, until data from forthcoming trials and longer-term follow-up from the WHS and PHS become available, this "impressive collection of data moves us another step closer to broadening recommendations for aspirin use," they conclude.

Metastasis in Randomized Trials

In the second study, also published online March 21 in the Lancet, Dr. Rothwell and colleagues analyzed data from 5 large randomized trials of daily aspirin (75 mg or more daily) for the prevention of vascular events in the United Kingdom. The cohort consisted of 17,285 trial participants, 987 of whom had a new solid cancer diagnosed during a mean follow-up of 6.5 years.

Aspirin use reduced the risk for cancer with distant metastasis (hazard ratio [HR] for all cancers, 0.64; P = .001). The risk for cancer with distant metastasis was reduced by 36%, and the risk for adencarcioma was reduced by 46% (P = .0007). Among patients with adenocarcinoma who did not have metastasis at their initial diagnosis and who remained on trial treatment up to or after diagnosis, the use of aspirin reduced the risk for metastasis on subsequent follow-up by about 70%.

Aspirin lowered the cancer mortality rate among patients who developed adenocarcinoma, especially in those without metastasis at diagnosis (HR, 0.50; P = .0006). Aspirin also lowered the overall risk for fatal adenocarcinoma (HR, 0.65; P = .0002), but not the risk for other fatal cancers (HR, 1.06; P = .64). These effects were independent of confounders such as age and sex, but the absolute benefit was greatest in smokers, the authors note.

Observation vs Randomized

The third study, published online March 21 in the Lancet Oncology, looked at the effect of aspirin on metastases, but with a different approach. The authors compared the effect of aspirin on the 20-year risk for cancer-specific mortality between observational studies and randomized trials.

They conducted this comparison because although randomized trials can clearly establish the risk for colorectal cancer, other solid tumors, and metastasis, such trials lack the statistical power to establish effects on less common cancers and on cancers in women.

Observational and case–control studies can provide these data if the results are shown to be reliable.

Overall, results from observational studies were similar to those from randomized trials, and showed that regular aspirin use lowered the long-term risk for several cancers and for distant metastasis.

In 6 eligible randomized trials, the aspirin group had a consistently lower 20-year risk for death from colorectal cancer than the control group (OR, 0.58; P = .0002). In the 26 case–control studies, any use of aspirin was associated with a lower risk for colorectal cancer (pooled OR, 0.67; P < .0001).

In 17 case–control studies, the regular use of aspirin was associated with a reduced risk for colorectal cancer (pooled OR, 0.62; P < .0001). In the randomized trials, there was good correlation between the effect of daily aspirin use and the 20-year risk for death from colorectal cancer (OR, 0.58; P = .0002).

The authors observed the same consistent reductions in risks for esophageal, gastric, biliary, and breast cancers, and estimates of the effect of aspirin on individual cancers in case–control studies were highly correlated with those seen in randomized trials (P = .0006). The largest effects were observed for gastrointestinal cancers.

In 5 studies, the regular use of aspirin was associated with a reduced proportion of cancers with distant metastasis (OR, 0.69; P < .0001); in 7 studies, it was not associated with a reduction in regional spread (OR, 0.98; P = .71). This was consistent with the findings from the randomized trials.

The authors note that "there is an urgent need for more data for effects on metastasis when aspirin is started after diagnosis of cancer."

More data are also needed for the effects of nonaspirin nonsteroidal anti-inflammatory drugs, they write, adding that "new case–control studies...have the potential to provide data quickly for each of these issues, with reasonable reliability and good statistical power."

All 3 studies were unfunded. Dr. Rothwell reports a financial relationship with several pharmaceutical companies with an interest in antiplatelet agents, including AstraZeneca, Bayer, Boehringer Ingelheim, sanofi-aventis, Bristol-Myers Squibb, and Servier; and being on the executive committee of the ARRIVE Trial. Coauthor F. Gerald R. Fowkes, FRCPE, from the Centre for Population Health Sciences, University of Edinburgh, United Kingdom, reports receiving research support and honoraria from AstraZeneca, Bayer, sanofi-aventis, and Bristol-Myers Squibb. Dr. Chan reports serving as a consultant to Bayer HealthCare and Millennium Pharmaceuticals. Dr. Cook reports being an investigator for the WHS.

NEW COLORECTAL CANCER SCREENING GUIDELINESS

A new American College of Physicians (ACP) guidance statement recommends individualized assessment of risk for colorectal cancer (CRC) in all adults. The new recommendations and an accompanying patient summary appear in the March 6 issue of the Annals of Internal Medicine.

"The [ACP] encourages adults to get screened for [CRC] starting at the age of 50," ACP President Virginia L. Hood, MBBS, MPH, FACP, said in a news release. "Only about 60 percent of American adults aged 50 and older get screened, even though the effectiveness of [CRC] screening in reducing deaths is supported by the available evidence."

In the United States, CRC is the second leading cause of cancer-related deaths for both men and women. The new ACP guidelines aim to educate physicians and patients regarding the benefits and harms of CRC screening, based on a review of current guidelines from other professional organizations.

A search of the National Guideline Clearinghouse revealed 4 guidelines meeting selection criteria: a joint guideline developed by the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology, and individual guidelines from the Institute for Clinical Systems Improvement, the US Preventive Services Task Force, and the American College of Radiology.

Specific ACP recommendations include the following:

1. Clinicians should perform individualized CRC risk evaluation in all adults. Risk factors for CRC incidence and mortality include older age; black race; personal history of polyps, inflammatory bowel disease, or CRC; and family history of CRC.
2. Clinicians should screen for CRC in adults at average risk beginning at 50 years of age, and in adults at high risk beginning at 40 years of age or at 10 years younger than the age at which the youngest affected relative was diagnosed with CRC. In these populations, the potential benefits of reduced mortality from earlier detection of CRC outweigh the potential harms of screening.
3. Patients at average risk may undergo CRC screening with a stool-based test, flexible sigmoidoscopy, or optical colonoscopy. Patients at high risk should undergo screening with optical colonoscopy. The benefits, harms, and availability of the specific screening test, as well as patient preferences, should affect choice of screening test. For adults older than 50 years who are at average risk, the recommended screening interval is 10 years for colonoscopy; 5 years for flexible sigmoidoscopy, virtual colonoscopy, and double contrast barium enema; and annually for fecal occult blood test.
4. Clinicians should stop CRC screening in adults older than 75 years or who have a life expectancy of less than 10 years because the potential harms of screening outweigh the potential benefits. Risks of colonoscopy include bleeding, intestinal perforation, and adverse reactions related to preparation for the procedure.

"We encourage patients to engage in shared decision making with their physician when selecting a [CRC] screening test so that they understand the benefits and harms," said Dr. Hood. "The success of any screening program, especially [CRC] screening, is dependent on the appropriate testing and follow-up of patients with abnormal screening results as well as following up with patients for repeat testing at designated intervals."