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.