Doctors have understood for decades that breast cancer is not one disease. Still, and with few exceptions, knowledge of breast cancer genetics -- information on cancer-causing mutations in the malignant cells -- has lagged. Here's the paradox: Because effective treatments exist for most patients with this disease, the pace of new drug development is slow; there's little impetus for people with early-stage tumors to try new forms of therapy. For women with metastatic breast cancer -- who've typically been through the mill with a combination of chemo and surgery, radiation or hormonal depletion -- most physicians still prescribe standard sorts of treatment.
A recent paper published in Nature could change this picture. The new analysis, based on patterns of DNA mutations and RNA expression in 2000 specimens, defines 10 molecular types of breast cancer. The enormously-detailed findings, augmented by virtual reams of open-access supportive data, should lead scientists and doctors to provide better, less toxic treatment options for women with all stages of the disease.
To keep this study in perspective -- it's about breast cancers in humans. No mice. The researchers examined nearly 2,000 specimens, with linked clinical records and follow-up through 15 years. First, they probed for inherited and acquired mutations in DNA from 997 tumors. They profiled gene expression by measuring tens of thousands of RNAs in each sample. They revealed mutation "hot spots," and correlated those findings with abnormal gene expression in the cancers. The list of implicated genes includes some old finds, like PTEN, MYC, CDK3 and -4, and others. They discovered that three genes, PPP2R2A, MTAP or MAP2K4 are deleted in some breast cancer cases. The paper is rich with details.
The scientists used cluster analyses to delineate 10 molecular subgroups. The new breast cancer categories, called "IntClust 1-10," defy old classifications of this disease. They turn out, also, to offer prognostic information. Finally -- in what's tantamount to a second report within the Nature paper -- the team probed a "validation set" of 995 more breast cancer specimens. Upon analyzing paired DNA mutations and profiles of RNA expression in these samples, the same 10 subtypes emerged. What's more, the prognostic (survival) information held up.
If confirmed, these observations could lead to smarter therapy for distinct breast cancer types. What's key -- and perhaps might deliver this work to the clinic -- is the investigators related the DNA abnormalities, including inherited and acquired variants in the copy numbers of particular genes, with altered RNA patterns. They observed turned-on gene sets, including enzymes that affect how cells grow and divide, and inflammatory regulators, among many examples. These "downstream" effects on gene expression -- apart from the DNA mutations -- might be vulnerable to innovative drugs. Through innovative trial strategies like I-SPY, it's possible that patients with particular molecular subgroups could be directed to small trials of new medications, including some agents already in the pipeline for this and other malignancies.
To be sure, these are preliminary findings. This is the first report on what's a proposed new molecular classification of breast cancer. That said, the paper reflects an enormous amount of cutting-edge work put together through an international consortium of investigators. It's an exquisite application of science in medicine. The results shouldn't be ignored, or sat upon for years, by researchers in the U.S. and elsewhere developing new drugs for breast cancer.
Until there's a way to prevent breast cancer, we need better ways to treat it. Oncologists see, now, that some cancers respond dramatically to drugs designed to hit specific genetic mutations. Recently-incurable malignancies, like advanced melanoma and GI stromal tumors, can be treated with pills, often with terrific responses. But for breast cancer, most treatments remain primitive -- like surgical carving, traditional chemotherapy and radiation. Herceptin and a few other monoclonal antibodies are used, but there's nothing approaching Gleevec-like pills for any form of this malignancy. Some doctors consider hormone therapy as targeted, and thereby "modern" and satisfactory. I don't.
This paper leads me to wonder if, in a few years, some breast cancers might be treated without surgery. Doctors could perform a small biopsy with a needle, check for the molecular type, and give the right breast cancer tablets. Perhaps patients would need a tad of chemo, later, to "mop up" any residual or resistant cells. But the mainstay of treatment would be a cocktail of drugs, by mouth, like patients take for hepatitis C, tuberculosis or AIDS. There'd be no lost breasts, no reconstruction, no lymphedema. Can you imagine?
Even if just a few of these newly-identified subtypes pan out and lead to this sort of radically-transformed breast cancer treatment, that would be a dream. This can't happen soon enough.
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