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It has been 15 years since researchers discovered that mutations in the BRAC1 and BRAC2 genes predispose some women to certain breast and ovarian cancers and 10 years since trastuzumab (Herceptin) became a cornerstone of treatment for women with HER2-positive breast cancer.
Such discoveries paved the way for more scientifically advanced approaches to breast cancer; whereas, oncologists once selected a treatment based on clinical presentation and hoped for the best, these days they can often tailor treatment to a patient’s particular circumstances. This has transformed the diagnosis of breast cancer from a sentence of early death or disfigurement to a disease that, although serious, is often manageable with the appropriate treatment.
While researchers have supplied more answers, they have also generated more questions as their attempts to fine-tune the diagnosis and treatment of breast cancers have uncovered new complexities about the nature of this disease, including the discovery of breast cancers that are resistant to multiple receptor-targeted treatments.Triple-negative breast cancer: Biology, pathology, and therapy
Researchers were elated when HER2-positive breast cancer was first identified. The discovery allowed them to develop drugs that targeted and disabled the receptors in women whose tumors were HER2-positive. Down the line, however, they found that some tumors were resistant not only to HER2 but also to progesterone receptors (PRs) and estrogen receptors (ERs). These tumors are referred to as triple-negative breast cancer because they are HER2-negative, PR-negative, and ER-negative.
About 15% of women with breast cancer in the United States have triple-negative tumors, according to Dan Silver, MD, of the Dana-Farber Cancer Institute at Harvard Medical School, who is studying the biological underpinnings of this condition. Triple-negative breast cancer primarily occurs in younger women, 70% of whom have BRAC1 genetic mutation, and it is more prevalent in black women than in white women. Dr. Silver says that, unfortunately, patients with triple-negative breast cancer have a poor prognosis. Although triplenegative breast tumors tend to be less aggressive than ones that test positive for one of the 3 growth receptors, they present their own challenges. If the cancer does not have a growth hormone receptor to target in an effort to disrupt tumor-cell growth, what course of treatment should be pursued?
Some researchers have begun to focus their efforts on turning these ‘negatives’ into a positive for such patients, reexamining older chemotherapies and hunting for new drugs that target other receptors known to contribute to tumor growth in triple-negative breast cancer. Most clinical discoveries are still in the preliminary stages of investigation and are not quite ready for prime time, but they do offer a glimpse into the future of treatment for patients who have triple-negative breast disease.Identifying cell lines and molecular markers in triple-negative breast cancer tumors
Dr. Silver and several of his colleagues believe that cell lines exist that could be used to identify women with triple-negative disease. Consensus on what these cell lines are and how to detect them remains elusive. “Oncologists are still rather in the dark in terms of sporadic triple-negative disease,” said Dr. Silver. “But we know most of them fall into the BRAC1 subtype.” Dr. Silver says it would be ideal if researchers found a way for physicians to determine the tumor’s specific cell line in patients with triple-negative cancer before they select a course of treatment.
Cisplatin may be one treatment option for women with triple-negative disease, regardless of whether they have the BRAC1 gene mutation. One clinical trial examined tumor response to neoadjuvant cisplatin in 23 women with stage II/III triple-negative breast cancer. The study found that 14 had either a “complete” or “significant” response to cisplatin therapy. A smaller trial involving 10 women with a BRAC1 mutation found that 9 showed complete pathologic response to cisplatin therapy.
Dr. Silver said that if these early observations are borne out, “it appears that a subset of sporadic triple-negative breast cancer will share the susceptibility to cisplatinum shown by the BRCA1-related breast cancers.” He said these early clinical observations are consistent with findings from preliminary laboratory models that show BRCA1 and triple-negative tumors demonstrate mitomycin C and poly (ADP-ribose) polymerase (PARP)–inhibitor sensitivity (PARP is a key enzyme in DNA repair). Dr. Silver cautioned “don’t try this at home,” emphasizing the preliminary nature of these findings. “These data are from preclinical models and are very small; there are many ways in which they could be wrong or misleading. These considerations, and others like them, should be used to think creatively about future clinical trials but not used in current clinical practice.”