BRCA1/2 Mutations Linked with Better Outcome in Triple-negative Breast Cancer


Cancer Connect

BRCA1/2 Mutations Linked with Better Outcome in Triple-negative Breast Cancer

According to the results of a small study, approximately 20% of women with triple-negative breast cancer are carriers of a BRCA1 or BRCA2 gene mutation. Triple-negative breast cancer patients with these mutations appear to have better survival than patients without these mutations. These results were recently presented at the 2010 Breast Cancer Symposium.[1]

Some breast cancers display different characteristics that require different types of treatment. The majority of breast cancers are hormone receptor-positive, meaning that the cancer cells are stimulated to grow by exposure to the female hormones estrogen and/or progesterone. These cancers are typically treated with hormonal therapy that reduces the production of these hormones or blocks their effects.  Other cancers are referred to as HER2-positive, which means that they overexpress the human epidermal growth factor receptor 2, part of a biologic pathway that is involved in replication and growth of a cell. HER2-positive breast cancers account for approximately 25% of breast cancers and are treated with agents that target the receptor to slow growth and replication.

Triple-negative breast cancer refers to cancers that are estrogen receptor-negative, progesterone receptor-negative, and HER2-negative. Triple-negative breast cancers tend to be more aggressive than other breast cancers and have fewer treatment options. Research is ongoing to determine prognostic factors such as gene mutations that may impact prognosis and help to individualize care.

In the current study, researchers from the M. D. Anderson Cancer Center evaluated the frequency and effects of BRCA1 and BRCA2 gene mutations among 77 women with triple-negative breast cancer. Inherited mutations in these genes can be passed down through either the mother’s or the father’s side of the family and greatly increase the risk of breast and ovarian cancer.

  • 15 of the 77 patients (20%) had a BRCA1 or BRCA2 mutation.
  • Five-year relapse-free survival was 86% for patients with a BRCA mutation compared with 52% for patients without a BRCA mutation.

The researchers concluded that triple-negative breast cancer patients with BRCA mutations experienced a significantly lower recurrence rate. These findings were unexpected because previous studies had not shown a difference in survival.

Patients with triple-negative breast cancer may wish to speak with their healthcare team regarding the risks and benefits of genetic testing.

Reference:

[1] Gonzalez-Angulo M, Chen H, Timms K, et al. Incidence and outcome of BRCA mutation carriers with triple receptor-negative breast cancer (TNBC). Presented at the 2010 Breast Cancer Symposium, Washington, DC, October 1-3, 2010. Abstract 160.

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A Targeted Agent for Triple-Negative Breast Cancer


Glycoprotein NMB (gpNMB) is a transmembrane protein and tumor-associated antigen that is expressed at higher levels in certain malignancies than in normal tissues. Glembatumumab vedotin (CDX-011) is an antibody-drug conjugate consisting of a fully human IgG2 monoclonal antibody against gpNMB linked to the microtubule inhibitor monomethyl auristatin E (MMAE). By targeting and binding to cells overexpressing gpNMB, the antibody is internalized, allowing for intracellular release of the cytotoxic MMAE.

A prior phase I/II trial of CDX-011 for refractory advanced breast cancer demonstrated an acceptable toxicity profile and an objective response rate (ORR) of 12% (NEJM JW Oncol Hematol Nov 2014 and J Clin Oncol 2014; 32:3619). In the subset of patients with triple-negative breast cancer (TNBC), the ORR was 20%, and progression-free survival (PFS) was 4.1 months; in TNBC patients with gpNMB-expressing tumors the ORR was 25%, and the PFS was 5.1 months. Now, investigators have conducted an industry-supported, randomized phase II trial (EMERGE) of CDX-011 versus investigator choice of chemotherapy (IC) in 124 refractory breast cancer patients with tumors overexpressing gpNMB (defined as ≥5% of malignant epithelial or stromal cells with any expression).

ORR was similar overall for patients receiving CDX-011 or IC (6% and 7%, respectively) and for those with gpNMB-expressing tumors (12% for both). ORR was higher with CDX-011 versus IC in patients with ≥25% of tumor cells expressing gpNMB (30% vs. 9%) as well as in TNBC patients (18% vs. 0%) and TNBC patients with overexpression of gpNMB (40% vs. 0%). Dose reduction occurred in 25% of patients in both treatment arms. The most common CDX-011 toxicities were rash, fatigue, nausea, neutropenia, and neuropathy.

Comment

The attraction of targeted therapy with an antibody delivery system is that it directs the cytotoxic agent preferentially to the malignant cell population, potentially enhancing efficacy and minimizing systemic toxicity. The use of ado-trastuzumab emtansine for HER2-positive breast cancer demonstrates the success of this approach (NEJM JW Oncol Hematol Sep 2014 and J Clin Oncol2014; 32:2750). The signal that CDX-011 is active in TNBC is exciting, but the observations from this study are based on very small numbers of patients. A larger, pivotal phase II trial (METRIC) is under way to more fully investigate this compound in TNBC.