Clinical Pearls & Morning Reports
BRCA1 and BRCA2 are tumor-suppressor genes that encode proteins involved in the repair of DNA double-strand breaks by way of the homologous recombination repair pathway. Patients with a BRCA1 mutation are predisposed to triple-negative breast cancer, whereas patients with a BRCA2 mutation most often have tumors that express estrogen receptors. Robson et al. conducted a randomized, open-label, phase 3 trial that compared the efficacy and safety of olaparib with the efficacy and safety of standard therapy with single-agent chemotherapy of the physician’s choice among patients with human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer and a germline BRCA mutation. Eligible patients had received no more than two previous chemotherapy regimens for metastatic disease. Read the Original Article.
Q. What subsets of patients with breast cancer are more likely to carry a germline BRCA mutation than others?
A. Approximately 5% of unselected patients with breast cancer carry a germline BRCA mutation. Such mutations are more likely to be present in patients who have a strong family history of breast cancer, younger patients, patients who have triple-negative (i.e., HER2–negative, estrogen-receptor–negative, and progesterone-receptor–negative) breast cancer, and patients who are members of an ethnic group with known founder mutations in the BRCA genes, such as the Ashkenazi Jewish population.
Q. What is olaparib?
A. Olaparib is an oral poly(adenosine diphosphate–ribose) polymerase inhibitor. Members of the poly(adenosine diphosphate–ribose) polymerase (PARP) family of enzymes are central to the repair of DNA single-strand breaks. Olaparib is approved for the treatment of patients with recurrent ovarian cancer and a BRCA mutation, and it has been shown to provide clinically meaningful benefit among such patients. Olaparib has also been shown to have promising activity in patients with metastatic breast cancer and a germline BRCA mutation.
A: The primary end point in the trial by Robson et al. was progression-free survival. The trial showed that, among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, median progression-free survival was significantly longer with oral olaparib monotherapy than with standard chemotherapy (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% CI, 0.43 to 0.80). The risk of disease progression or death was 42% lower and the median progression-free survival was 2.8 months longer with olaparib than with standard therapy. The response rate in the olaparib group was approximately double the rate in the standard-therapy group (59.9% vs. 28.8%). Although no significant difference in overall survival was observed between olaparib treatment and standard therapy, the trial was not powered to assess differences in overall survival between treatment groups.
A: In the trial by Robson et al. the safety profile of olaparib was similar to that reported in other studies of olaparib monotherapy. Fewer grade 3 or higher adverse events and adverse events leading to discontinuation occurred with olaparib than with standard therapy. In the olaparib group, the most common adverse event was grade 1 or 2 nausea, and the most common grade 3 or higher adverse event was anemia.