The Impact of BRCA Mutation on Ovarian Cancer Treatment Outcomes

Abstract & Commentary

By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.

Dr. Coleman reports no financial relationship to this field of study.

Synopsis: BRCA mutation carriers demonstrate improved survival characteristics relative to age- and stage-matched population controls. The performance gains are likely due to higher than expected platinum-based cytotoxicity and have implications for future therapeutic investigation.

Source: Tan DS, et al. "BRCAness" syndrome in ovarian cancer: A case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 2008 Oct 27; Epub ahead of print.

Hereditary ovarian cancer syndromes are uncommon, but are most often represented by mutation in BRCA1/2. The natural history expectations in mutation carriers who develop ovarian cancer is debated; however, the gene's function in repair of DNA double strand breaks by homologous recombination would suggest heightened sensitivity to agents, like platinum, when compromised.

To address this hypothesis, 22 women with germ-line BRCA1 or BRCA2 mutations and epithelial ovarian cancer were age-, stage-, histology- and year of diagnosis-matched (1:2) to 44 non-hereditary ovarian cancer patients. All received platinum-based primary therapy. Compared with controls, BRCA-positive women had higher overall and complete response rates to first-line treatments. They also had higher response rates to second- and third-line platinum-based therapy and a remarkable increase in both overall survival from time of diagnosis (8.4 years vs 2.9 years; P < 0.002) and overall survival from the time of first recurrence (5.0 years vs 1.6 years; P < 0.001). Multivariate analysis demonstrated that BRCA status, and stage and length of first response were independent prognostic factors from time of first relapse. Remarkably, the duration of secondary platinum-based therapy was no different than when administered in the primary setting; this contrasted with a decreased median treatment-free interval in the control population. The effect was limited to platinum-based treatments.

This retrospective study suggests that platinum-based therapy among BRCA mutation carriers is associated with substantially improved response rates and overall survival characteristics relative to women without BRCA-related hereditary cancer. The reason for this may lie in the inability of affected women to repair platinum-associated DNA strand breaks. Future prospective therapeutic studies will need to confirm these findings and carefully consider BRCA status in addressing inference in treatment efficacy.

Commentary

Hereditary ovarian cancer accounts for about 10% of all ovarian epithelial cancers. Identification of at-risk women prior to the development of disease is important as interventional strategies, such as prophylactic surgery, can dramatically reduce the expression of the malignant phenotype. From the study discussed here, it is likely that identification of BRCA status in affected women is also of both prognostic and therapeutic benefit. The relationship between carrier status and outcome has been debated with some reports demonstrating improved clinical outcomes and others, adverse. However, as the function of the BRCA genes is becoming clearer, it is likely the latter associations have come from biased or incomplete analyses of population data.

The BRCA genes appear to play a dominant role in the repair of DNA strand breaks through homologous recombination. When impaired, increased pressure is placed on other DNA repair mechanisms, such as poly(ADP-ribose)-polymerase (PARP) promoting the likelihood that catastrophic cellular insults will go unrepaired. In tumors of BRCA patients, this deficit may be leveraged, therapeutically, by inducing strand breaks with agents such as platinum or by inhibiting PARP. Inhibitors of PARP are now in active clinical investigation in women selected based on their BRCA status. Preliminary results have been quite promising and appear relevant in both platinum-sensitive and platinum-resistant patients, even when administered as a single agent. Findings such as those in this report suggest attention should also be placed on DNA-damaging agents. The demonstration of improved survival from the time of first progression suggests a real treatment effect, as this reference point is less likely to be influenced by primary treatment factors such as postoperative tumor residuum and chemotherapy.

BRCA mutation status in unselected ovarian cancer patients has been added to a few ongoing and recently completed randomized ovarian cancer treatment trials, which should elucidate its prognostic and, potentially, predictive role. It is possible that a future direction in applied therapy could be the co-administration of agents, which may target BRCA function; successful modulation could broaden the therapeutic options in both selected and unselected patients with ovarian cancer.

Suggested Reading

  1. Lord CJ, Ashworth A. Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol 2008;8:363-369.
  2. Chiang JW, et al. BRCA1 promoter methylation predicts adverse ovarian cancer prognosis. Gynecol Oncol 2006;101:403-410.
  3. Pal T, et al. Improved survival in BRCA2 carriers with ovarian cancer. Fam Cancer 2007;6:113-119.