Analysis Shows No 10-year Survival Advantage in Patients with Ovarian Cancer and BRCA1 or BRCA2 Mutations 


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Several studies have suggested that short-term overall survival for women with ovarian cancer and BRCA1 or BRCA2 mutations is better than that in patients without such mutations. Indeed, a recent report by Kelly L. Bolton, PhD, and colleagues indicated that 5-year overall survival was 36% for mutation noncarriers, 44% for BRCA1 carriers, and 52% for BRCA2 carriers.1 However, a more recent analysis by John R. McLaughlin, PhD, and colleagues reported in the Journal of the National Cancer Institute indicates that although patients with such mutations have significantly reduced risk of death from cancer at 3 years, there is no difference between mutation carriers and noncarriers at 10 years.2

The analysis included 1,626 unselected women diagnosed with invasive ovarian cancer between 1995 and 2004 in Ontario, Canada, or Tampa, Florida, for whom mutation status could be ascertained. Mutation screening showed BRCA1 (n = 129) or BRCA2 (n = 89) mutations in 218 women (13.4%). Age at diagnosis was 51 years in BRCA1 carriers, 58 years in BRCA2 carriers, and 58 years in noncarriers. Eighty-five percent of BRCA1 carriers, 76% of BRCA2 carriers, and 88% of noncarriers were from Ontario. Patients were followed for a mean of 6.9 years.

Baseline Characteristics

There were marked imbalances in disease characteristics between mutation carriers and noncarriers at baseline, including worse stage, grade, and histology among carriers. Stage III or IV tumors were present at baseline in 81% of carriers (74% with BRCA1 mutation and 84% with BRCA2 mutation) vs 63% of noncarriers (P < .0001). Grade 1 disease was present in 15% of noncarriers vs 2% of BRCA1 mutation and 0% of BRCA2 mutation carriers, whereas grade 3 disease was present in 32% of noncarriers vs 57% of BRCA1 mutation and 53% of BRCA2 mutation carriers. Serous histology was present in 53% of noncarriers vs 74% and 73% of carriers (overall 53% vs 73%, P < .01).

On crude survival analysis, despite the baseline imbalances, mutation carriers had better 3-year survival than noncarriers, including improved survival among patients with stage III or IV tumors, although no difference between groups was apparent at 10 years. Among patients with serous cancer, which was associated with the greatest mortality, there was no difference in survival between mutation carriers and noncarriers at 10 years.

Annual Mortality

Analysis of ovarian cancer mortality in yearly intervals showed that annual mortality was lower among carriers for years 1 and 2 after diagnosis but similar or higher thereafter. Among 309 women who survived for 12 years, only 1 death from ovarian cancer occurred thereafter in 588 person-years of observation, suggesting that 12-year survival is a reasonable surrogate for cure. At 12 years after diagnosis, 29.5% of BRCA1 mutation carriers, 27.7% of BRCA2 mutation carriers, and 41.2% of noncarriers were alive, including 27.4%, 27.7%, and 27.1% of those with serous ovarian cancer, and 39.2%, 35.0%, and 40.8% of those with stage III disease at diagnosis.   

To address the baseline imbalances in disease severity, a multivariable analysis was performed to adjust for histology, age at diagnosis, disease stage, and disease grade. On the adjusted analysis, mortality from ovarian cancer was significantly lower at 3 years among carriers vs noncarriers, with carriers having a 32% reduction in risk of death (adjusted hazard ratio [HR] = 0.68, P = .03). At 5 years, there was a 21% reduction in risk of death in carriers that approached significance (HR = 0.79, 95% confidence interval [CI] = 0.63–1.01, P = .06). At 10 years, there was no difference in ovarian cancer mortality between groups (HR = 1.00, 95% CI = 0.83–1.22, P = .90).

Among women with stage III disease, adjusted hazard ratios for ovarian cancer death for carriers vs noncarriers were 0.60 (P = .07) at 3 years, 0.73 (P = .08) at 5 years, and 0.95 (P = .70) at 10 years. Among women with serous ovarian cancer, carriers had a significantly reduced risk of death on adjusted analysis at 5 years (HR = 0.75, P = .04) but not at 10 years (HR = 0.92, P = .49).

Study Limitations

There are several potential drawbacks in the analysis. Blood samples for mutation screening were obtained from only a minority of eligible cases. In Toronto, for example, blood samples were obtained from 42% of 3,367 eligible cases. More than 1,000 patients who died before samples could be obtained were not included in the analysis, thus biasing the analysis in favor of survivors; the analysis included a statistical method (left-truncated survival analysis) meant to adjust for the fact that patients dying shortly after diagnosis often could not have mutations status ascertained.

In addition, many patients or their physicians declined to participate in testing and many patients could not be located. Participation may thus have differed by age, ethnicity, or other factors. Finally, no data on treatment were included in the model used in the analysis; the authors note, however, that treatment regimens were relatively standard across North America and treating physicians were unaware of the mutation status of the study patients.

Different Survival Patterns

As noted by the authors, the finding of an early survival advantage in mutation carriers followed by higher mortality rates suggests that hereditary and nonhereditary case patients have distinct survival patterns. Available data suggest that the differences between carriers and noncarriers in this regard are not due to difference in intrinsic aggressiveness of the cancers, but rather due to better initial response to chemotherapy in carriers; in this regard, a number of studies have showed better responses to chemotherapy in BRCA1 or BRCA2 carriers. In the current analysis, peak mortality occurred at 2 years after diagnosis in noncarriers and at 3.5 years after diagnosis in carriers, raising the issue of whether hazard ratios calculated at 5 years after diagnosis are likely to give an accurate picture of long-term survival differences among mutation carriers and noncarriers.

The investigators concluded: “Our data indicate that the short-term survival benefit of carrying a BRCA1 or BRCA2 mutation is not reflected in long-term differences in the proportions of women who ultimately survive their ovarian cancer. We believe that there is insufficient evidence to conclude that survival from ovarian cancer differs between carriers and noncarriers, and we disagree with [any recommendations] that health-care providers should counsel women with ovarian cancer and carrying BRCA mutations that they should expect their survival to be better than that of noncarriers or that treatment could be tailored to reflect the difference in survival.” ■

Disclosure: The study authors reported no potential conflicts of interest.

References

1. Bolton KL, Chenevix-Trench G, Goh C, et al: Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 307:382-390, 2012.

2. McLaughlin JR, Rosen B, Moody J, et al: Long-term ovarian cancer survival associated with mutation in BRCA1 or BRCA2. J Natl Cancer Inst 105:141-148, 2013.



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