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BRCA1/2 provided no long-term survival benefit in invasive ovarian cancer
Carriage of a BRCA1/2 mutation was associated with improved short-term survival but provided no long-term survival benefit in a cohort of women with ovarian cancer, according to study results.
The researchers conducted the prospective analysis to determine whether carriage of a BRCA1 or BRCA2 mutation affected survival outcomes.
The researchers identified eligible participants who had been diagnosed with invasive ovarian cancer in Ontario, Canada, or Tampa, Fla., between 1995 and 2004.
The analysis included 1,626 patients, of whom 218 carried BRCA1/2 mutations. None of the patients were aware of their genetic status at the time of diagnosis. Results were not shared with patients until at least 1 year elapsed from diagnosis, so patients’ genetic status did not influence treatment decisions, according to the researchers.
The mean follow-up was 6.9 years (range, 0.3-15.7 years).
Mutation was associated with better prognosis at 3 years after diagnosis (adjusted HR=0.68, 95% CI, 0.48-0.98). However, at the 10-year mark, the HR was 1.00 (95% CI, 0.83-1.22).
Among women with serous disease, 27.4% of those with a BRCA1 mutation, 27.7% of those who carried BRCA2 and 27.1% of noncarriers were still alive 12 years after diagnosis.
“We believe that there is insufficient evidence to conclude that survival from ovarian cancer differs between carriers and noncarriers,” the researchers wrote. “We disagree with the recommendation 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 differences in survival.”
Perspective
Back to TopAlthough the study from McLaughlin and colleagues is provocative, its results are somewhat unexpected, given almost a dozen studies have previously suggested improved short-term survival for BRCA-associated ovarian cancer. Given this potential discrepancy, there are several issues in the current study design that need to be examined.
First, ascertainment to the present study occurred a median of 20 months from diagnosis. Given a substantial fraction of patients with unselected stage III-IV serous ovarian cancer will have progressed in this time frame and better short term survival for BRCA-associated cancer has been seen in multiple studies — including the current one — it is likely that noncarrier patients with poor prognosis were less likely to be ascertained. This would lead to a selection bias that may not have been adequately corrected for by the left-truncation method used. In several recent studies showing improved short-term survival (Hyman DM. Cancer. 2012;118:3703-3709. Yang D. JAMA. 2012;307:363), this issue was addressed by only including patients who were ascertained either at or near the time of diagnosis.
Second, the vast majority of BRCA-associated ovarian cancers are both high grade and of serous histology. Although the authors did perform subanalysis for patients with serous histology, they did not limit this analysis to patients with high-grade disease. As low-grade serous cancer is associated with a substantially more indolent course and does not appear to be a component tumor of the hereditary breast and ovarian cancer syndrome, the inclusion of these patients likely led to a relative improvement in the long-term survival seen in the BRCA-negative patients.
Both of these potential biases likely at least partially explains the much better than expected prognosis of noncarriers in the present study with stage IV disease, who had a 10-year survival of 25% as opposed to the 10.4% rate seen in SEER data. Given these issues, it is not clear that results presented by McLaughlin and colleagues can be considered any more than hypothesis generating. Further studies are needed to confirm or refute whether the short-term survival advantage seen in BRCA-associated ovarian cancer is maintained long term.