From this analysis, we report a progression-free and overall survival advantage for ovarian cancer patients with germline BRCA1
mutations not associated with Ashkenazi Jewish heritage. Our data are consistent with reports of the survival advantage afforded patients with Ashkenazi Jewish BRCA founder mutations [12
]. Boyd et al. showed that eighty-one Jewish patients with BRCA-associated ovarian cancer had a significantly longer disease-free interval after primary chemotherapy (p
< 0.001), and improved overall survival (p
= 0.004) compared to those patients without a BRCA mutation [12
]. Ben David et al. demonstrated that 234 Israeli ovarian cancer patients carrying Ashkenazi Jewish BRCA mutations had an improved survival of 3 years (p
< 0.001) over non-carriers [13
]. Our study demonstrates that, compared to matched, ovarian cancer patients, non-AJ BRCA mutation carriers had longer PFS (p
<0.001) and OS (p
<0.001). In addition, BRCA status was an independent predictor of both progression-free and overall survival. A recent retrospective-cohort study by Tan et al., reported similar finding regarding differences in overall survival (p
<0.002) and time to first relapse (p
<0.001), using matching criteria similar to that of the current study [17
]. However, the Tan study included only 22 BRCA-positive patients, which included patients with both BRCA Jewish founder mutations and non-Jewish BRCA mutations. Our study included a large number of ovarian cancer patients with non-Jewish BRCA mutations and was consistent in finding a survival advantage for women with BRCA mutations. In addition, this report clarifies previous earlier reports of conflicting data regarding BRCA-positive ovarian cancer patients not of Jewish heritage [15
The control group from GOG 182 provides a second, large group of advanced-stage ovarian cancer patients for comparison and validates the results obtained with our sporadic-matched patients. The survival advantage afforded to BRCA mutation carriers is evident, even though the GOG control group may include BRCA mutation carriers. In fact, the inclusion of BRCA mutation carriers would tend to shift the results toward the null hypothesis of no difference in survival. The GOG control group is similar to our control group, in that it includes only advanced-stage epithelial ovarian cancer patients. Also, both control groups include a variety of patients that may have had optimal or suboptimal tumor reduction/cytoreductive surgery, as well as possible interval cytoreductive surgery.
It is noted that overall survival is shorter in the GOG control group than our sporadic-matched group (42.9 months vs. 54.3 months). The difference could be attributed to younger age of the matched-sporadic cohort (as a result of matching). In addition, because the sporadic patients had to survive for a certain period of time in order to be matched for the “interval to testing,” their survival times may be longer than that of a random group of advanced-stage epithelial ovarian cancer patients.
Our study failed to demonstrate a significant difference in odds of complete response to initial chemotherapy between the BRCA mutation carriers and their sporadic counterparts. This may be due to the fact that data on response to initial chemotherapy was unknown in 10.8% of patients.
There is an inherent dilemma in performing a study based on a genetic test, when that particular test is not “standard of care” for all patients with ovarian cancer. This dilemma is easily overcome in the Jewish population because a majority of Jewish mutation carriers carry one of only three founder mutations. Genetic testing is not only warranted, but is less expensive, in that specific population. When not all patients in both cohorts are tested, there is concern for possible “survival bias,” a criticism of the Rubin study [20
] and others [21
]. Our goal was to overcome these confounding factors in study design in order to address the question of a possible survival advantage afforded by non-AJ BRCA mutations. In order to be included in this matched group, a sporadic patient had to have survived at least as long as the corresponding BRCA mutation carrier lived to undergo genetic testing. Thus, the date of genetic testing was the starting point for any difference in survival. Matching for “interval to testing” may have actually underestimated the survival advantage, because sporadic patients who died early of their disease would have been excluded from the sporadic-matched group and would not have been included in the analysis. This specific bias would potentially affect the results by shifting the survival of the sporadic group toward the null, lessening the reported difference in both progression-free and overall survival in the matched comparison. Therefore, the difference in survival, between the non-AJ BRCA patients and the sporadic patients, may have been underestimated in our study.
As defined, even patients in the sporadic group have up to a 35% risk of carrying a deleterious BRCA mutation, with a negative personal and family history [22
], leading to possible misclassification of BRCA-associated cancers within the sporadic group. In addition, age-matching within in the sporadic group led to a younger median age of diagnosis then the “typical” sporadic patients. Although these patients have no other risk factors for BRCA mutation, young age alone may increase risk of BRCA mutation. The possibility of undetected BRCA mutations in the sporadic group may have lead to a bias toward the null hypothesis, underestimating the survival difference attributable to BRCA mutations.
This study gives insight into the natural history of ovarian cancer in BRCA mutations carriers. This is the largest evaluation of survival in a group of non-Ashkenazi Jewish BRCA mutation carriers. Given that U.S. population data estimates that less than two percent of the U.S. population is of Ashkenazi Jewish heritage, this study provides information on survival of BRCA mutations carriers that is more generalizable than information provided in previous studies of Jewish BRCA mutation carriers alone.