BRCA1/2 Testing in Ovarian Cancer Misses Many Mutations

A study using next-generation sequencing showed that genetic testing limited toBRCA1/2mutations would have missed 29% of mutations that carry hereditary risk of ovarian cancer.

Moreover, the sequencing results from 2 large clinical trials identified mutations in 75% more patients compared with previous estimates. Neither tumor histology nor primary disease site informed the likelihood of an association with mutations. Survival varied by mutation status, particularly the presence ofBRCA2mutations.

“All ovarian cancer patients should have genetic counseling,” Barbara Norquist, MD, a gynecologic oncologist at the University of Washington in Seattle, reported at the Society of Gynecologic Oncology 45th Annual Meeting on Women’s Cancer. “Testing forBRCA1andBRCA2only, will miss a substantial proportion of mutations that could confer hereditary risk.”

“Histology should not be used to guide referrals for genetic testing,” she added. “Clinical trials should stratify by mutation status when assessing survival.”

Estimates of the prevalence of hereditary ovarian cancer traditionally have topped out at about 10% of all ovarian cancer.BRCA1/2mutations have been shown to account for the vast majority of hereditary cases, followed by mutations associated with Lynch syndrome, according to Norquist.

Recently, several published reports have documented previously unrecognized mutations associated with ovarian cancer. In one such study, investigators employed new sequencing technology to identify mutations in 23% of patients with ovarian cancer. Mutations other thanBRCA1/2accounted for 25.9% of all the mutations.

To continue the investigation of the number and frequency of mutations associated with ovarian cancer, Norquist and colleagues used the 47- gene BROCA-HR targeted capture and massively parallel sequencing test to analyze bloods samples from patients in 2 Gynecologic Oncology Group (GOG) trials (GOG 218 and 262). In both trials, patients with newly diagnosed ovarian cancer had debulking surgery followed by chemotherapy.

The BROCA-HR test was used to sequence samples from 1347 women in the 2 trials combined. After discarding common and functionally inconsequential mutations, they validated the remaining mutations by Sanger sequencing.

The final results showed that clinically significant mutations were identified in 258 of the 1347 samples (19.2%).BRCA1/2accounted for 185 of the mutations (13.7%), and other cancer-associated mutations were detected in 75 samples (5.6%; includes samples with more than 1 mutation).

Consistent with other recent studies, the results showed substantially more risk-conferring mutations (~29% vs ~10%) compared with historical estimates. Mutations associated with Lynch syndrome accounted for 2.3% of the total.

Five other mutations contributed more to the total number than did Lynch syndrome:BRIP1(7.1%),PALB2(3.4%),CHEK2, (2.6%),NBN(3%), andATM(3.4%). Another mutation occurred with the same frequency as Lynch syndrome (RAD51D, 2.3%).

Using clinical data from GOG 218, investigators examined the relationship between mutations and the data. The analysis showed that patients withBRCA1mutations had a median age of 49.2 years compared with 61.6 for wildtype tumors, 59.7 forBRCA2tumors, and 58.8 for other mutations (P <.001 forBRCA1vs others).

Tumor histology proved to be uninformative about mutation status, as no consistent pattern emerged for wildtype tumors,BRCA1,BRCA2, or other mutations. Similarly, wild-type status and the mutations were represented in ovarian, primary peritoneal, and Fallopian tube cancers.

Median progression-free survival was highest forBRCA2-mutated tumors (21.8 months), followed by BRCA1 (15.6 months), wild-type (14 months), and other mutations (13.8 months). Median overall survival was 57.1 months for patients withBRCA1mutations, 54.2 months for other mutations, 46.1 months for wild-type tumors, and had yet to be reached in patients with BRCA2 mutations.

&ldquo;We found that survival was influenced by mutation status, particularlyBRCA2mutations,&rdquo; said Norquist.