Studies Suggest New Approaches in Hereditary Ovarian Cancer

SAN FRANCISCO–Ovarian cancers associated with mutations in the BRCA gene have a different underlying biology than nonhereditary cancers and may respond better to treatments not routinely applied in ovarian cancer, according to a study reported at the 30th Annual Meeting of the Society of Gynecologic Oncologists.

The study showed that women with certain types of hereditary ovarian cancer survive longer and are typically diagnosed at younger ages than is the case with sporadic (nonhereditary) ovarian cancer.

Jeff Boyd, PhD, and his associates at Memorial Sloan-Kettering Cancer Center reported that:

Ovarian cancer patients with BRCA gene mutations were diagnosed at a mean age of 56, compared to age 61 for similar patients with nonhereditary cancers.

The median survival of patients with a mutation was 47 months vs 27 months for controls (P = .004).

Tumors of patients with a mutation appeared to be more responsive to certain types of chemotherapy not typically thought of as first-line treatment in ovarian cancer.

In an interview, Dr. Boyd said that progression-free survival was “significantly longer” for patients with the BRCA-related cancers than for control subjects.

About 10% of epithelial ovarian carcinomas are thought to be linked to inherited mutations in the BRCA1 or BRCA2 genes. These genes normally function as tumor suppressors. Mutations that impede DNA repair and gene expressions may lead to malignancies with distinct molecular, genetic, pathologic, and clinical features.

Study Limited to Jewish Women

Dr. Boyd explained that in order to attain greater genetic homogeneity, the researchers limited their study to Jewish women with ovarian cancer. “Jewish women who have ovarian cancer and test negative for the three founder mutations, we can be confident truly do not have hereditary cancers,” Dr. Boyd explained. “In the non-Jewish population, there is a relatively high prevalence of false-negative genetic tests.”

Archival tissue specimens from a consecutive series of 933 cases of epithelial ovarian carcinoma were analyzed for the presence of one of the common founder mutations in BRCA1 (185delAG or 5382insC) or BRCA2 (6174delT).

All those positive for such a mutation were the “subject” group (n = 88), while 101 matched patients negative for BRCA mutations were the “controls.” Of the 88 cases, 67 were linked to BRCA1 and 21 were linked to BRCA2.

In BRCA-linked hereditary ovarian cancers, the mean age at diagnosis was 54 (range, 31 to 79) for BRCA1 and 62 (range, 44 to 77) for BRCA2. “The BRCA1 mutations are seen at diagnosis in significantly younger women, but that is not true for BRCA2,” Dr. Boyd said.

The majority of hereditary cancers were of advanced stage, all were moderately to poorly differentiated, and papillary serous tumors predominated.

A survival difference for BRCA1-linked cases correlated with the extent of primary surgical cytoreduction. The ratio of optimally debulked to suboptimally debulked cases in these women was 65 to 35; this ratio was reversed (35 to 65) in controls and BRCA2-linked cases.

Dr. Boyd said that his data suggest that proteins from BRCA mutations are responding differently and more completely to chemotherapy than is the case with tumors of patients without the mutation, since the cases and controls were matched closely for all other prognostic factors known to affect survival.

He suspects that this means that these mutations alter proteins involved in DNA repair and that cancers caused by BRCA mutations may respond best to treatments that cause double-stranded DNA breaks, such as etoposide (VePesid) or radiation therapy, since the mutated BRCA proteins cannot repair the damage.

“We may want to consider treating hereditary ovarian cancer with radiation or with etoposide, which are not typical front-line treatments,” he said.

Dr. Boyd’s group is currently studying the function of BRCA mutations in cancer cells by putting BRCA back into mutant cells and testing response to chemotherapy. A future step might be clinical trials in women who have these mutations based on the regimens found most effective in these laboratory studies.

“This is a good example of translational research in action,” Dr. Boyd said. “We take a clinical observation, use it to lay the foundation for and then prove a scientific hypothesis in the lab (ie, the biologic function of these proteins), then return to the clinic with trials that can alter clinical applications and affect patient survival.

For a “lab guy,” he said, “it is exciting to be able to take a clinical observation and laboratory data and then go back to the clinic with something that has an immediate impact on human health.”