BRCA1/2 Protection Factor Decreases over Time in Epithelial Ovarian Cancer, Study Reports

Women with invasive epithelial ovarian cancer have better survival rates at five years of diagnosis if they carry mutations in the BRCA1 and BRCA2 genes. However, this benefit decreases over 15 years of follow-up, according to a long-term study from Israel.

The research, “Fifteen-year survival of invasive epithelial ovarian cancer in women with BRCA1/2 mutations – the National Israeli Study of Ovarian Cancer,” appeared in the journal Gynecologic Oncology.

Although studies have shown that ovarian cancer patients with BRCA1/2 mutations respond better to platinum-based chemotherapy and have extended survival at up to five years of diagnosis compared to patients without such mutations, whether this translates into prolonged survival in the long term remains unclear.

Aiming to address this gap, scientists analyzed the 5-, 10-, and 15-year survival rates of 779 Jewish women (median age at diagnosis 60 years) with invasive epithelial ovarian cancer with or without BRCA1/2 mutations.

All patients were diagnosed between 1994 and 1999 and were followed up to November 2015 through the Israel National Population Registry. Also, all patients were treated by tumor-debulking surgery, followed by platinum-based chemotherapy.

A total of 229 women were carriers of the Ashkenazi Jewish founder mutations in BRCA1 — known as 185delAG and 5382insC – and BRCA2 (6174delT), while 550 were non-carriers. The carriers were significantly younger at diagnosis (57.3 vs 60 years) and had a higher proportion of grade III/IV cancer, which refers to cells with increasingly abnormal appearance and more likely to spread.

Among the total group of patients, 77.7% were of Ashkenazi origin and 22.3% were non-Ashkenazi. The proportion of women of Ashkenazi origin was higher in the carrier than in the non-carrier group (93% vs. 71%).

The results revealed 629 deaths by the end of the follow-up period. A total of 306 women (39.3%) were alive at five years; 202 (25.9%) were alive at 10 years, and 171 (22%) were alive at 15 years of follow-up. The median survival in the overall study population was 42 months.

At each timepoint, women with more advanced cancer stage, grade III/IV, serous morphology — the most common type of epithelial ovarian cancer — 60 years or older at diagnosis, and of Ashkenazi origin showed shorter survival.

Compared to non-carriers, women carrying BRCA1/2 gene mutations had significantly higher survival rates throughout the study period, although the difference declined over time — 46.7% vs. 36.2% at five years, 28% vs 25.1% at 10 years, and 22.3% vs. 21.8% at 15 years.

A subsequent analysis revealed that carriers had lower likelihood of death from any cause. At five years, being a carrier correlated with 26% less mortality compared to non-carriers. However, this benefit disappeared at 10 and 15 years.

“In other words, after surviving the first five years following the diagnosis, being a BRCA carrier did not provide any survival protection,” the scientists stated. They hypothesized that ovarian cancer recurrences after the initial five years may be chemotherapy-resistant, which would mean that having BRCA gene mutations would no longer confer an advantage.

“Our results show that while indeed better survival among carriers is evident up to 15 years following the diagnosis, the advantage in survival observed among the carriers is driven by the first five years and decreases over time,” the team said. “Clinically, this may have implications for follow-up and therapy, especially of new agents that are particularly effective in BRCA carriers.”