Letrozole Maintenance Demonstrates Improved RFS in Ovarian Cancer

According to a small, single-site prospective observation, women with ER-positive advanced high-grade serous ovarian cancer who received maintenance therapy with letrozole (Femara) were more likely to be recurrence-free at 24 months, suggesting that letrozole may have a role to play in this setting, especially for patients with chemotherapy resistance or residual disease.

In the study at University Hospital Basel, a group of 50 ER-positive high-grade serous ovarian cancer (HGSOC) FIGO III/IV patients were treated with standard adjuvant platinum-based chemotherapy. Then 23 patients received 2.5 mg of daily letrozole maintenance therapy and 27 patients served as a control group. The letrozole arm consisted of 60% FIGO III and 40% FIGO IV patients compared with 75% FIGO III and 25% FIGO IV in the control group. The groups were comparable for residual disease (R0 in 58%).

Investigators found that 60% of patients assigned to letrozole were recurrence-free versus 38.5% in the control group (P= .035). The control group reached IC₅₀after 13.2 months, but recurrence-free survival (RFS) could not be calculated for the experimental group because only 1 patient had reached that endpoint at the time of the analysis.

“In our small single-site prospective observation in HGSOC FIGO III/IV patients, we could demonstrate a significant progression-free survival benefit from maintenance treatment with letrozole following standard of care,” corresponding author Viola Heinzelmann-Schwarz, MD, PhD, University Hospital Basel, et al wrote. “This positive effect could particularly be seen when the treatment was initiated within 3 months after the end of adjuvant chemotherapy.”

Investigators also observed the RFS benefit with letrozole in a group of high-risk patients with residual disease who were treated with bevacizumab (Avastin) maintenance: after 12 months, the RFS rate was 87.5% with letrozole in addition to bevacizumab versus 20.8% with bevacizumab alone (P = .026).

In the overall study, investigators working in Australia and Switzerland performed a retrospective analysis on data from 4278 patients collected in 4 cohorts:

• ESR1 gene expression was measured in the publicly available US-American TCGA and the Australian Tothill datasets (cohort A; n = 527)
• ER expression in HGSOC FIGO III/IV cancer patients was measured in another US-American cohort from Caris Life Sciences (cohort B; n = 4071)
• primary and matched recurrent HGSOC FIGO stage III/IV patients were examined for ER expression (cohort C; n = 80)
• all newly diagnosed HGSOC FIGO III/IV with positive ER expression using IHC were prospectively included in the investigators’ single-site letrozole maintenance treatment approach at the University Hospital Basel, Gynecological Cancer Centre (cohort D; n = 50)

Since 2013, all newly diagnosed HGSOC FIGO III/IV patients with ER positive cancers equal or above 1% treated at University Hospital Basel have been offered 2.5 mg of daily letrozole as an off-label maintenance treatment following debulking surgery and adjuvant platinum-based chemotherapy.

Reviewing the TCGA PANCAN database, investigators foundESR1expression to be a predictor in all cancers for overall disease-free survival (n = 8901; hazard ratio [HR], 0.935; 95% CI, 0.9222-0.9474; p-value based on Cox regression <2e&minus;16), and RFS (n = 5664; HR, 0.909; 95% CI, 0.8905-0.9287; p-value based on Cox regression <2e&minus;16).

Investigators then analyzed the expression of ESR1 in different TCGA cancer types and found that ESR1 expression was &ldquo;strikingly&rdquo; upregulated in breast, endometrial, and ovarian cancers. They noted that this suggests that endometrial and ovarian cancer might be targetable with similar drugs as currently used in ER-positive breast cancer patients.

Almost half of FIGO III/IV US-American patients with high-grade serous ovarian cancer (cohort B; n = 4071) expressed ER-positivity as measured by IHC. The ER-expression pattern was similar at different treatment sites, and therefore had no effect on the overall result.

Reference:

Heinzelmann-Schwarz V, Mészaros AK, Stadlmann S, et al. Letrozole may be a valuable maintenance treatment in high-grade serous ovarian cancer patients [published online November 17, 2017]. Gynecol Oncol. doi: 10.1016/j.ygyno.2017.10.036.