Melphalan as a Promising Treatment for BRCA-Related Ovarian Carcinoma

Abstract

Introduction: Melphalan, as a bifunctional alkylating agent has been shown to be selectively efficient in BRCA-deficient case reports of epithelial ovarian cancer (EOC). The clinical benefit of melphalan on unselected platinum-resistant EOC population and stratified by BRCA status has not been clearly elucidated. We aimed to determine the response to melphalan in patients with recurrent EOC after platinum-based therapy.

Material and methods: This retrospective observational study included patients with recurrent EOC treated with melphalan between February 2007 to July 2020. Eligibility criteria included having a histological confirmation of EOC, previous treatment with carboplatin plus paclitaxel regimens, and disease recurrence during treatment with or within 6 months of the end of the platinum-based chemotherapy.

Results: A total of 75 platinum-resistant EOC patients were enrolled. Median age was 69 years (range 41-82). Median of previous therapies before melphalan was 4 (range 1-7). We observed a median follow-up of 32 months (range 1-62), progression-free survival (PFS) and overall survival (OS) of 3.6 months (range 2.9-4.7) and 9.5 months (range 8.0-14.1), respectively. In the whole population, 1 complete response, 6 partial responses and 37 stable diseases were registered with an overall clinical benefit rate of 58.7%. In BRCA1/2 mutant patients, we showed a significant longer PFS compared to BRCA1/2 wild type patients (6.2 versus 2.6 months; hazard ratio (HR) 0.25, 95% confidence interval (CI) 0.10-0.61; p=0.002). Moreover, a trend was seen for BRCA1/2 mutants to have a better OS (25.9 versus 8.0 months; HR 0.38; 95% CI 0.12-1.19; p=0.097).

Conclusions: Our study represents the largest cohort of heavily-pretreated EOC patients receiving melphalan treatment. Here, we report a considerable clinical activity of melphalan chemotherapy, more evident in a subset of BRCA1/2 mutated patients. Prospective studies to validate these findings are warranted.

Keywords: BRCA; melphalan; ovarian cancer; platinum resistance; survival.

Figure 1

Melphalan and DNA repair mechanisms. DNA is continually exposed to a series of insults that cause a range of lesions, from single-strand breaks to base alkylation events. Several mechanisms of DNA repair (such as base excision repair, homologous recombination, non-homologous endjoining, and nucleotide excision repair) can be involved recruiting different key proteins which belong to pathways used in the therapeutic strategy in ovarian cancer. Alkylating agents, platinum salts, and PARP inhibitors are particularly effective in DNA defect repair deficient tumors, albeit through different molecular mechanisms. Melphalan is a bifunctional alkylating agent that produces intra- and inter-strand cross-links in double-strand DNA and provides base alkylation, whereas platinum mainly generates intra-strand crosslinks through platinum coordinated complexes and PARP1 inhibitors block base excision repair leading to single-strand breaks. As a different spectrum of DNA damage is produced by each drug, it is possible that the DNA damage produced by melphalan may be more reliant on BRCA protein products for repair.

Figure 2

Melphalan treatment outcomes in ovarian cancer patients according to BRCA status. Progression-free survival (A) and Overall survival (B) in melphalan-treated ovarian cancer patients according to BRCA status.