Neoadjuvant therapy of BRCA1-driven ovarian cancer by combination of cisplatin, mitomycin C and doxorubicin

Tatiana V Gorodnova,Olga A Smirnova,Khristina B Kotiv,Evgeny N Imyanitov,Anna P Sokolenko,Ekaterina A Nekrasova,Alexandr O Ivantsov,Igor V Berlev,Tatiana N Sokolova,Konstantin D Guseynov

doi:10.1186/s13053-021-00173-2

Abstract

BackgroundCisplatin, mitomycin C and anthracyclines demonstrate high activity in BRCA1-deficient tumors. This study aimed to evaluate the efficacy of the triplet combination of these drugs in BRCA1-driven high-grade serous ovarian carcinomas (HGSOCs).MethodsTen HGSOC patients with germ-line BRCA1 mutation received neoadjuvant chemotherapy (NACT) consisting of mitomycin C 10 mg/m2 (day 1), doxorubicin 30 mg/m2 (days 1 and 8) and cisplatin 80 mg/m2 (day 1), given every 4 weeks (MAP regimen). The comparator group included 16 women, who received standard NACT combination of paclitaxel 175 mg/m2 and carboplatin (6 AUC), given every 3 weeks (TCbP scheme).ResultsNone of the patients treated by the MAP scheme demonstrated complete pathologic response in ovaries, while 4 women showed absence of tumor cells in surgically excised omental specimens. When chemotherapy response scores (CRS) were considered, poor responsiveness (CRS 1) was not observed in the MAP group, but was common for the TCbP regimen (6/16 (38 %) for ovaries and 5/16 (31 %) for omentum; p = 0.05 and 0.12, respectively). Median treatment-free interval (TFI) was not reached in women treated by the MAP, but was 9.5 months for the TCbP scheme (p = 0.1). The rate of the recurrence within 1 year after the completion of the treatment was 4/10 (40 %) for the MAP and 10/13 (77 %) for the TCbP (p = 0.1).ConclusionsThe attempt to intensify NACT by administering combination of 3 drugs did not result in high rate of complete pathologic responses. However, there was a trend towards higher efficacy of the MAP regimen versus conventional TCbP scheme with regard to CRS and clinical outcomes.

Highlights

Cisplatin, mitomycin C and anthracyclines demonstrate high activity in BRCA1-deficient tumors
It was decided that the pilot trial would include 10 patients with initially inoperable BRCA1-driven High-grade serous ovarian cancer (HGSOC), and the main end-point will be the rate of pathologic complete responses
Five patients included in the study of the neoadjuvant combination of mitomycin C, cisplatin and doxorubicin had stage IIIC HGSOC and another 5 women were diagnosed with stage IV disease (Table 1)

Summary

Introduction

Mitomycin C and anthracyclines demonstrate high activity in BRCA1-deficient tumors. Ovarian tumors often do not cause symptoms at early stages; most HGSOC patients are diagnosed with already inoperable disease These women are often subjected to neoadjuvant chemotherapy (NACT), which is aimed to reduce tumor burden and allow surgical intervention [5]. BRCA1-associated ovarian malignancies demonstrate significantly better responses to the NACT as compared to sporadic neoplasms [6] These patients usually undergo complete cytoreductive surgery followed by adjuvant therapy, most BRCA1-driven HGSOCs eventually relapse [7]. The most known mechanism of acquired platinum resistance is the emergence of mutations, which restore the open reading frame in the BRCA1 gene [4] This route is mainly applicable to heavily pretreated patients but appears to be less characteristic for the initial phases of OC therapy [8]. NACT often results in the selection of BRCA1proficient cells, which exist in small amounts in chemonaive tumors and repopulate tumor mass during platinum exposure [9]

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