Mitomycin C plus cisplatin for systemic treatment of recurrent BRCA1-associated ovarian cancer.

Background Previous studies on neoadjuvant therapy for BRCA1-driven ovarian cancer (OC) demonstrated higher efficacy of mitomycin C plus cisplatin combination as compared to standard drug schemes. These data call for evaluation of the utility of this regimen for the treatment of recurrent BRCA1-associated OC. Methods The study included 12 BRCA1 germ-line mutation carriers, whose disease relapsed after one (n = 4) or two (n = 8) lines of chemotherapy. The patients received cisplatin 100 mg/m2 and mitomycin C 10 mg/m2, given every four weeks, for 6 (n = 10), 8 (n = 1) or 5 (n = 1) cycles. Retrospective data on conventional treatment of OC relapses in BRCA1 heterozygotes (n = 47) served as a control. Results Grade 3-4 toxicities were observed in 4/12 (33%) cases. There were 6 complete responses (CR), 4 partial responses (PR) and 2 instances of stable disease (SD). Comparison of patients receiving mitomycin C plus cisplatin (n = 4) or conventional therapy (n = 44) at first relapse demonstrated marginal improvement of the progression-free survival (PFS) (16.6 months vs. 10.2 months, P = .067). Use of mitomycin C plus cisplatin (n = 8) for the treatment of second relapse resulted in significant prolongation of PFS as compared to standard regimens (n = 31) (14.8 months vs. 4.8 months, P = .002). Conclusions Mitomycin C plus cisplatin shows promising activity in recurrent BRCA1-driven ovarian cancer.

Efficacy of Neoadjuvant Therapy With Cisplatin Plus Mitomycin C in BRCA1-Mutated Ovarian Cancer.

OBJECTIVES: Cisplatin and mitomycin C exert high activity towards BRCA1-deficient cells. This study aimed to evaluate the efficacy of a combination of these drugs in hereditary BRCA1-associated ovarian cancer (OC). METHODS: Twelve OC patients, who could not be treated by primary debulking surgery owing to extensive tumor spread, were given neoadjuvant cisplatin (100 mg/m) and mitomycin C (10 mg/m) every 4 weeks for 3 (n = 9), 2 (n = 2), or 4 (n = 1) cycles. RESULTS: The decrease of tumor burden and complete surgical cytoreduction were achieved in all patients. Pathologic complete response, defined as the absence of tumor cells in surgically removed tissues, was observed in 2 (17%) of 12 cases. Retrospective analysis of 62 OC in BRCA1 mutation carriers subjected to conventional neoadjuvant chemotherapy schemes revealed 36 objective tumor responses (58%) and 37 instances (60%) of complete cytoreductive surgery; however, none of these patients demonstrated pathologic complete response. CONCLUSIONS: The combination of cisplatin plus mitomycin C showed promising results in BRCA1-driven OC and therefore deserves further clinical evaluation.

High frequency of BRCA1, but not CHEK2 or NBS1 (NBN), founder mutations in Russian ovarian cancer patients.

BACKGROUND: A significant portion of ovarian cancer (OC) cases is caused by germ-line mutations in BRCA1 or BRCA2 genes. BRCA testing is cheap in populations with founder effect and therefore recommended for all patients with OC diagnosis. Recurrent mutations constitute the vast majority of BRCA defects in Russia, however their impact in OC morbidity has not been yet systematically studied. Furthermore, Russian population is characterized by a relatively high frequency of CHEK2 and NBS1 (NBN) heterozygotes, but it remains unclear whether these two genes contribute to the OC risk. METHODS: The study included 354 OC patients from 2 distinct, geographically remote regions (290 from North-Western Russia (St.-Petersburg) and 64 from the south of the country (Krasnodar)). DNA samples were tested by allele-specific PCR for the presence of 8 founder mutations (BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, BRCA1 300T>G, BRCA2 6174delT, CHEK2 1100delC, CHEK2 IVS2+1G>A, NBS1 657del5). In addition, literature data on the occurrence of BRCA1, BRCA2, CHEK2 and NBS1 mutations in non-selected ovarian cancer patients were reviewed. RESULTS: BRCA1 5382insC allele was detected in 28/290 (9.7%) OC cases from the North-West and 11/64 (17.2%) OC patients from the South of Russia. In addition, 4 BRCA1 185delAG, 2 BRCA1 4153delA, 1 BRCA2 6174delT, 2 CHEK2 1100delC and 1 NBS1 657del5 mutation were detected. 1 patient from Krasnodar was heterozygous for both BRCA1 5382insC and NBS1 657del5 variants. CONCLUSION: Founder BRCA1 mutations, especially BRCA1 5382insC variant, are responsible for substantial share of OC morbidity in Russia, therefore DNA testing has to be considered for every OC patient of Russian origin. Taken together with literature data, this study does not support the contribution of CHEK2 in OC risk, while the role of NBS1 heterozygosity may require further clarification.