Skip to main content

Evidence for clinical efficacy of mitomycin C in heavily pretreated ovarian cancer patients carrying germ-line BRCA1 mutation

Abstract

Ovarian carcinomas (OC) arising in BRCA1 and BRCA2 mutation carriers demonstrate pronounced sensitivity to platinum-based therapy due to deficiency of double-strand break DNA repair. However, the choice of subsequent treatment lines for this category of women remains complicated. We considered mitomycin C for heavily pretreated hereditary OC patients, based on multiple evidence for BRCA-specific activity of this drug. Twelve patients carrying BRCA1 germ-line mutation were included in the study. All women had a history of surgical intervention followed by adjuvant platinum-based therapy; three patients also received platinating agents prior the operation. The number of preceding treatment lines for metastatic disease was one for three patients, two for four patients, three for two patients, four for two patients and six for one woman. Administration of mitomycin C (10 mg/m2, every 4 weeks) resulted in one complete response (duration 36 weeks), two partial responses (duration 36 and 48 weeks) and six instances of disease stabilization (duration 12, 16, 20, 24, 24 and 24 weeks). In addition, three patients with the stable disease showed a decline of CA-125 level. We conclude that mitomycin C may deserve further evaluation in clinical trials involving BRCA1/2-related cancers.

This is a preview of subscription content, access via your institution.

References

  1. Imyanitov EN, Moiseyenko VM. Drug therapy for hereditary cancers. Hered Cancer Clin Pract. 2011;9:5.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  2. Suspitsin EN, Sherina NY, Ponomariova DN, Sokolenko AP, Iyevleva AG, Gorodnova TV, Zaitseva OA, Yatsuk OS, Togo AV, Tkachenko NN, Shiyanov GA, Lobeiko OS, Krylova NY, Matsko DE, Maximov SY, Urmancheyeva AF, Porhanova NV, Imyanitov EN. High frequency of BRCA1, but not CHEK2 or NBS1 (NBN), founder mutations in Russian ovarian cancer patients. Hered Cancer Clin Pract. 2009;7:5.

    PubMed  Article  PubMed Central  Google Scholar 

  3. Alsop K, Fereday S, Meldrum C, de Fazio A, Emmanuel C, George J, Dobrovic A, Birrer MJ, Webb PM, Stewart C, Friedlander M, Fox S, Bowtell D, Mitchell G. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30:2654–63.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  4. Bast RC Jr, Mills GB. Personalizing therapy for ovarian cancer: BRCAness and beyond. J Clin Oncol. 2010;28:3545–8.

    PubMed  Article  CAS  Google Scholar 

  5. Hennessy BT, Timms KM, Carey MS, Gutin A, Meyer LA, Flake DD 2nd, Abkevich V, Potter J, Pruss D, Glenn P, Li Y, Li J, Gonzalez-Angulo AM, McCune KS, Markman M, Broaddus RR, Lanchbury JS, Lu KH, Mills GB. Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol. 2010;28:3570–6.

    PubMed  Article  PubMed Central  Google Scholar 

  6. Sun C, Li N, Ding D, Weng D, Meng L, Chen G, Ma D. The role of BRCA status on the prognosis of patients with epithelial ovarian cancer: a systematic review of the literature with a meta-analysis. PLoS One. 2014;9:e95285.

    PubMed  Article  PubMed Central  Google Scholar 

  7. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott C, Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt A. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376:245–51.

    PubMed  Article  CAS  Google Scholar 

  8. Adams SF, Marsh EB, Elmasri W, Halberstadt S, Vandecker S, Sammel MD, Bradbury AR, Daly M, Karlan B, Rubin SC. A high response rate to liposomal doxorubicin is seen among women with BRCA mutations treated for recurrent epithelial ovarian cancer. Gynecol Oncol. 2011;123:486–91.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  9. Safra T, Borgato L, Nicoletto MO, Rolnitzky L, Pelles-Avraham S, Geva R, Donach ME, Curtin J, Novetsky A, Grenader T, Lai WC, Gabizon A, Boyd L, Muggia F. BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther. 2011;10:2000–7.

    PubMed  Article  CAS  Google Scholar 

  10. Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, Amnon A, Bell-McGuinn KM, Chen LM, Friedlander M, Safra T, Vergote I, Wickens M, Lowe ES, Carmichael J, Kaufman B. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol. 2012;30:372–9.

    PubMed  Article  CAS  Google Scholar 

  11. Moynahan ME, Cui TY, Jasin M. Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res. 2001;61:4842–50.

    PubMed  CAS  Google Scholar 

  12. Yun J, Zhong Q, Kwak JY, Lee WH. Hypersensitivity of Brca1-deficient MEF to the DNA interstrand crosslinking agent mitomycin C is associated with defect in homologous recombination repair and aberrant S-phase arrest. Oncogene. 2005;24:4009–16.

    PubMed  Article  CAS  Google Scholar 

  13. Santarosa M, Del Col L, Tonin E, Caragnano A, Viel A, Maestro R. Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers. Mol Cancer Ther. 2009;8:844–54.

    PubMed  Article  CAS  Google Scholar 

  14. Creech RH, Shah MK, Catalano RB, Dierks K, Dayal H, Goldberg-Alberts R. Phase II study of low-dose mitomycin in patients with ovarian cancer previously treated with chemotherapy. Cancer Treat Rep. 1985;69:1271–3.

    PubMed  CAS  Google Scholar 

  15. Hoskins PJ, McMurtrie E, Swenerton KD. A phase II trial of mitomycin in patients with epithelial ovarian carcinoma resistant to cisplatin or carboplatin. Am J Clin Oncol. 1990;13:416–9.

    PubMed  Article  CAS  Google Scholar 

  16. Sokolenko AP, Rozanov ME, Mitiushkina NV, Sherina NY, Iyevleva AG, Chekmariova EV, Buslov KG, Shilov ES, Togo AV, Bit-Sava EM, Voskresenskiy DA, Chagunava OL, Devilee P, Cornelisse C, Semiglazov VF, Imyanitov EN. Founder mutations in early-onset, familial and bilateral breast cancer patients from Russia. Fam Cancer. 2007;6(3):281–6.

    PubMed  Article  CAS  Google Scholar 

  17. Romero I, Bast RC Jr. Minireview: human ovarian cancer: biology, current management, and paths to personalizing therapy. Endocrinology. 2012;153:1593–602.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  18. Villarroel MC, Rajeshkumar NV, Garrido-Laguna I, De Jesus-Acosta A, Jones S, Maitra A, Hruban RH, Eshleman JR, Klein A, Laheru D, Donehower R, Hidalgo M. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol Cancer Ther. 2011;10:3–8.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  19. Chalasani P, Kurtin S, Dragovich T. Response to a third-line mitomycin C(MMC)-based chemotherapy in a patient with metastatic pancreatic adenocarcinoma carrying germline BRCA2 mutation. JOP. 2008;9:305–8.

    PubMed  Google Scholar 

  20. James E, Waldron-Lynch MG, Saif MW. Prolonged survival in a patient with BRCA2 associated metastatic pancreatic cancer after exposure to camptothecin: a case report and review of literature. Anticancer Drugs. 2009;20:634–8.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the by the Russian Scientific Fund (Grant Number 14-25-00111).

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Evgeny N. Imyanitov.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Moiseyenko, V.M., Chubenko, V.A., Moiseyenko, F.V. et al. Evidence for clinical efficacy of mitomycin C in heavily pretreated ovarian cancer patients carrying germ-line BRCA1 mutation. Med Oncol 31, 199 (2014). https://doi.org/10.1007/s12032-014-0199-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-014-0199-x

Keywords

  • BRCA1
  • BRCA2
  • Ovarian cancer
  • Mitomycin C
  • Hereditary cancer syndromes