Annals of Surgical Oncology

, Volume 21, Issue 5, pp 1468–1473 | Cite as

Ovarian Cancer in BRCA Mutation Carriers: Improved Outcome After Intraperitoneal (IP) Cisplatin

  • Maryann Kwa
  • Susan Edwards
  • Andrea Downey
  • Elsa Reich
  • Robert Wallach
  • John Curtin
  • Franco Muggia
Regional Cancer Therapies



Ovarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes.


Among 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (n = 18), with floxuridine (n = 30), and with topotecan (n = 14)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials.


Ten patients that were confirmed to have BRCA mutations—all with high-grade and stages IIC to IV disease—survived a median of 10 years (range: 4–18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11 years, respectively.


This experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires further study.


Ovarian Cancer Cancer Stem Cell BRCA Mutation Topotecan BRCA Mutation Carrier 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





  1. 1.
    Rubin SC. BRCA-related ovarian cancer: another piece of the puzzle. Cancer. 2003;97:2127–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Safra T. Hereditary ovarian cancer: biology, response to chemotherapy and prognosis. Women’s Health. 2009;5:543–53.PubMedCrossRefGoogle Scholar
  3. 3.
    Venkitaraman AR. Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu Rev Pathol Mech Dis. 2009; 4: 461–487.CrossRefGoogle Scholar
  4. 4.
    Foulkes WD. BRCA 1 and BRCA 2: chemosensitivity, treatment outcomes and prognosis. Fam Cancer. 2006;5:135–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Rubin SC, Benjamin I, Behbakht K, et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med. 1996;335(19):1413–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Rubin SC, Blackwood MA, Bandera C, Behbakht K, Benjamin I, Rebbeck TR, Boyd J. BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing. Am J Obstet Gynecol. 1998;178(4):670–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Boyd J, Sonoda Y, Federici MG, et al. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA. 2000;283(17):2260–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Cass I, Baldwin RL, Varkey T, et al. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer. 2003;97:2187–95.PubMedCrossRefGoogle Scholar
  9. 9.
    Ben-David Y, Chetrit A, Hirsh-Yechezkal G, et al. Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol. 2002;20(2):463–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Chetrit A, Hirsch-Yechezkal G, Ben-David Y, Lubin F, Friedman E, Sadetzki S. Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the National Israeli Study of Ovarian Cancer. J Clin Oncol. 2008;26(1):20–-5.PubMedCrossRefGoogle Scholar
  11. 11.
    Tan DS, Rothermundt C, Thomas K, et al. “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 Mutations. J Clin Oncol. 2008;26(34):5530–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Safra T, Borgato L, Nicoletto MO, et al. BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther. 2011;10(10):2000–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New Engl J Med. 2006;354:34–43.PubMedCrossRefGoogle Scholar
  14. 14.
    Lesnock J, Darcy K, Tian C, et al. Association between reduced BRCA1 expression and survival in patients with sporadic epithelial ovarian cancer treated with intraperitoneal versus intravenous cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Gynecol Oncol. 2010;116(3):S3 (abstract 4).CrossRefGoogle Scholar
  15. 15.
    Muggia FM. Platinum compounds 30 years after the introduction of cisplatin: implications for the treatment of ovarian cancer. Gynecol Oncol. 2009;112:275–81.PubMedCrossRefGoogle Scholar
  16. 16.
    Trimble EL, Thompson S, Christian MC, Minasian L. Intraperitoneal chemotherapy for women with epithelial ovarian cancer. Oncologist. 2008;13(4):403–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Muggia FM, Groshen S, Russell C, et al. Intraperitoneal carboplatin and etoposide for persistent epithelial ovarian cancer: analysis of results by prior sensitivity to platinum-based regimens. Gynecol Oncol. 1993;50:232–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Muggia FM, Jeffers S, Muderspach L, et al. Phase I/II study of intraperitoneal floxuridine and platinums (cisplatin and/or carboplatin). Gynecol Oncol. 1997;66:290–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Lu MJ, Sorich J, Hazarika M, et al. Intraperitoneal therapy as consolidation for patients with ovarian cancer and negative reassessment after platinum-based chemotherapy. Hematol Oncol Clin N Am. 2003;17:969–75.CrossRefGoogle Scholar
  20. 20.
    Andreopoulou E, Chen T, Liebes L, et al. Phase 1/pharmacology study of intraperitoneal topotecan alone and with cisplatin: potential for consolidation in ovarian cancer. Cancer Chemother Pharmacol. 2011;68(2):457–63.PubMedCrossRefGoogle Scholar
  21. 21.
    Los G, Mutsaers PH, Lenglet WJ, Baldew GS, McVie JG. Platinum distribution in intraperitoneal tumors after intraperitoneal cisplatin treatment. Cancer Chemother Pharmacol. 1990;25(6):389–94.PubMedCrossRefGoogle Scholar
  22. 22.
    Safra T, Wei-Chu VL, Berman T, et al. BRCA mutations and outcome in epithelial ovarian cancer: experience in ethnically diverse groups. Ann Oncol. 2013(supplement) (in press).Google Scholar
  23. 23.
    Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. New Engl J Med. 1996;335(26):1950–5.PubMedCrossRefGoogle Scholar
  24. 24.
    National Cancer Institute (2006). NCI issues clinical announcement for preferred method of treatment for advanced ovarian cancer. Accessed 2 April 2012.
  25. 25.
    Trimble EL, Alvarez RD. Intraperitoneal chemotherapy and the NCI clinical announcement. Gynecol Oncol. 2006;103:S18–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Fasano J, Muggia F. Breast cancer arising in BRCA-mutated background: therapeutic implications from an animal model and drug development. Ann Oncol. 2009;20:609–14.PubMedCrossRefGoogle Scholar
  27. 27.
    Liu X, Holstege H, van der Gulden H, et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci USA. 2007;104:12111–6.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al. Ovarian cancer side population defines cells with stem cell-like characteristics and Müllerian inhibiting substance responsiveness. Proc Natl Acad Sci USA. 2006;103(30):11154–9.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nature Med. 2005;11:63–70.PubMedCrossRefGoogle Scholar
  30. 30.
    Sakai W, Swisher EM, Karlan BY, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated carriers. Nature. 2008;451:1116–20.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Swisher EM, Sakai W, Karlan BY, Wurz K, Urban N, Taniguchi T. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 2008;68(8):2581–6.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Cooke SL, Brenton JD. Evolution of platinum resistance in high-grade serous ovarian cancer. Lancet Oncol. 2011;12(12):1169–74.PubMedCrossRefGoogle Scholar
  33. 33. (2012) Bevacizumab and intravenous or intraperitoneal chemotherapy in treating patients with stage II, stage III, or stage IV ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer. Accessed 22 July 2012.

Copyright information

© Society of Surgical Oncology 2013

Authors and Affiliations

  • Maryann Kwa
    • 1
  • Susan Edwards
    • 2
  • Andrea Downey
    • 1
  • Elsa Reich
    • 1
  • Robert Wallach
    • 1
  • John Curtin
    • 1
  • Franco Muggia
    • 1
  1. 1.New York University Medical CenterNYU Cancer InstituteNew YorkUSA
  2. 2.University of Southern California Medical CenterNorris Cancer CenterLos AngelesUSA

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