Have you uncovered the full potential of BRCA testing?

In ovarian cancer, some patients with BRCA mutations may be hiding in plain sight.

    THE CURRENT REALITY

For women diagnosed with ovarian cancer,

Is there more we can do for them?

Ovarian cancer is a life-threatening disease. Approximately 70% of women will experience their first recurrence within just 3 years, and with each recurrence, their prognosis gets progressively worse.1-7 With an estimated 5-year survival rate of less than 50%, this amounts to the highest mortality rate of all gynecological cancers.8

“Watchful waiting” after chemotherapy is a common approach.9 However, disease recurs in the majority of women.1 With each additional line of systemic therapy after recurrence, the length of subsequent treatment-free intervals decreases.10 Therefore, this approach may not be enough for certain women with BRCAm ovarian cancer.

BRCAm=BRCA-mutated.

Recurrence may not have to be the reality. If uncovered, women with BRCAm ovarian cancer have targeted treatment options.11

    THE UNSEEN OPPORTUNITY

For women diagnosed with ovarian cancer,

Are we discovering all possible BRCA mutations?

The most recent guidelines recommend that all women with ovarian cancer receive testing for BRCA mutations.12,13 However, estimates for testing rates in women with ovarian cancer ranged from only 10% to 32% in a 2017 review article.14 It is critical that all women with ovarian cancer receive early testing to identify both somatic and germline BRCA mutations, as this knowledge may inform treatment decisions.11,12

What Is the Difference Between Somatic and Germline BRCA Testing?

Somatic mutations are not inherited mutations; these mutations occur without familial history. They arise in the cancer itself. Somatic mutations can only be detected by tumor testing.15 Germline mutations are inherited and can be detected by tumor testing and blood testing.15,16

The BRCA Testing Gap

Tumor testing may identify approximately 50% more women who have a BRCAm—including both somatic and germline mutations.15 With germline testing alone, 1 out of 3 women with BRCA mutations remains hidden.17,18

Up to 40% of BRCA mutations may be missed if testing is only performed in women with a family history of breast or ovarian cancer.14

Approximately 15% of women with ovarian cancer have a germline BRCAm.19 While nearly 7% have a somatic BRCAm.20

Identify more somatic and germline BRCA mutations by ordering tumor testing for BRCA mutations in all women with ovarian cancer.14,18

Uncovering your patients’ BRCA status early can be an active step toward determining an optimal treatment plan.11,12,21,22

View the latest BRCA testing recommendations in the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian
    THE BRCAm POTENTIAL

In ovarian cancer,

Could PARP-mediated DNA repair impact BRCAm tumors?

Due to their impaired homologous recombination repair capabilities, BRCAm tumor cells rely on the PARP enzyme’s corrective response to repair their damaged DNA.21,22 Because of this, BRCAm tumor cells may be particularly vulnerable to disruption of the PARP repair mechanism, which can lead to accelerated cell death in vitro.21,22


Recent studies have demonstrated a dual effect of PARP inhibition and trapping in experimental models of BRCAm cancer cell lines.22-25,*

Inhibit

Inhibition of PARP can prevent the repair of single-strand breaks, which may then be converted to more cytotoxic double-strand breaks.22,24,25 In BRCAm ovarian cancer, PARP inhibition can potentiate the occurrence of double-strand breaks in DNA to help drive programmed cell death.21,22

Trap

PARP inhibition binds and traps PARP during DNA repair. The newly formed PARP-DNA complex exerts cytotoxic effects on cells.23

PARP=poly (ADP-ribose) polymerase.
*May also affect healthy cells.

Tumor testing enables you to develop an informed treatment plan earlier11,12,15

After tissue is collected using your method of choice, tumor testing can detect both types of BRCA mutations.15 While your patient undergoes chemotherapy, you may receive the test results from the pathologist laboratory. Results typically arrive within 2 weeks.26

  • If your patient is found to have a BRCAm through tumor testing, you can develop a treatment plan without further testing.16,18 However, any patient with a BRCAm should be referred to a genetic counselor for germline BRCA testing.15,18

Test all women with ovarian cancer for somatic and germline BRCA mutations. The results could inform the development of an optimal treatment plan—and uncover the opportunity for different outcomes.11,12

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REFERENCES: 1. Ozols RF, Bundy BN, Greer BE, et al; Gynecologic Oncology Group. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21(17):3194-3200. 2. du Bois A, Lück HJ, Meier W, et al; Arbeitsgemeinschaft Gynäkologische Onkologie Ovarian Cancer Study Group. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst. 2003;95(17):1320-1329. 3. Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 2009;27(9):1419-1425. 4. Burger RA, Brady MF, Bookman MA, et al; Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483. 5. Chan JK, Brady MF, Penson RT, et al. Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer. N Engl J Med. 2016;374(8):738-748. 6. Perren TJ, Swart AM, Pfisterer J, et al; ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-2496. 7. Hanker LC, Loibl S, Burchardi N, et al; AGO and GINECO study group. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol. 2012;23(10):2605-2612. 8. National Cancer Institute. Expected survival life tables. National Cancer Institute website. https://seer.cancer.gov/expsurvival/. Accessed September 6, 2018. 9. NCI Dictionary of Cancer Terms: watchful waiting. National Cancer Institute website. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/watchful-waiting. Accessed September 6, 2018. 10. Eng KH, Hanlon BM, Bradley WH, et al. Prognostic factors modifying the treatment-free interval in recurrent ovarian cancer. Gynecol Oncol. 2015;139(2):228-235. 11. Koczkowska M, Zuk M, Gorczynski A, et al. Detection of somatic BRCA1/2 mutations in ovarian cancer - next-generation sequencing analysis of 100 cases. Cancer Med. 2016;5(7):1640-1646. 12. Lancaster JM, Powell CB, Chen LM, et al; SGO Clinical Practice Committee. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2015;136(1):3-7. 13. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian V.2.2019. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed September 6, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org. 14. Hoskins PJ, Gotlieb WH. Missed therapeutic and prevention opportunities in women with BRCA-mutated epithelial ovarian cancer and their families due to low referral rates for genetic counseling and BRCA testing: a review of the literature. CA Cancer J Clin. 2017;67(6):493-506. 15. Frey MK, Pothuri B. Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature. Gynecol Oncol Res Pract. 2017;4(4):2-11. 16. BRCA mutations: cancer risk and genetic testing. National Cancer Institute website. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet. Accessed October 19, 2018. 17. Vergote I, Banerjee S, Gerdes AM, et al. Current perspectives on recommendations for BRCA genetic testing in ovarian cancer patients. Eur J Cancer. 2016;69:127-134. 18. Hennessy BT, Timms KM, Carey MS, et al. 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(22):3570-3576. 19. Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 20. Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20(3):764-775. 21. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913-917. 22. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921. 23. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588-5599. 24. Haber JE. DNA recombination: the replication connection. Trends Biochem Sci. 1999;24(7):271-275. 25. Dexheimer TS. DNA repair pathways and mechanisms. In: Mathews LA, Cabarcas SM, Hurt E, eds. DNA Repair of Cancer Stem Cells. Dordrecht, Netherlands: Springer Science+Business Media Dordrecht; 2013:19-32. 26. Foundation Medicine website. Genomic testing. https://www.foundationmedicine.com/genomic-testing. Accessed October 18, 2018.