Have you considered the unique link between PARP-mediated DNA repair and BRCA-mutated metastatic breast cancer?1,2

PARP proteins play an integral part of the tumor DNA repair process.1,2 BRCA-mutated tumor cells rely more on PARP and, subsequently, may be particularly vulnerable to PARP disruption.1,2 Disrupting PARP may lead to accelerated cancer cell death.1,2

In metastatic breast cancer (mBC), patients with BRCA-mutated disease are different. Identifying these patients early has many potential implications.3

Leveraging the Link: BRCA-mutated Tumor Cells May Be Vulnerable to Disruption of PARP

Click to Download Additional Information on the MOD

DNA damage and repair occur naturally.

DNA Damage and Repair Occur Naturally

  • DNA is subject to continual damage from both endocellular defects and exocellular forces such as chemotherapy and radiation4
  • DNA damage occurs in different ways, including single-strand breaks (SSBs) and double-strand breaks (DSBs)4
  • Specific repair mechanisms exist to address SSBs and DSBs:
    • PARP enzymes play a fundamental role in SSB repair by helping to recruit other DNA repair proteins4
    • BRCA1/2 proteins are essential for DSB repair through a high-fidelity process called homologous recombination4
  • Unrepaired SSBs become DSBs, which can be more harmful to the cell4,5
DNA Repair May be compromised in Tumor Cells.

DNA Repair May Be Compromised in Tumor Cells

  • If SSBs and DSBs go unrepaired in normal cells, they can lead to the development of cancer4
  • Cancerous tumor cells continue to accumulate DNA damage as they grow6
    • This damage may be caused by errors in DNA damage repair processes or defects in cell cycle checkpoints6
  • Deficiencies in DNA repair mechanisms, including loss of PARP and BRCA function within the tumor cell, can accelerate the buildup of DNA damage, prompting potential tumor cell death1,2
BRCAm Tumors rely on PARP to Repair DNA.

BRCA-mutated Tumors Rely More on PARP to Repair DNA

  • BRCA-mutated tumor cells are more vulnerable to the effects of DNA damage compared with normal cells1
  • Mutations to the BRCA gene prevent BRCA-mutated tumor cells from using homologous recombination to repair damaged DSBs1
  • In the absence of homologous recombination, BRCA-mutated tumor cells have a greater reliance on PARP for DNA repair1
Targeting PARP may prevent DNA damage repair. Loss of PARP May Result in selective and accelerated cancer cell death.

Targeting PARP May Prevent DNA Damage Repair. Loss of PARP May Result in Selective and Accelerated Cancer Cell Death

  • Disrupting PARP-mediated DNA repair has shown antitumor activity in BRCA-mutated tumor cells1,2
  • Loss of the PARP repair process, coupled with impaired ability to repair DSBs in BRCA-mutated tumor cells, may result in the accumulation of additional DNA damage, leading to potential tumor cell death1,2

PARP ENZYMES PLAY A KEY ROLE IN DNA REPAIR ESSENTIAL FOR TUMOR CELL SURVIVAL IN BRCA-MUTATED mBC.

There may be potential in disrupting the PARP repair mechanism in BRCA-mutated mBC

  • PARP proteins play an integral part of the tumor DNA repair process by helping to repair single-strand DNA breaks (SSBs) before they become more cytotoxic double-strand breaks (DSBs)4,5
  • BRCA-mutated tumor cells are prevented from using homologous recombination to repair these damaging DSBs, making them particularly reliant on PARP for DNA repair1
  • The underlying deficiencies in DNA repair pathways observed in BRCA-mutated mBC that lead to genomic instability may increase sensitivity to modalities that target PARP1

Research is focusing on the PARP repair mechanism in BRCA-mutated breast cancer.7

BRCA Mutations May Be More Prevalent Than Expected

BRCA gene mutations greatly increase cancer risk and are the most common cause of hereditary breast cancer. Although BRCA mutations can occur in any patient with breast cancer, they’re more common in certain breast cancer subtypes.8,9

In 2017, an estimated 255,180 new cases of invasive breast cancer were diagnosed in the United States10

BRCA Mutations are more prevalent in certain breast cancer subtypes. BRCA Mutations are more prevalent in certain breast cancer subtypes.

Remember: BRCA-mutated breast cancer cannot be easily identified based on patient or tumor characteristics alone.

Below, consider the common characteristics of a “typical” patient with a BRCA mutation. Then, contrast them against other patient characteristics you may not have considered9:

Patient characteristics commonly associated with BRCA-mutated metastatic breast cancer. Patient characteristics commonly associated with BRCA-mutated metastatic breast cancer.

Patients With BRCA-mutated mBC May Have Worse Outcomes

BRCA-mutated mBC has tumor characteristics that are linked to more aggressive disease and poor prognosis, including:

  • High grade19-21
  • Bulky disease22,23
  • Basal-like subtype (BRCA1)24-26
  • Visceral metastasis19,27
  • High mitotic activity22,28
  • Ki67 positivity27,29
  • Low ER/PR expression29,30
  • Luminal B subtype (BRCA2)16,31

Early Identification of BRCA Status May Offer Important Information3

BRCA testing helps patients and their families learn about their risk of developing breast, ovarian, and other familial cancers. Test results could also help determine options to manage cancer risk, such as enhanced screening, prophylactic surgery, and chemoprevention.3

Identify BRCA status according to testing guidelines in patients with mBC.

View the NCCN Guidelines® for Breast Cancer Screening and Diagnosis

NCCN=National Comprehensive Cancer Network® (NCCN®).

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

SEE REFERENCES

1. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913-917. 2. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917-921. 3. BRCA1 and BRCA2: cancer risk and genetic testing. National Cancer Institute website. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet. Accessed September 27, 2017. 4. Dexheimer TS. DNA repair pathways and mechanisms. In: Mathews LA, Cabarcas SM, Hurt E, et al, eds. DNA Repair of Cancer Stem Cells. Dordrecht, Netherlands: Springer Science+Business Media; 2013:19-32. 5. Haber JE. DNA recombination: the replication connection. Trends Biochem Sci. 1999;24(7):271-275. 6. Pikor L, Thu K, Vucic E, et al. The detection and implication of genome instability in cancer. Cancer Metastasis Rev. 2013;32:341-352. 7. Livraghi L, Garber JE. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med. 2015;13:188. doi:10.1186/s12916-015-0425-1. 8. Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5). doi:10.1093/jnci/dju055. 9. Tung N, Lin NU, Kidd J, et al. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol. 2016;34(13):1460-1468. 10. American Cancer Society. Breast Cancer Facts & Figures 2017-2018. Atlanta: American Cancer Society, Inc. 2017. 11. Malone KE, Daling JR, Doody DR, et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res. 2006;66(16):8297-8308. 12. Couch FJ, Farid LM, DeShano ML, et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet. 1996;13(1):123-125. 13. Pal T, Bonner D, Cragun D, et al. A high frequency of BRCA mutations in young black women with breast cancer from Florida. Cancer. 2015;121(23):4173-4180. 14. John EM, Miron A, Gong G, et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA. 2007;298(24):2869-2876. 15. Kurian AW. BRCA1 and BRCA2 mutations across race and ethnicity: distribution and clinical implications. Curr Opin Obstet Gynecol. 2010;22:72-78. 16. Larsen MJ, Kruse TA, Tan Q, et al. Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling. PLoS One. 2013;8(5):e64268. doi:10.1371/journal.pone.0064268. 17. Mavaddat N, Barrowdale D, Andrulis IL, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev. 2012;21:134-147. 18. Stratton MR. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet. 1997;349:1505-1510. 19. Bayraktar S, Gutierrez-Barrera AM, Lin H, et al. Outcome of metastatic breast cancer in selected women with or without deleterious BRCA mutations. Clin Exp Metastasis. 2013;30(5):623-641. doi:10.1007/s10585-013-9567-8. 20. Bane AL, Beck JC, Bleiweiss I, et al. BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. Am J Surg Pathol. 2007;31(1):121-128. 21. Largillier R, Ferrero J-M, Doyen J, et al. Prognostic factors in 1038 women with metastatic breast cancer. Ann Oncol. 2008;19(12):2012-2019. 22. Lakhani SR, Jacquemier J, Sloane JP, et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst. 1998;90(15):1138-1145. 23. Silverberg SG, Chitale AR, Levitt SH. Prognostic significance of tumor margins in mammary carcinoma. Arch Surg. 1971;102:450-454. 24. Foulkes WD, Stefansson IM, Chappuis PO, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst. 2003;95(19):1482-1485. 25. Lakhani SR, Reis-Filho JS, Fulford L, et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res. 2005;11(14):5175-5180. 26. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329-2334. 27. Savci-Heijink CD, Halfwerk H, Hooijer GKJ. Retrospective analysis of metastatic behaviour of breast cancer subtypes. Breast Cancer Res Treat. 2015;150:547-557. doi:10.1007/s10549-015-3352-0. 28. van Diest PJ, van der Wall E, Baak JPA. Prognostic value of proliferation in invasive breast cancer: a review. J Clin Pathol. 2004;57:675-681. 29. van der Groep P, Bouter A, van der Zanden R, et al. Distinction between hereditary and sporadic breast cancer on the basis of clinicopathological data. J Clin Pathol. 2006;59:611-617. 30. Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 2007;9(1):R6. 31. Tran B, Bedard PL. Luminal-B breast cancer and novel therapeutic targets. Breast Cancer Res. 2011;13(6):221. doi:10.1186/bcr2904.