When a patient is diagnosed with pancreatic cancer,

Can the presence of BRCA1/2 mutations help inform prognosis?

Approximately 5% to 9% of patients with pancreatic cancer have a BRCA1/2m.1-5

BRCA1/2 gene mutations can compromise the ability of tumor cells to correct damage to the genome through the loss of homologous recombination repair (HRR)—which may increase reliance on PARP-mediated DNA repair pathways for survival.9

HRR proteins, such as BRCA1 or BRCA2, play an essential role in DNA damage repair mechanisms10,11

Single Strand Breaks
Double Strand Breaks
BRCA repair chart

Tumor cells that lose the ability to repair damage through HRR must fix double-strand breaks (DSBs) through an error-prone pathway called nonhomologous end joining (NHEJ).9 Due to their impaired HRR capabilities, BRCA1/2m tumor cells may rely on the PARP enzyme’s corrective response to repair single-strand breaks (SSBs) before they result in DSBs that require NHEJ.9
BRCA1/2m tumor cells may be particularly vulnerable to disruption of the PARP repair mechanism, which can lead to accelerated cell death in vitro.12,13

Testing rates for BRCA1/2 are low in patients with pancreatic cancer.

Nearly 80% of patients with pancreatic cancer do not receive BRCA1/2 testing—but uncovering their status could inform treatment decisions.6,7

Understanding the molecular profile of a patient’s pancreatic cancer may help identify a distinct patient population that could be more responsive to certain kinds of chemotherapy.8

In a pair of retrospective studies in patients with advanced BRCA1/2m pancreatic cancer, patients who received platinum-based chemotherapy (n=42*) had better overall survival when compared with patients who did not (n=33*).14,15

*Combined n from both studies.

Uncover hidden information—test for BRCA1/2 mutations.

Testing your patient with pancreatic cancer for a BRCA1/2m can help as you develop a treatment plan

NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) recommend tumor molecular testing for all patients with metastatic pancreatic cancer who are candidates for anticancer therapy, including the option of platinum-based chemotherapy, and germline testing for all patients diagnosed with pancreatic cancer.8

Discovering that a tumor harbors a BRCA1/2m or PALB2m may inform the use of chemotherapies, including the option of platinum-based treatment, as well as guide assessment of familial risk.8 If tumor molecular testing uncovers a BRCAm, refer patients with a positive result for additional germline testing to understand familial risk.

View the latest testing recommendations for pancreatic cancer in the NCCN Guidelines® for Pancreatic Adenocarcinoma

VIEW RECOMMENDATIONS

Test all patients with pancreatic cancer for BRCA1/2 mutations.

Discovering if your patient has BRCA1/2m pancreatic cancer is an important step to:

1Help inform prognosis14,15

2Uncover treatment opportunities with certain chemotherapies8

3Provide information about familial risk8

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53BP1=p53-binding protein 1; ATM=ataxia-telangiectasia mutated; BRCA1/2m=BRCA1/2 mutation; CDK=cyclin-dependent kinase; G1=gap 1; G2=gap 2; HRRm=HRR-mutated; LIG3=DNA ligase 3; MRE11=MRE11 homolog A; NBS1=nibrin; NCCN=National Comprehensive Cancer Network® (NCCN®); P=phosphate; PALB2=partner and localizer of BRCA2; PALB2m=PALB2 mutation; PARP=poly (ADP-ribose) polymerase; PARP1=poly (ADP-ribose) polymerase 1; PNKP=polynucleotide kinase 3'-phosphatase; POLβ=DNA polymerase beta; RAD50=RAD50 double-strand break repair protein; RAD51D=RAD51 paralog D; RPA=replication protein-A; S=synthesis; SSBR=single-strand break repair; XRCC1=x-ray repair cross-complementing 1.

REFERENCES: 1. Singhi AD, George B, Greenbowe JR, et al. Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers. Gastroenterology. 2019. doi:10.1053/j.gastro.2019.02.037. 2. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495-501. 3. Aguirre AJ, Nowak JA, Camarda ND, et al. Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discov. 2018;8(9):1096-1111. 4. Sausen M, Phallen J, Adleff V, et al. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nat Commun. 2015;6:7686. 5. Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell. 2017;32(2):185-203.e13. 6. Walker EJ, Carnevale JC, Pedley C, et al. Referral patterns and attrition rate for germline testing in pancreatic cancer (PC) patients. J Clin Oncol. 2018;36(15 suppl):1591. 7. Yurgelun MB, Chittenden AB, Ukaegbu CI, et al. Implementing universal genetic counseling (GC) and multigene germline testing (MGT) for pancreatic cancer (PC) patients (pts). J Clin Oncol. 2018;36(15 suppl):1512. 8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma V.2.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed April 16, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. 9. Minchom A, Aversa C, Lopez J. Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies. Ther Adv Med Oncol. 2018;10:1-18. 10. Caldecott KW. DNA single-strand break repair. Exp Cell Res. 2014;329(1):2-8. 11. O'Kane GM, Connor AA, Gallinger S. Characterization, detection, and treatment approaches for homologous recombination deficiency in cancer. Trends Mol Med. 2017;23(12):1121-1137. 12. 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. 13. 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. 14. Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 2014;111(6):1132-1138. 15. Aung KL, Holter S, Borgida A, et al. Overall survival of patients with pancreatic adenocarcinoma and BRCA1 or BRCA2 germline mutation. J Clin Oncol. 2016;34(15 suppl):4123.