BRCA1 and BRCA2 Germline Mutations Are Frequently Demonstrated in a Pancreatic Ductal Adenocarcinoma Cohort Referred For Genetic Testing

Purpose The main purpose of this study was to determine the prevalence of pathogenic BRCA1 and BRCA2 mutations in a consecutively ascertained clinic-based cohort of patients with pancreatic ductal adenocarcinoma and describe the clinical and family history characteristics. Patients and Methods Unselected, consecutive, incident patients with pancreatic ductal adenocarcinoma were recruited at a single cancer center over a 2-year period. Participants provided blood for DNA analysis and cancer family history, and cancer treatment records were reviewed. DNA from all patients was analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1 and BRCA2. Results Three hundred six patients were eligible for analysis. Pathogenic germline BRCA mutations were identified in 14 patients (4.6%; 95% CI, 2.2% to 6.9%), including 11 patients with a BRCA2 mutation and three patients with a BRCA1 mutation. Having a cancer family history that met genetic testing criteria of the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care or self-reporting as Ashkenazi Jewish was significantly associated with BRCA mutation carrier status (P = .02, P < .001, and P = .05, respectively). However, the majority of the BRCA mutation–positive patients did not actually meet these genetic testing criteria. Conclusion Pathogenic BRCA mutations were identified in 4.6% of a large cohort of clinic-based patients. Considering the implications for family members of BRCA carriers, and possibly tailored chemotherapeutic treatment of patients, our finding has implications for broader BRCA genetic testing for patients with pancreatic ductal adenocarcinoma.

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Germline Genetic Testing for Pancreatic Ductal Adenocarcinoma at Time of Diagnosis

JAMA ◽

10.1001/jama.2018.6227 ◽

2018 ◽

Vol 319 (23) ◽

pp. 2383 ◽

Cited By ~ 6

Author(s):

Sapna Syngal ◽

C. Sloane Furniss

Keyword(s):

Genetic Testing ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma

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1538P Deleterious germline mutations in patients with pancreatic ductal adenocarcinoma

Annals of Oncology ◽

10.1016/j.annonc.2020.08.2021 ◽

2020 ◽

Vol 31 ◽

pp. S945

Author(s):

Z. Zhao ◽

X. Li ◽

Q. Liu ◽

T. Ma ◽

H. Yuan ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Germline Mutations ◽

Ductal Adenocarcinoma

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Retrospective Survival Analysis of Patients With Resected Pancreatic Ductal Adenocarcinoma and a Germline BRCA or PALB2 Mutation

JCO Precision Oncology ◽

10.1200/po.18.00271 ◽

2019 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Shun Yu ◽

Parul Agarwal ◽

Ronac Mamtani ◽

Heather Symecko ◽

Kelsey Spielman ◽

...

Keyword(s):

Homologous Recombination ◽

Pancreatic Ductal Adenocarcinoma ◽

Germline Mutation ◽

Germline Mutations ◽

Ductal Adenocarcinoma ◽

Negative Group ◽

Positive Group ◽

Platinum Based Chemotherapy ◽

Palb2 Mutation ◽

Brca1 Brca2

PURPOSE Germline mutations in the homologous recombination genes BRCA1, BRCA2, and PALB2 confer an increased risk for pancreatic ductal adenocarcinoma (PDAC). Tumors associated with mutations in homologous recombination genes are sensitive to DNA-damaging agents. We retrospectively studied patients with resected PDAC and a pathogenic germline mutation in one of these three genes. The planned analyses included overall survival (OS) and changes therein when platinum chemotherapy was used in the perioperative setting. MATERIALS AND METHODS Thirty-two individuals with pathogenic germline mutations in BRCA1, BRCA2, or PALB2 and resected PDAC (mutation positive) were matched in a 1:2 fashion to patients who were noncarriers or untested (mutation negative) by age, year of diagnosis, stage, and sex. Patients were identified via one of two available databases at University of Pennsylvania: the Basser Center for BRCA Registry or the electronic medical record. The primary outcome was OS. RESULTS Patients in the mutation-positive group had a median OS (mOS) of 46.6 months; those in the mutation-negative group had an mOS of 23.2 months (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.88). With platinum exposure in the perioperative setting, mOS in the mutation-positive group had not yet been met versus a mOS of 23.1 months in the mutation-negative group (HR, 0.12; 95% CI, 0.01 to 1.00). When neither group was treated with platinum, there was no significant OS difference between groups (HR, 0.52; 95% CI 0.12 to 2.24). Patients in the mutation-positive group who received perioperative treatment with platinum had a trend toward improved mOS compared with those who did not (HR, 0.15; 95% CI, 0.02 to 1.23; P = .07). CONCLUSION Platinum-based chemotherapy may confer a survival benefit in patients with resected PDAC and a pathogenic germline BRCA1, BRCA2, or PALB2 mutation. Knowledge of a germline mutation may be important to determine best choice of perioperative chemotherapy.

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Germline genetic testing in unselected pancreatic ductal adenocarcinoma (PDAC) patients.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.1501 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 1501-1501 ◽

Cited By ~ 2

Author(s):

Mary Linton Bounetheau Peters ◽

Randall Brand ◽

Erkut Hasan Borazanci ◽

Lindsey Stobie ◽

Beth Dudley ◽

...

Keyword(s):

Genetic Testing ◽

Germline Mutations ◽

Ductal Adenocarcinoma ◽

Familial Pancreatic Cancer ◽

Cancer Risks ◽

Mutation Status ◽

Mutation Carriers ◽

History Of ◽

Brca1 Brca2 ◽

Current Guidelines

1501 Background: The aim of this study is to assess the prevalence of known heritable germline mutations in unselected PDAC patients and to determine how well current guidelines for genetic testing identify mutation carriers. Methods: Consecutive, unselected patients with recently diagnosed PDAC from three centers were enrolled from May to December 2016 in an ongoing prospective study. A three-generation pedigree was obtained. Germline mutations in 12 genes associated with PDAC risk ( APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, PALB2, PMS2, STK11, TP53) and in 19 genes related to other cancer risks were screened for by NGS. American College of Gastroenterology and NCCN criteria for genetic testing for BRCA1/2, Lynch syndrome, and Familial Pancreatic Cancer (FPC) were assessed. Results: Among 183 patients, 46% are female, 79% are Caucasian and 10% are Ashkenazi Jewish, with median (IQR) age 68 (62,75) years at diagnosis. 41% of patients met ³1 criteria for genetic testing (35.5% BRCA1/2, 2.7% Lynch, 9.3% FPC). Twenty patients (11%) were found to have a total of 21 pathogenic mutations (table). Mutation status was not associated with age at diagnosis, sex, or personal history of cancer (all p > 0.05). Six mutation carriers (30% of positives) did not meet current criteria for genetic testing. Conclusions: Preliminary results show that 6.6% of unselected PDAC patients carry a germline mutation in a gene known to increase PDAC risk and 4.3% have a mutation in genes not previously linked to PDAC. Existing testing criteria did not identify 30% of carriers. Continued refinement of guidelines is necessary to align genetic testing with inherited PDAC risk. Clinical trial information: NCT02790944. [Table: see text]

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Genetic Testing in Pancreatic Ductal Adenocarcinoma: Implications for Prevention and Treatment

Clinical Therapeutics ◽

10.1016/j.clinthera.2016.03.006 ◽

2016 ◽

Vol 38 (7) ◽

pp. 1622-1635 ◽

Cited By ~ 8

Author(s):

Mary Linton B. Peters ◽

Jennifer F. Tseng ◽

Rebecca A. Miksad

Keyword(s):

Genetic Testing ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Prevention And Treatment

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BRCA 1/2 Germline Mutation Predicts the Treatment Response of FOLFIRINOX with Pancreatic Ductal Adenocarcinoma in Korean Patients

Cancers ◽

10.3390/cancers14010236 ◽

2022 ◽

Vol 14 (1) ◽

pp. 236

Author(s):

Ji Hoon Park ◽

Jung Hyun Jo ◽

Sung Ill Jang ◽

Moon Jae Chung ◽

Jeong Youp Park ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Treatment Response ◽

Response Rate ◽

Brca Mutation ◽

Progression Free Survival ◽

Germline Mutations ◽

Ductal Adenocarcinoma ◽

Korean Patients ◽

Significant Difference ◽

Brca 1

We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 and 2020, were pathologically confirmed to have PDAC, and had undergone targeted next-generation sequencing-based germline genetic testing. Sixty-six patients were included in the study (24 men; median age 57.5 years). In the germline test, BRCA 1/2 pathogenic mutations were found in nine patients (9/66, 13%, BRCA 1, n = 3; BRCA 2, n = 5; and BRCA 1/2, n = 1). There was no significant difference in the baseline characteristics according to BRCA mutation positivity. Among patients who underwent FOLFIRINOX chemotherapy, patients with a BRCA 1/2 mutation showed a higher overall response rate than those without a BRCA 1/2 mutation (71.4% vs. 13.9%, p = 0.004). Patients with a germline BRCA 1/2 mutation showed longer progression-free survival than those without a BRCA 1/2 mutation, without a significant time difference (18 months vs. 10 months, p = 0.297). Patients with a BRCA 1/2 mutation in the germline blood test had a higher response rate to FOLFIRINOX chemotherapy in PDAC. The high proportion of BRCA 1/2 germline mutations and response rate supports the need for germline testing in order to predict better treatment response.

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Retrospective Survival Analysis of Patients With Advanced Pancreatic Ductal Adenocarcinoma and Germline BRCA or PALB2 Mutations

JCO Precision Oncology ◽

10.1200/po.17.00152 ◽

2018 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Kim A. Reiss ◽

Shun Yu ◽

Renae Judy ◽

Heather Symecko ◽

Katherine L. Nathanson ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Germline Mutations ◽

Primary Objective ◽

University Of Pennsylvania ◽

Ductal Adenocarcinoma ◽

Platinum Based Chemotherapy ◽

Increased Risk ◽

Significant Difference ◽

Brca1 Brca2 ◽

The University

Purpose Germline mutations in the homologous recombination (HR) genes BRCA1, BRCA2, and PALB2 confer an increased risk for pancreatic ductal adenocarcinoma (PDAC). Tumors associated with mutations in HR genes are sensitive to DNA-damaging agents, such as platinum chemotherapies. We hypothesized that patients with PDAC with germline BRCA1, BRCA2, or PALB2 mutations may benefit preferentially from platinum-based chemotherapy. Materials and Methods Twenty-nine individuals with deleterious germline mutations in BRCA1, BRCA2, or PALB2 and a diagnosis of advanced PDAC (mut-positive) were matched 2:1 to patients who were noncarrier or untested (control) by age at diagnosis, year of diagnosis, stage, and sex. Patients were identified via one of two available databases at the University of Pennsylvania: the Basser Center for BRCA Registry or the University of Pennsylvania Electronic Medical Patient Record. Treatment history, including exposure to platinum-based chemotherapy, was ascertained. Primary objective was overall survival (OS). Results Patients who were mut-positive had an OS of 21.8 months; control patients had an OS of 8.1 months (hazard ratio [HR], 0.35; 95% CI, 0.2 to 0.62; P < .001). With platinum exposure, patients who were mut-positive had an undefined OS (median follow-up, 20.1 months), versus an OS of 15.5 months in the control patients (HR, 0.25; 95% CI, 0.1 to 0.61; P = .002). In patients not treated with platinum, there was no significant difference in OS between groups (HR, 0.54; 95% CI, 0.25 to 1.17; P = .12). When treated with platinum therapy, patients who were mut-positive had a 1-year OS of 94%, compared with a 1-year OS of 60% in control patients. Conclusion Platinum-based therapy may confer a survival benefit in patients with advanced PDAC who carry a deleterious germline BRCA1, BRCA2, or PALB2 mutation.

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Excellent Response to Olaparib in a Patient with Metastatic Pancreatic Adenocarcinoma with Germline BRCA1 Mutation after Progression on FOLFIRINOX: Case Report and Literature Review

Case Reports in Oncology ◽

10.1159/000508533 ◽

2020 ◽

Vol 13 (2) ◽

pp. 904-910

Author(s):

Jefferson Rios Pimenta ◽

Serli Kiyomi Nakao Ueda ◽

Renata D’Alpino Peixoto

Keyword(s):

Back Pain ◽

Disease Progression ◽

Brca Mutation ◽

Brca1 Mutation ◽

Large Mass ◽

Germline Mutations ◽

Ductal Adenocarcinoma ◽

Brca1 And Brca2 ◽

Pancreatic Lesion ◽

Dismal Prognosis

Metastatic pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Until recently, cytotoxic chemotherapy was the only treatment option. Currently, there are subgroups of patients with PDAC either with somatic or germline mutations who are candidates for targeted agents. Germline mutations in the BRCA1 and BRCA2 genes promote the incapacity of tumor cells to recover from DNA-accumulated damage caused by cytotoxic drugs, like platinum agents, and, most recently, through a diverse process by poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi). A 59-year-old female who was treated for a triple negative breast cancer 8 years ago with surgery, adjuvant chemotherapy and radiotherapy, presented with increasing back pain. Investigation revealed multiple liver nodules and a large mass in the head of the pancreas. Biopsy confirmed PDAC. She received 13 cycles of FOLFIRINOX, achieving partial response both in the liver and pancreatic lesion, with resolution of symptoms. Due to increasing neuropathy, chemotherapy was stopped, and the patient was followed. Sixteen months later, her CA19-9 levels increased. Given limiting neuropathy, the patient was restarted on FOLFIRI only. After 8 cycles, there was disease progression plus uncontrolled back pain. A mutational test was requested and confirmed a BRCA1 germline mutation. The patient was started on olaparib. After 3 cycles, images showed a significant response and after 6 cycles, it remained stable, with persistent fall in CA19-9 levels. She is currently on treatment, with ongoing response. In conclusion, patients with metastatic PDAC and BRCA mutation may benefit from PARPi even after progression on chemotherapy. We hypothesize that olaparib works even in the setting of disease progression and not solely as a maintenance therapy following platinum-based therapy. Randomized trials are needed investigating the role of olaparib following disease progression in PDAC.

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