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Update on Pancreatic Cancer Genetics Research

March 30, 2016

By Talia Golan, MD and Sue Friedman, DVM

BRCA and pancreatic cancer

The link between breast and ovarian cancer and BRCA mutations has been known since the 1990s. However, the awareness that these mutations also increase pancreatic cancer risk is more recent. If all patients with pancreatic cancer were tested for a BRCA1 or BRCA2 mutation, about 5% would test positive. That number is higher—about 10-15%—for people who are Ashkenazi Jewish, a population in whom BRCA mutations are quite prevalent.

People with inherited BRCA1 and BRCA2 mutations have an increased cancer risk; for pancreatic cancer, their estimated lifetime risk is about 5%. Because BRCA genes are involved in the repair of some types DNA damage in cells, BRCA-related cancers may be more sensitive to anti-cancer therapies that damage DNA, such as certain types of chemotherapy, radiation, and some targeted therapies, including PARP inhibitors. Studies show that both ovarian cancer and pancreatic cancer patients with inherited BRCA mutations may survive longer than those who do not have BRCA mutations.

BRCA and platinum sensitivity

A recent study showed that patients with stage 3 or 4 pancreatic cancer who had a BRCA mutation and were treated with platinum-containing chemotherapy had longer overall survival of 22 months, compared to 7 months for those who did not get a platinum-containing drug. These results suggest that knowing pancreatic cancer patients’ BRCA mutation status can predict how much they might benefit from the use of platinum-based chemotherapy.

BRCA and PARP inhibition

Poly (ADP-ribose)-polymerase (PARP) is an enzyme found in our bodies that is involved in repairing DNA damage. A new class of cancer treatments called “PARP inhibitors” focus on inhibiting the PARP enzyme. Cancers caused by BRCA mutations appear to be sensitive to PARP inhibitors. The PARP inhibitor olaparib (Lynparza) is approved by the Food and Drug Administration for treating ovarian cancer patients with BRCA1 or BRCA2 mutations who have completed 3 prior lines of chemotherapy. PARP inhibitors are being researched for treating other types of cancer, both alone and in combination with chemotherapy, immunotherapy, and radiation. Clinical trials testing PARP inhibitors in pancreatic cancer patients with inherited mutations in BRCA1 or BRCA2 are ongoing, and preliminary results are promising. A phase II study of olaparib BRCAmutant cancers was recently reported; 23 patients with advanced pancreatic cancers were included, all of whom had previously received the drug gemcitabine. The overall response rate was 22% with a progression-free survival of 4.6 months and an overall survival of 9.8 months. These preliminary data suggest that pancreatic cancer patients with inherited BRCA mutations may benefit from PARP inhibitors.

These studies suggest that pancreatic cancers in people with BRCA1 and BRCA2 mutations are different from other pancreatic cancers, and require a different treatment approach. It is very important for patients with pancreatic cancer to learn if they have a BRCA mutation, so that they can receive platinum chemotherapy and have the opportunity to participate in appropriate clinical trials if they so choose. For example, the POLO Study is an important phase III clinical trial enrolling metastatic pancreatic cancer patients with BRCA mutations to determine whether adding the PARP inhibitor, olaparib after first line chemotherapy improves survival. Additionally, relatives of people with pancreatic cancer may benefit from genetic counseling and testing and may qualify for medical options to lower their risk for cancer.

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Dr. Talia Golan is the Medical Director, Phase I Program at the Chaim Sheba Medical Centre of the Tel Aviv University. Dr. Golan is a clinician-scientist currently conducting translational laboratory research while also serving as the Medical Director. Her clinical interest is in patients with pancreatic cancer. Dr. Golan’s career goals include expertise in clinical medicine, translational laboratory research and drug development.

References:

Holter S, Borgida A, Dodd A, et al. “Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma.” Journal of Clinical Oncology. 2015;33(28):3124-3129.

Venkitaraman AR. “Functions of BRCA1 and BRCA2 in the biological response to DNA damage.” Journal of Cell Science. 2001;114(Pt 20):3591-3598.

Venkitaraman AR. “Cancer susceptibility and the functions of BRCA1 and BRCA2.” Cell. 2002;108(2):171-182.

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.

Tutt AN, Lord CJ, McCabe N, et al. “Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer.” Cold Spring Harbor symposia on quantitative biology. 2005;70:139-148.

Cass I, Baldwin RL, Varkey T, Moslehi R, Narod SA, Karlan BY. “Improved survival in women with BRCA-associated ovarian carcinoma.” Cancer. 2003;97(9):2187-2195.

Golan T, Kanji ZS, Epelbaum R, et al. “Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.” British Journal of Cancer. 2014;111(6):1132-1138.

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.

van der Heijden MS, Brody JR, Dezentje DA, et al. “In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor.” Clinical cancer research : an official journal of the American Association for Cancer Research. 2005;11(20):7508-7515.

Andrei AZ, Hall A, Smith AL, et al. “Increased in vitro and in vivo sensitivity of BRCA2-associated pancreatic cancer to the poly(ADP-ribose) polymerase-1/2 inhibitor BMN 673.” Cancer Lett. 2015;364(1):8-16.

Brennan GT, Relias V, Saif MW. “BRCA and pancreatic cancer.” JOP : Journal of the pancreas. 2013;14(4):325-328.

Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(3):244-250.

 

 

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  1. […] about an open clinical trial looking at the use of a targeted therapy called a PARP inhibitor in Updates on Pancreatic Cancer Genetic Research Study by Talia Golan, MD and Sue Friedman, […]

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