BRCA2 and Pancreatic Cancer: What’s the Connection?

Pancreatic cancer is notorious for being difficult to treat—and it is often not detected until it advances beyond the pancreas. While smoking and obesity are two established risk factors that impact this disease, another risk factor can be mutations in the BRCA2 gene, also associated with breast and ovarian cancer.

Research studies have identified a link between mutations in the BRCA2 gene and pancreatic cancer, meaning that individuals who test positive for a BRCA2 (BReast Cancer susceptibility gene) mutation demonstrate a heightened risk of pancreatic cancer. Recent studies have identified inherited BRCA2 mutations in approximately 1 to 4 percent of pancreatic cancer cases, according to Sahar Nissim, MD, PhD, of the Gastrointestinal Cancer Treatment Center at Dana-Farber Cancer Institute.

A BRCA2 mutation is either inherited (passed on from mother or father) or somatic (occurring by chance in an individual, and not inherited from a parent). Either kind of mutation in BRCA2, or in the closely related gene BRCA1, can potentially cause cancer by failing to repair broken DNA and rearranging chromosomes.

“Carrying the mutation is not a cancer diagnosis or an indication that you will definitely develop cancer,” Nissim says. “It just means that in comparison to the general population, you have an increased lifetime risk for developing cancer.”

Who Needs Screening?

About 10 percent of pancreatic cancers are thought to occur due to a strong family history of the disease, but most cases develop with no clear reason. For people who have a strong family history of pancreatic cancer, screening is now recommended at age 50, or 10 years before the earliest onset of pancreatic cancer in the family. In families in which the pancreatic cancer history is clearly associated with an inherited BRCA2 mutation, genetic testing for the BRCA2 mutation found in the family can help guide screening recommendations.

Sahar Nissim, MD, PhD.
Sahar Nissim, MD, PhD.

Individuals in the family who test positive for the BRCA2 mutation are recommended to undergo screening, whereas individuals in the family who test negative for the BRCA2 mutation are not thought to be at high risk and therefore need not undergo screening.

Screenings involve two types of imaging techniques: a magnetic resonance cholangiopancreatography (MRCP) that works similar to an MRI scan, and an endoscopic ultrasound (EUS). The MRI can provide a baseline for imaging the pancreas at a high resolution. The EUS also images the pancreas, and can provide complementary information about lesions to help determine if they are benign or cancerous. In addition, if a lesion is suspicious, the EUS can allow a fine-needle aspiration biopsy to determine if the lesion is benign or cancerous.

For patients at high risk for developing pancreatic cancer, a standard recommendation is to perform annual MRCP alternating with EUS.

Treatment for Pancreatic Cancer

Over the past 10 years, treatment options for pancreatic cancer have improved. There are first-line chemotherapy regimens, such as FOLFIRINOX or Gemcitabine, which target cancer cells that are rapidly dividing for any pancreatic cancer, including those associated with BRCA2. Second line treatments include PARP inhibitors that are more specific for patients that have pancreatic cancer and the BRCA2 or BRCA1 mutation.

In cancers associated with a BRCA2 or BRCA1 mutation, it turns out that the mutation creates a unique vulnerability in the cancer that can be targeted by PARP inhibitors. PARP inhibitors block the repair of single strand DNA breaks, and these single strand DNA breaks become double strand breaks.

In normal cells exposed to PARP inhibitors, these double strand breaks are repaired in a process that requires BRCA2 and BRCA1. But, in pancreatic cancers associated with BRCA2 or BRCA1 mutations and therefore lack normal BRCA2 or BRCA1, these double strand breaks cannot be repaired, and the cancer cells will die.

“So, specifically in cancers associated with a BRCA2 or BRCA1 mutation, we think that we can exploit this unique vulnerability using PARP inhibitors,” Nissim says. “This is a wonderful example of how research into this disease can uncover new targets for treatment.”

According to the National Cancer Institute, about 10 percent of patients are diagnosed with local pancreatic cancer (cancer only localized to the pancreas) that is curative and able to be surgically resected. Unfortunately, over 50 percent of individuals are diagnosed with metastatic pancreatic cancer—cancer that has spread beyond the pancreas—and are unable to receive surgery because the cancer has spread to other organs.

At this point, resection surgery on pancreatic tumors remains the only curative option for patients—and only some patients, at that. “It’s not a guarantee of a cure, but it’s the only measure that we have today that gives someone a chance of a cure,” Nissim says. “But with intensive and collaborative research efforts, we are learning more about this disease every day in the hopes of uncovering new treatment strategies.”

5 responses to “BRCA2 and Pancreatic Cancer: What’s the Connection?

  1. My maternal grandmother had ovarian cancer & melanoma, my mother had melanomas and pancreatic cancer and I have had stage 1 breast cancer. I was tested at Memorial Sloan Kettering and do not have the BRCA mutation- I had a total hysterectomy just to be sure, as well as the lumpectomy & radiation for the breast cancer. Is there anything else I should test for- there seems to be an obvious family connection between these 4 types of cancer. Thanks Susan Nierenberg (susannierenberg@gmail.om)

  2. My maternal grandmother died in 1963 from uterine and/or ovarian cancer. I am not sure which. She was about 70 years old. My mother was cancer free up through age 60. She did suffer from endometriosis. After she was 40 years old, I was no longer in contact with her. I learned she died at age 96, but I have no idea about any health problems she may have had after age 40. I was diagnosed with DCIS in 2001. I had both breasts removed that year. It was a simple mastectomy of both breasts in one surgery. I did not have radiation or chemotherapy. My surgeon at the time was Beth Lesnikoski, who worked at Dana Farber.
    I’m writing as there is history of uterine and/or ovarian cancer and DCIS. I’m not sure if any genetic or other testing of me would be helpful in determining the possibility of pancreatic or other forms of cancer. A final question. Given that my maternal grandmother died from uterine and/or ovarian cancer, would my having a hysterectomy be beneficial to avoid cancer in these reproductive organs? I was born in 1953. Thank you.

  3. BRCA 1 positive; BRCA 2 indeterminant. 18 year survivor. Bi-lateral mastectomies and ovaries removed. Take Victoza to aid in controlling blood glucose. Given these finding is the use of this drug cause for concern?

    1. Hi Leslie,

      Thank you for reading. Unfortunately, we cannot provide medical advice without a consultation. If you have concerns about your health, please talk to your care team.

      We are wishing you all the best,
      DFCI

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