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Experimental Targeted Therapy May Help Treat People With Advanced-Stage Cancer Due to Abnormal BRCA Gene

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A study found that more than 25% of people with an abnormal BRCA1 or BRCA2 gene being treated for advanced-stage breast, ovarian, pancreatic, or prostate cancer got some benefit from olaparib, an experimental targeted therapy medicine.

The research was published online on Nov. 3, 2014 by the Journal of Clinical Oncology. Read the abstract of “Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation.”

Most inherited cases of breast cancer are associated with mutations in two genes: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two). Women with a BRCA1 or BRCA2 genetic mutation have up to a 72% risk of developing breast cancer by age 80. Their risk of ovarian cancer also is higher than average. Men with an abnormal BRCA gene have a higher risk of both breast and prostate cancer.

DNA carries genetic information in both healthy cells and cancer cells. Cells can develop DNA damage spontaneously or from exposure to specific things in the environment (too much sun, for example) that make DNA damage more likely to happen. But cells can detect and repair damage to DNA. When DNA is damaged in a healthy cell and the damage isn't fixed, that cell can become cancerous. Abnormal BRCA1 and BRCA2 genes are thought to increase the risk of breast and other cancers because these abnormal genes interfere with cells' ability to repair damaged DNA.

The poly ADP-ribose polymerase (PARP) enzyme fixes DNA damage in both healthy and cancer cells. Researchers believe that a medicine like olaparib, which interferes with (inhibits) the PARP enzyme, might make it even harder for cancer cells with an abnormal BRCA1 or BRCA2 gene to fix DNA damage. This would make it harder for the cancer cells to survive. In other words, a PARP inhibitor might make some cancer cells less likely to survive their DNA damage.

Research in the lab on cancer cells with an abnormal BRCA1 or BRCA2 gene showed that the cells were 1,000 times more sensitive to PARP inhibition than cancer cells that didn’t have an abnormal BRCA gene. Based on those results, the researchers felt that treating cancers in people with an abnormal BRCA1 or BRCA2 gene with olaparib would probably be effective.

In this study, 298 people diagnosed with advanced-stage ovarian, breast, pancreatic, or prostate cancer that had stopped responding to standard treatments received olaparib, a pill taken by mouth twice a day. All the people in the study had an abnormal BRCA1 or BRCA2 gene.

This study was a phase II study. This means it was looking at the effectiveness of a new treatment, in this case olaparib. If a certain percentage of people benefit from the new treatment, it’s likely the treatment will go on to a phase III trial, which is the last step a new treatment goes through before the U.S. Food and Drug Administration considers approving it.

Overall, 26.2% (78) of the cancers responded (either shrunk or disappeared) to olaparib. Response rate by type of cancer was:

  • 31.1% (60 of 193) for ovarian cancer
  • 12.9% (8 of 62) for breast cancer
  • 21.7% (5 of 23) for pancreatic cancer
  • 50% (4 of 8) for prostate cancer

The researchers also found that 42% of the people had no cancer growth for at least 8 weeks after being treated with olaparib.

One year after being treated with olaparib:

  • 64% of people with ovarian cancer were alive
  • 45% of people with breast cancer were alive
  • 41% of people with pancreatic cancer were alive
  • 50% of people with prostate cancer were alive

About 50% of the people in the study had side effects, though most weren’t severe. The most common side effects were fatigue, nausea, and vomiting. About 17% of the people in the study had anemia, a low red blood cell count, which is a more severe side effect. The researchers thought this somewhat high level of anemia was because so many people in the study had been treated with several different chemotherapy regimens before they received olaparib. Most of the side effects were eased by reducing the daily dose of olaparib.

Because these results were so encouraging, the researchers believe that olaparib should be studied in a phase III trial.

If you have an abnormal BRCA1 or BRCA2 gene and are being treated for advanced-stage breast cancer, you and your doctor may be considering a number of treatment options. If the cancer has stopped responding to standard treatments, other treatment options may include a PARP inhibitor such as olaparib if you’re willing to participate in a clinical trial. Ask your doctor if there are any clinical trials that might be a good fit for you and your unique situation. Visit the Clinical Trials pages for more information.

Editor’s Note: On Jan. 12, 2018, Lynparza (chemical name: olaparib) was approved by the U.S. Food and Drug Administration to treat metastatic HER2-negative breast cancer in women with a BRCA1 or BRCA2 mutation that has been previously treated with chemotherapy.

Editor’s Note: This article was updated on Jan. 24, 2019, with updated information on cancer risk associated with BRCA mutations.

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