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Research & Clinical Trials > Research Findings > Update from ASCO 2015

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Update from ASCO 2015

by Lisa Rezende, PhD

PARP Inhibitor Research

Use of rucaparib in advanced ovarian cancer: Results from the ARIEL 2 trial

The PARP inhibitor olaparib has been approved for ovarian cancer patients with inherited mutations in BRCA1 or BRCA2. Some studies have shown that PARP inhibitors could also be effective in treating ovarian cancers in certain women who have not inherited mutations in one of these genes. If researchers could identify the characteristics of tumors that respond to PARP inhibitors, they could develop ways of finding women whose cancers can be successfully treated with these agents. Dr. Iain McNeish presented results from the ARIEL 2 trial that studied the use of the PARP inhibitor rucaparib in women with recurrent ovarian cancer. Researchers looked at tumor cells characteristics called “genome scarring” to see if these tumors could be treated with PARP inhibitors.

In this study, 204 women who had high-grade serous ovarian cancer and had relapsed after taking a platinum drug were given rucaparib. Tumors from these women were analyzed for BRCA mutations and genomic scarring and were categorized into one of three groups:

  • 20% had BRCA mutations in their tumor cells. These women experienced a median of 9.4 months without disease progression.
  • 40% did not have BRCA mutations but were called “BRCA-like” based on genome scarring. These women had a median of 7.1 months.
  • 40% were negative for either BRCA mutations or BRCA-like characteristics. These women had only a median of 3.7 months before their disease progressed.

Rucaparib was most effective in treating tumors from women with BRCA mutations, having an overall response rate of over 80%. BRCA-like tumors also responded to rucaparib. The drug was well tolerated; nausea and fatigue were the most commonly reported side effects. The ARIEL 2 trial is ongoing. Please see our featured studies page for more information.

Other PARP inhibitor news

  • Dr. Katherine Bell-McGuinn presented results from a phase I trial treating newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer patients with the PARP inhibitor veliparib in combination with the approved drugs paclitaxel, carboplatin, and bevacizumab. The 185 participants were divided into three groups based on the dose and method of delivery of the approved drugs. Side effects included anemia and low white blood cell counts (including blood counts that were low enough to delay the next therapy), one patient with myelodysplastic syndrome, and one death due to sepsis. Preliminary data on progression-free survival showed that 53-68% of patients had not progressed after 24 months. The study will be used to set the dose for further trials.
  • Dr. Alan Ashworth described the development of PARP inhibitors for treating cancer in patients with mutations in BRCA1 or BRCA2. He noted that the PARP inhibitor olaparib was approved in the U.S. for use in women with inherited BRCA mutations who had undergone 3 prior chemotherapy regimens—this is the first new ovarian cancer drug approved since 2006. Ashworth also discussed ongoing PARP inhibitor research including:
    • the challenge of PARP inhibitor resistance: One challenge is that some patients develop resistance to PARP inhibitors, particularly those with advanced or metastatic disease. Ashworth and colleagues found that study participants’ cancer cells that were resistant to PARP inhibitors had regained a functional copy of BRCA.
    • finding more patients who will respond to PARP inhibitors: Ashworth also discussed the use of PARP inhibitors in cancers that behave as though there is a BRCA mutation, often called “BRCAness.” For example, cancer cells with mutations in the genes PALB2, ATM, or ATR have been shown to respond to PARP inhibitors in the laboratory. These data will be used to identify tumors that will respond to PARP inhibitors, thereby expanding the pool of patients who can be treated with the drugs. Research on identifying and treating patients whose tumors display BRCAness is ongoing.

Universal screening for BRCA1/2 mutations: Good idea or bad idea?

A session at the 2015 ASCO national meeting was devoted to discussing the proposal by Dr. Mary-Claire King to offer screening for BRCA mutations to all women at age 30.

Dr. Elizabeth Swisher presented arguments for universal testing. Noting that inexpensive and accurate testing is now available, the current testing criteria based on family history would miss about one-third of mutation carriers even if all eligible women were referred for testing. Dr. Swisher outlined how BRCA testing fits the criteria for a broad screening program, including:

  • risk of breast and ovarian cancer in mutations carriers is high.
  • recent studies suggest that people identified based on population screening had similar risk to those identified by family history.
  • mutations associated with increased cancer can be accurately identified.
  • effective interventions exist including breast MRI for detection and bilateral mastectomy for risk reduction of breast cancer, and removal of ovaries and fallopian tubes to reduce risk of ovarian cancer.

Dr. Swisher noted that when genetic testing is based on family history alone, many women are missed because they come from small families or families with a mutation that is inherited from the father’s side. Studies have shown that physicians do not always record or recognize family cancer history, and in some cases women who meet current guidelines for genetic counseling and testing are not referred. Dr. Swisher closed with a quote from Dr. Mary-Claire King: “Every breast or ovarian cancer patient with a BRCA1 or BRCA2 mutation detected after diagnosis is a missed opportunity to prevent cancer.”

Dr. Mark Robson discussed arguments against universal testing for BRCA mutations. He noted that no population-based genetic screening programs for adult-onset disorders exist—universal BRCA testing would be the first. He presented the potential benefits and harms of universal screening from a public health prospective. He noted that only a fraction of all breast and ovarian cancers are associated with inherited BRCA mutations, therefore universal screening will have only minimal impact on the entire population. The majority of women will receive a negative test result, which will not change their health care management. Women with a negative result will have to be counseled appropriately to be sure they understand their risk of breast cancer, particular if they have a family history, but no mutation in BRCA1 or BRCA2.

Dr. Robson also outlined potential harms associated with the frequency of false positive tests, the possibility of over diagnosis, and harms from treatments. He noted that no test is 100% accurate. Based on recent studies of genetic testing accuracy, approximately 1 in 1,000 women will receive a false positive, meaning they will be told they have a mutation in BRCA1 or BRCA2 when they do not. Second, Dr. Robson noted that not all women who have a BRCA mutation will develop cancer. Because many factors influence overall lifetime cancer risk in BRCA mutation carriers it is unclear how many women identified by population-based BRCA screening would eventually develop cancer. Dr. Robson agrees we need to do a better job of identifying BRCA mutation carriers before they develop cancer. He proposed a number of alternatives including:

  • expanded testing of the family members of known BRCA mutation carriers through “cascade screening.”
  • more aggressive identification of people at risk based on their family history.
  • offering testing to men, for whom a false positive test will not lead to surgery. If a man tests positive then his female relatives can have single-site testing.

Both speakers and audience members who asked questions after the presentation agreed that we must do a better job finding BRCA mutation carriers before they develop cancer.

posted August 29, 2015

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