1. Fuerst, Mark L.

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SAN DIEGO-Women with advanced ovarian cancer with either germline or somatic mutations live significantly longer than those without mutations, according to a new study.

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"We were surprised at how large the effect was, particularly in the difference in overall survival (OS)," said lead author Barbara S. Norquist, MD, Gynecologic Oncologist at the University of Washington in Seattle, in an interview. "Women with BRCA2 mutations achieved an OS of 75 months, which was 33 months more than those with no mutations. For those with mutations in other genes than BRCA1 and BRCA2, the survival rates looked similar. Others have shown before that BRCA 1 and 2 impact survival, but we also saw a strong signal in other mutations as well."


The large, phase III, randomized clinical trial Gynecologic Oncology Group 218 examined the impact of adding the drug bevacizumab upfront to standard chemotherapy with carboplatin and paclitaxel for advanced primary ovarian, fallopian tube, and peritoneal carcinoma. The results showed bevacizumab followed by maintenance bevacizumab improved progression-free survival (PFS) by 3.8 months as compared to chemotherapy alone in the frontline setting for patients with stage III/IV ovarian cancer.


Knowing that translational samples of blood and tumor existed from these patients, "we looked back at the patient population to sequence DNA to see if there was a signal of response," Norquist said.


In the new study, she and her colleagues searched for damaging mutations in BRCA1 and BRCA2 and other genes, and applied this to survival information.


Norquist presented the results of study at the 2016 Society of Gynecologic Oncology meeting. The presentation was recognized with a Presidential Award.


Study Specifics

The researchers sequenced DNA from blood or tumors or both from 1,195 women using the sequencing test BROCA-HR, the gene panel test first developed at the University of Washington. One quarter of them had a mutation in a gene predicted to affect homologous recombination. Of those with mutations, about half had mutations in BRCA1, about one-quarter in BRCA2, and another quarter in one of the other homologous recombination genes.


Median PFS and OS for women with no mutations were 12.6 and 42.1 months, respectively. For women with BRCA1 mutations, PFS and OS were longer at 15.7 and 55.3 months. For BRCA2, median PFS and OS were even longer at 21.6 and 75.2 months. And for mutations in non-BRCA genes, median PFS and OS were 16 and 56 months, similar to that seen for BRCA1 mutations.


"All three mutation-carrier groups had significantly better PFS and OS when compared to those with no mutations," Norquist said.


The reason that women with mutations live longer, she said, is that having defective DNA repair makes the tumor more sensitive to platinum chemotherapy. "The thing that might give the patient a problem [mutation] in actuality helps these patients," Nordquist said.

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The researchers also found that these mutations were present in all histologic types of ovarian cancer. "This underscores the message that women with any type of ovarian cancer should have genetic testing, and they should be included in clinical trials of drugs that work best in the setting of homologous recombination defects. And if a clinician feels their patient is a candidate for bevacizumab, mutation status does not have a large impact on that decision," Norquist said.


Histology was not predictive of mutation status, she emphasized. "We didn't find a big difference in mutation rate by histological subtype of cancer. The guideline is to test all women with epithelial ovarian cancer, but in some settings, clinicians only test those women with high-grade serous cancers. Our data does not support that. All patients with invasive ovarian cancer qualify for genetic testing," she said.


For ovarian cancer patients with defect homologous combinations, the most effective treatment may be PARP inhibition, she said. The next step in this research is to apply genetic testing in clinical trials of PARP inhibitors. "We expect to see a benefit, that is, patients will respond better to PARP inhibitors," she said.


Norquist's message to practicing oncologists is "know that all patients should get offered mutational testing. It has an impact on prognosis and allows for identification of hereditary risk of family members of patients. And don't use histologic type of tumor to guide testing. It is not a good predictor."


Mark L. Fuerst is a contributing editor.