A study published in Lancet Oncology by Dr. Iain McNeish (2016 Rivkin Pilot Award Recipient), Dr. Elizabeth Swisher (2009 Rivkin Pilot Award Recipient), and colleagues provided key data that helped fuel the FDA’s recent approval of rucaparib for ovarian cancers with defects in the BRCA1 and BRCA2 genes in women previously treated with two or more chemotherapies. The BRCA genes are essential for the cell’s ability to repair damage that occurs to DNA. In women who have inherited BRCA mutations, the genes are not able to do their job and the unrepaired DNA can lead to cancer-causing mutations. Ironically, this defect in DNA repair serves as an Achilles heel for ovarian cancers in women with inherited BRCA mutations. It turns out that rucaparib and other PARP inhibitor drugs specifically kill cancer cells that have defective DNA repair. Only 15% of women with high-grade serous ovarian cancer have inherited BRCA mutations, limiting the number of women who can receive benefit from rucaparib treatment. However, almost 50% of ovarian cancers are thought to have defective DNA repair, even in those in women without BRCA mutations. In order to increase the number of women who can benefit from rucaparib therapy, we need to be able to identify cancers with a defect in DNA repair.
In this study, Drs. Swisher, McNeish and colleagues did just that. They used the FoundationFocus CDxBRCA diagnostic test to identify a signature of defective DNA repair, called “Loss of Heterozygosity” or LOH, in ovarian cancers in women with inherited BRCA mutations and those without BRCA mutations. They then asked how different groups of women (women with BRCA mutations, women without BRCA mutations who high LOH signature indicating defective DNA and women without BRCA mutations who do not have high LOH signature) responded to rucaparib treatment. They found that, as had been previously reported, women with inherited BRCA mutations received significant benefit from rucaparib treatment. Importantly, they also found that women without inherited mutations who had ovarian tumors with a high LOH signature for defective DNA repair also benefited from rucaparib therapy compared to women who did not show the signature (See Figure).
Resistance to Rucaparib and other chemotherapies still poses a significant hurdle for achieving a long-term cure for advanced stage ovarian cancer. However, this study provides a means to increase the number of women who can benefit from treatment with rucaparib and possibly other PARP inhibitors. Recent biopsy tissue can be tested to determine if a tumor has the high LOH signature for defective DNA repair signature to identify women who would benefit from rucaparib. This study only included women who were believed to still be responsive to platinum therapy, which is the first-line treatment used for ovarian cancer. An extension of this study is investigating whether women who are resistant to platinum therapy may also benefit from rucaparib. As BRCA and other DNA repair gene mutations are also associated with other cancers including breast, pancreatic and prostate, the findings from this study may also have bearing on the treatment of those cancers.
This study was funded by Clovis Oncology, the US Department of Defense, Stand up To Cancer & V Foundation Translational Award. This study was not funded by Rivkin Center grants.