Researchers from Myriad Genetics, the Royal College of Surgeons, and elsewhere have published data showing that the company's homologous recombination deficiency assay can gauge whether ovarian tumor cells have impaired ability to repair DNA function that cancer cells need to survive.
Genetic defects hindering homologous recombination – the process by which cells repair DNA breaks – have been shown in studies to predispose people to breast and ovarian cancer. In a study published in the British Journal of Cancer earlier this month, researchers analyzed 57 cancer cell lines – 21 ovarian, 32 breast, 3 colon, and 1 pancreatic – in an attempt to determine whether Myriad's homologous recombination deficiency score correlates with loss of heterozygosity, which often causes the inactivation of tumor suppressor genes and drives cancer.
Myriad is developing the homologous recombination deficiency, or HRD, test as a tool that oncologists can use to determine which patients will likely benefit from DNA damaging agents such as platinum therapies and PARP inhibitors.
"Hereditary and somatic defects in genes that support homologous recombination have been implicated in predisposition to a variety of cancers. BRCA 1 or BRCA 2 mutations and other HR defects have potential therapeutic relevance when used to direct the use of therapeutics that introduce or exploit double-stranded DNA breaks," Myriad said in a statement discussing the paper. The "HRD score could be utilized to identify patients with a variety of cancers who have a high likelihood of responding to DNA damaging agents such as the platinum drugs, as well as PARP inhibitors."
In the latest study, a tumor sample was considered homologous recombination deficient if it harbored a germline or somatic mutation in BRCA1 or BRCA2, had methylated or low mRNA expression of BRCA1, or showed loss of heterozygosity for BRCA1 or BRCA2. Tumor suppressor genes BRCA1 and BRCA2 bind to RAD51 and produce proteins that regulate the DNA repair pathway. Breast and ovarian cancer patients with germline mutations in BRCA1 and BRCA2 have shown loss of heterozygosity in these genes, but also respond well to platinum-based treatments and PARP inhibitors.
"The HRD score is strongly associated with the integrity of homologous recombination, as measured by BRCA1, BRCA2, and RAD51C defects," researchers led by Victor Abkevich wrote in the BJC paper. "The correlation of [the] score and [homologous recombination] deficiency was validated in two independent epithelial ovarian cancer data sets, as well as breast and pancreatic cancer cell lines."
The study authors also reported that "intermediate sized" loss of heterozygosity regions showed up more frequently in tumors with defective BRCA1 or BRCA2 genes.
The researchers noted in the paper that "a substantial fraction" of tumors with intact BRCA1, BRCA2, and RAD51C have elevated homologous recombination deficiency scores. "Two possible explanations are that there is a substantial rate of defects in other genes in the HR pathway in many of these samples, or that the HRD score is non-specific," the researchers wrote.
Myriad has companion diagnostic development agreements with several drug companies who are developing PARP inhibitors, including Abbott Pharmaceuticals, Astra Zeneca, BioMarin Pharmaceuticals, as well as with Pharma Mar for a DNA damaging agent (PGx Reporter 8/1/2012).