Study: Tests Used to Predict Response to PARP Inhibitors Yield Inconsistent Result

Study: Tests Used to Predict Response to PARP Inhibitors Yield Inconsistent Result

Tests used in clinical trials of ovarian cancer to determine if tumors lack the ability to repair their DNA — a status termed “homologous recombination deficiency” (HRD), and likely would respond to treatment with PARP inhibitors — yield inconsistent results, a recent study shows.

Study findings were presented in the poster “Comparison of genomic instability test scores used for predicting PARP activity in ovarian cancer,” at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, held online due to the global pandemic.

PARP inhibitors are medications that work by blocking the activity of PARP enzymes, which are involved in DNA repair. By blocking the activity of the enzymes, these agents prevent cancer cells from repairing their DNA, eventually eliminating them.

PARP inhibitors tend to be more effective in patients with HRD-positive tumors, meaning those that either have a mutation in BRCA, a DNA repair gene, that impairs its function, or have high genomic instability (high number of genetic mutations).

There are several tests that can be used to determine the HRD status or the degree of genomic instability of a tumor. Of all the options currently available, Myriad’myChoice CDx is the only clinically-validated, FDA-approved test to assess the HRD status of a tumor. The test does so by detecting the presence of mutations in BRCA1 or BRCA2 genes, while using three biomarkers to assess genomic instability.

At ASCO, researchers at Myriad and their colleagues reported the findings of a study that aimed to determine if different methods used to evaluate the degree of genomic instability and the HRD status of tumors in women with ovarian cancer would yield similar results.

To that end, they compared the proportion of women who were deemed to benefit from treatment with PARP inhibitors by two HRD tests — the percentage loss of heterozygosity (%LOH) and the 11-gene panel — to myChoice CDx.

To calculate myChoice CDx scores and %LOH, a whole-genome SNP analysis was performed to reconstruct the genomic profile of tumors found in two groups of women with ovarian cancer: 3,278 who were part of a clinical laboratory cohort; and 248 who participated in the SCOTROC4 Phase 3 trial (NCT00098878).

SNPs, or single nucleotide polymorphisms, are variations in a single nucleotide (DNA building blocks) in the DNA sequence of a gene. In a whole-genome SNP analysis, researchers examine all the SNPs found in the genome (all of the genes present in human DNA).

Mutation screening in the 11-gene panel was performed on a subset of 187 tumors from women who participated in SCOTROC4.

The myChoice CDx test was considered positive when scores were greater than those defined by the threshold (in this case 33 and 42). The %LOH was considered positive when the test score was greater than 16%, and the 11-gene panel was considered positive when at least one mutation was found in any of the 11 genes analyzed.

Investigators then examined the percentage of patients who tested positive from myChoice CDx and also for %LOH or for the 11-gene panel, to analyze the degree of consistency between the different tests.

They found that 19–61% of the women who tested positive in myChoice CDx, were missed by the other two HRD tests.

According to investigators, “these data show that HRD tests used in published and ongoing clinical trials are not equivalent, and they should not be considered interchangeable in predicting PARP inhibitor response in clinical practice.”