A homologous recombination deficiency (HRD) assay testing for impaired double-strand DNA break repair did not predict pathologic response to preoperative chemotherapy in a randomized trial of women with early-stage triple-negative breast cancer (TNBC) and no known BRCA germline mutation,1 adding to evidence that suggests that HRD score currently has no clinical role in the selection of treatment for women with this breast cancer subtype.
“Among TNBC that develop[s] in people that do not have germline BRCA1/2 deficiency, there may exist a subset that have a similar phenotype that we might define as ‘BRCA-like’,” explained study author Erica L. Mayer, MD, MPH, assistant professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, Boston, Massachusetts. “HRD biomarker assays are being studied to see if they can identify BRCA-like cancers and possibly help direct chemotherapy selection for patients, for example, considering agents that target DNA or create DNA damage, like platinum chemotherapy.”
DNA Damage Repair
Research into HRD was pioneered by Daniel Silver, MD, PhD, associate professor of medical oncology and cancer biology at Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania, and colleagues. In early experiments, they showed that tumors have certain chromosomal abnormalities that indicate defective DNA repair and the number of these abnormalities predict platinum sensitivity in breast cancer cell lines.
“The higher the number of abnormalities, the more likely that cell line was defective in BRCA1 or BRCA2 or the pathway that the BRCA1/2 proteins function in, and the more likely the cell lines were sensitive to platinum,” Dr Silver said.
In 2012, Dr Silver and colleagues published a paper showing that the number of these abnormalities, chromosomal regions with allelic imbalance extending to the end of the chromosome, could predict sensitivity to cisplatin and pathologic response to preoperative cisplatin in patients with TNBC.2 Based on these results, they suggested that this genomic measure — the basis of the HRD assay — could possibly identify patients who would benefit from treatments targeting defective DNA repair in TNBC and other cancer types.
The clinical usefulness of the HRD assay has been defined in several large trials that studied PARP inhibitor use in ovarian cancer.3,4,5,6 These studies have resulted in the US Food and Drug Administrations’s (FDA’s) approval of HRD assays for several indications in ovarian cancer.
However, retrospective studies looking at HRD assay-based scores have failed to confirm that a positive HRD score specifically predicts response to platinum chemotherapy in breast cancer. For example, the GeparSixto trial (ClinicalTrials.gov Identifier: NCT01426880) analyzed carboplatin added to anthracycline/taxane-based neoadjuvant chemotherapy in women with TNBC. A retrospective exploratory analysis suggested that a positive HRD score in patients without known BRCA mutation predicted response to chemotherapy, but not specifically to carboplatin.7 Similarly, in BrighTNess (ClinicalTrials.gov Identifier: NCT02032277), those patients with high HRD scores had higher rates of response across all treatment arms, but HRD score did not predict for specific response to carboplatin.8
More recently, Dr Mayer led a prospective randomized phase 2 study designed specifically to evaluate the use of an HRD assay as a biomarker to predict if the HRD status of triple-negative breast cancer in women without a known BRCA germline mutation was associated with more or less sensitivity to preoperative treatment with cisplatin or paclitaxel.
The trial, led by the Translational Breast Cancer Research Consortium (TBCRC), included 139 patients who were randomly assigned to 12 weeks of preoperative cisplatin or paclitaxel. Crossover to an alternative chemotherapy was allowed if there was inadequate clinical response before planned surgery.
HRD results were available for 104 of the 139 patients (74.8%) and the majority were HRD positive (71.1%). About one-quarter of patients in both arms were found to have responded to chemotherapy, defined as a residual cancer burden score of 0 or 1: 26.4% for cisplatin and 22.3% for paclitaxel.
There was no association between HRD score at baseline and response to either chemotherapy.
“Based on the results of the study, we are not able to recommend that an HRD assay be utilized as a way to select specific preoperative chemotherapy for patients with TNBC,” Dr Mayer told Cancer Therapy Advisor.
Priyanka Sharma, MD, professor of medicine at The University of Kansas, pointed out several limitations with the study that should be taken into consideration when looking at the results.
“This was a small proof-of-principle study that did not complete accrual,” Dr Sharma said.
Target study accrual was 160 patients and the study included 139. The researchers noted in the study that accrual was terminated prematurely due to withdrawal of sponsor support. However, Dr Sharma noted that she does not think completion of accrual would have changed the results.
“There was also a much larger proportion of patients deemed to have HRD positivity than anticipated, so that left too low a number of HRD-negative patients to make a good assessment,” Dr Sharma pointed out.
Finally, Dr Mayer noted that the HRD assay produced results for about 75% of patients, a lower-than-expected assay success rate.
“This lower number weakens the power of the study to look for an association and is a limitation of the trial,” Dr Mayer said.
However, she added that “this was the first prospective study to specifically look at the predictive capacity of HRD and one can say that despite the results not showing a connection between the HRD assay and response to specific chemotherapy, there remains great interest in the scientific community in identifying predictive biomarkers in TNBC to help select therapy.”