At ASCO 2023, Foundation Medicine presented two new analyses supporting the use of their innovative Homologous recombination deficiency signature (HRDsig) for detecting genomic scars from patient tissue samples analyzed using FoundationOneCDx or FoundationOne, expanding upon clinical evidence published over the past year. These findings, the researchers say, support HRDsig as a strong predictor of response to PARP inhibition.
HRD biomarkers are critical for identifying patients who may benefit from the use of PARP inhibitors (PARPi) and other DNA-damaging therapeutics. Mutations in genes involved in homologous recombination repair (HRR), such as BRCA1 and 2, are associated with response to PARPi. However, patients may have HR-deficient tumors that will respond to PARPi but do not have known genomic mutations associated with HRD, creating a need for methods to assess HRD beyond the detection of known alterations.
Functional assessment of HRD analyzing genomic scars — aberrations across the genome likely resulting from HRD — has the potential to improve both sensitivity and specificity for detecting HRD beyond current approaches relying upon the detection of genomic alterations. Foundation Medicine’s HRDsig biomarker is a next-generation sequencing scar-based method that does not rely on detecting HRR gene alterations to detect HRD, but instead on identifying genome-wide copy number (CN) features. The approach of analyzing CN features enables the detection of genomic and non-genomic mechanisms of HRD in a patient. Specifically, epigenetic mechanisms of HRD, like BRCA1 promoter hypermethylation, have been reported in ovarian and triple-negative breast cancer, thus a substantial portion of the HRD population may be missed using gene alteration biomarkers alone.
HRDsig for genomic scar detection in early-stage breast and advanced ovarian cancers
In the first study presented at ASCO, June Jeon and colleagues presented a landscape analysis applying Foundation Medicine’s HRDsig biomarker to a cohort of 896 patients with early-stage breast cancer. They observed that the rates of HRDsig positivity (HRDsig+) were similar across receptor subtype groups, and present at a similar frequency to patients with late-stage breast cancer, indicating HRDsig applicability to the clinical population. High rates of HRDsig+ were observed in early-stage breast cancer patients with germline or somatic BRCA or genomic PALB2 mutations, where clinical trial data already support the use of PARPi for early and advanced disease. Interestingly, HRDsig positivity was also seen in 16 percent of patients with early breast cancer who were wild type for the above-mentioned alterations, capturing an HRD population potentially missed when relying solely on the detection of relevant genomic alterations. Future clinical trials will be needed to determine if genomic-scar-based biomarkers like HRDsig have clinical utility in early-stage breast cancer to identify patients benefitting from HRD-directed therapies.
In the second study, Debra Richardson and colleagues presented an analysis of real-world outcomes associated with maintenance PARPi use — the current standard of care — versus no maintenance therapy use — the prior standard of care — in patients with advanced ovarian cancer. HRDsig+ was strongly associated with benefit from PARPi (HR of 0.31 for PFS), an analysis which included patients identified as BRCA wild-type (BRCAwt) Furthermore, in this cohort of patients, those who were HRDsig- did not show benefit from PARPi maintenance therapy use (hazard ratio (HR) of 0.98 for PFS). Together, these data support Foundation Medicine’s HRDsig as a candidate biomarker to differentiate patients most likely to benefit from PARPi maintenance therapy in ovarian cancer.
HRDsig represents a next-generation approach for detecting genomic scars
At AACR 2022, Emmanuel Antonarakis presented with Foundation Medicine that high rates of HRDsig positivity were seen in BRCA-associated cancers, but also in gastrointestinal and lung cancers, with a 6.4 percent overall positivity across solid tumor types, and that HRDsig+ patients exhibited favorable PARPi outcomes in ovarian cancer and prostate cancer. At AACR 2023, this observation was extended in a retrospective analysis of the all-comers ARIEL2 trial analyzing rucaparib use in advanced ovarian cancer. Elizabeth Swisher and team collaborated with Foundation Medicine to demonstrate that HRDsig+ was able to predict favorable clinical outcomes (HR=0.66 for PFS) in the intention to treat (ITT) and to detect epigenetic HRD in BRCAwt patients with BRCA1 promoter hypermethylation (97 percent detection rate).
Potential for HRDsig beyond PARPi and in non-BRCA associated cancers
Selection of first-line therapy for pancreatic cancer patients is challenging, with the goal of maximizing survival and minimizing toxicity. At ESMO 2022, in a real-world analysis of 1,081 patients with pancreatic cancer, Atul Singhi and team identified HRDsig+ in 9 percent of cases on Foundation Medicine’s platform and found an association with platinum-based 1L FOLFIRINOX benefit with a doubled median overall survival relative to gemcitabine and paclitaxel (GP) (OS 14.8 vs 6.3 months, adjusted HR 0.50). Beyond prediction of clinical response in BRCA-associated cancers, HRDsig may also have value in predicting response to PARPi in non-BRCA-associated cancers, including NSCLC. HRDsig is a score based on the functional detection of HRD, which may serve to distinguish HRD in tumors with high tumor mutational burden (TMB) like NSCLC. Preliminary evidence presented at ESMO 2022 by Jonathan Reiss and team demonstrated that HRDsig+ is detected in almost 5 percent of NSCLC cases, and with enrichment in driver-negative patients. Further investigation is needed to understand if Foundation Medicine’s HRDsig biomarker can help optimize selection for PARPi in non-BRCA cancers like NSCLC, and beyond PARPi including use for platinum-based chemotherapy, ATR inhibitors, and other emerging DNA-damaging therapeutics.
Charting the path for clinical use of emerging complex biomarkers
Foundation Medicine has a robust history in developing complex genomic biomarkers for clinical and companion diagnostic use on their tissue (FoundationOneCDx) and blood-based (FoundationOneLiquid CDx) platforms, including genomic loss of heterozygosity (gLOH) in ovarian cancer on FoundationOneCDx, and pan tumor reporting of TMB on both platforms. Advancing biomarker science is performed in the context of optimizing clinical patient care, and, to support those broader efforts, Foundation Medicine regularly contributes to consortium thought leadership, as with Friends of Cancer Research (FOCR) HRD harmonization efforts to examine the factors that influence variability in HRD assessment. “Our data at ASCO […] reinforces our leadership in detection of complex genomic biomarkers, and supports increased confidence and ease in our tests’ use by doctors and researchers,” says Mia Levy, chief medical officer at Foundation Medicine. “Much of this research was conducted in collaboration with our partners across the oncology ecosystem, underscoring our commitment to working together in order to make faster, more impactful progress for patients.”