Research indicates that homologous recombination deficiency (HRD) status can be employed to identify patients who are eligible for treatment with DNA damaging agents. Studies have previously investigated the relationship between HRD status and outcomes in patients with triple negative breast cancer (TNBC) utilizing a 3-biomarker Genomic Instability Score (GIS) threshold of ≥42.  However, clinical evidence implies that a GIS threshold of ≥33 may be more appropriate.

In a recent analysis, lead author Dr Kirsten Timms, Myriad Genetics Inc, Salt Lake City, Utah and colleagues reported their discoveries from an exploratory analysis assessing the capability of ≥33 and ≥42 GIS thresholds to predict response to platinum-based treatment in patients with TNBC. 

In this analysis, patients across 5 cohorts (TBCRC030, TBCRC008, NCT01372579, PrECOG 0105, combined cisplatin cohort) were included if they had a primary TNBC diagnosis, received neoadjuvant platinum-based treatment, had a valid GIS, and had known pathologic complete response (pCR) status. 

The GIS was established by a combination of loss of heterozygosity, telomeric-allelic imbalance, and large-scale state transitions. BRCA mutation status was defined by loss of function resulting from a pathogenic variant in BRCA1 or BRCA2. By comparing binary threshold status and binary pCR status, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed. 

Researchers discovered a total of 204 tumors (158 BRA wild-type (BRCAwt); 33 BRCAm; 13 unknown) were included; pCR to platinum-based treatment occurred in 55 cases (39 BRCAwt; 14 BRCAm; 2 unknown). Sensitivity, specificity, PPV, and NPV were comparable between the ≥33 and ≥42 GIS thresholds, with the ≥33 threshold generating higher sensitivity values. 

Researchers noted that this was valid when thresholds were applied to all samples and to BRCAwt samples only. Among patients who reached pCR in response to platinum-based treatment, 5.5% of patients in the full cohort and 7.7% of those in the BRCAwt cohort had a GIS between 33-41. 

Dr Timms and colleagues concluded, “To ensure that the majority of patients likely to benefit from treatment are identified, a GIS of ≥33 may be the most appropriate threshold to predict response to platinum-based treatment in patients with TNBC; however, a prospective trial will be needed to confirm these findings. Additional studies will be important to determine whether this threshold may be appropriate to determine eligibility for other DNA-damaging agents such as PARP inhibitors.”

Resource:

Timms K, Lenz L, Cogan E, Mayer E, Kaklamini V, Stearns V et al. Exploring homologous recombination deficiency thresholds for predicting response to platinum-based treatment in triple negative breast cancer. Abstract presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago, IL, and virtual. Abstract 525.