BRCAness digitalMLPA profiling predicts benefit of intensified platinum-based chemotherapy in triple-negative and luminal-type breast cancer

Abstract

Background: We previously showed that BRCA-like profiles can be used to preselect individuals with the highest risk of carrying BRCA mutations but could also indicate which patients would benefit from double-strand break inducing chemotherapy. A simple, robust, and reliable assay for clinical use that utilizes limited amounts of formalin-fixed, paraffin-embedded tumor tissue to assess BRCAness status in both ER-positive and ER-negative breast cancer (BC) is currently lacking. Methods: A digital multiplex ligation-dependent probe amplification (digitalMLPA) assay was designed to detect copy number alterations required for the classification of BRCA1-like and BRCA2-like BC. The BRCA1-like classifier was trained on 71 tumors, enriched for triple-negative BC; the BRCA2-like classifier was trained on 55 tumors, enriched for luminal-type BC. A shrunken centroid-based classifier was developed and applied on an independent validation cohort. A total of 114 cases of a randomized controlled trial were analyzed, and the association of the classifier result with intensified platinum-based chemotherapy response was assessed. Results: The digitalMLPA BRCA1-like classifier correctly classified 91% of the BRCA1-like samples and 82% of the BRCA2-like samples. Patients with a BRCA-like tumor derived significant benefit of high-dose chemotherapy (adjusted hazard ratio (HR) 0.12, 95% CI 0.04-0.44) which was not observed in non-BRCA-like patients (HR 0.9, 95% CI 0.37-2.18) (p = 0.01). Analysis stratified for ER status showed borderline significance. Conclusions: The digitalMLPA is a reliable method to detect a BRCA1-and BRCA2-like pattern on clinical samples and predicts platinum-based chemotherapy benefit in both triple-negative and luminal-type BC.

Homologous Recombination Deficiency Detection Algorithms: A Systematic Review

“…The sensitivity ranged from 53% to 100%, and the specificity ranged from 40% to 100%. The HRD test with the highest sensitivity and corresponding specificity was HRD-DNA [43], followed by BRCA1-like digitalMLPA classifier [36], BRCA1 classifier [22], ShallowHRD [35], BRCA1-like MLPA classifier [23], DNA-methylation-based RF classifier [38], and BRCA2 classifier [24]. The HRD score [16], LST [7], BRCA1ness signature [29], and Ovarian cancer BRCA1-like classifier [40] had high sensitivity, but the corresponding specificities were relatively low (Figure 4).…”

Treatment of Metastatic Castration-resistant Prostate Cancer: Are PARP Inhibitors Shifting the Paradigm?

“…For patients with breast, ovarian, and pancreatic cancers harboring BRCA alterations, PARP inhibitors are used after chemotherapy. BRCA mutations predict the response of ovarian and breast cancers to platinum (51,52). Niraparib and olaparib are recommended as maintenance therapies after platinumbased chemotherapy only for platinum-sensitive cancer (53)(54)(55).…”

Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status

“…Moreover, g BRCA1 m or BRCA1 -like tumors often present with aggressive phenotypes [ 22 , 23 ] and are hypothesized to be associated with a worse prognosis compared to germline BRCA1 wild-type (g BRCA1 wt) or non- BRCA1 -like tumors. However, many studies observed that in chemotherapy-treated TNBC patients, those with g BRCA1 m or BRCA1 -like tumors had equivalent or even better survival compared to those with g BRCA1 wt or non- BRCA1 -like tumors [ 5 , 6 , 24 – 27 ]. This suggests that chemotherapy might obscure the worse survival of patients with g BRCA1 m or BRCA1- like tumors [ 28 ].…”