Integrated Multimodal Analyses of DNA Damage Response and Immune Markers as Predictors of Response in Metastatic Triple-Negative Breast Cancer in the TNT Trial (NCT00532727)

Purpose: The TNT trial (NCT00532727) showed no evidence of carboplatin superiority over docetaxel in metastatic triple-negative breast cancer (mTNBC), but carboplatin benefit was observed in the germline BRCA1/2 mutation subgroup. Broader response-predictive biomarkers are needed. We explored the predictive ability of DNA damage response (DDR) and immune markers.Experimental Design: Tumor-infiltrating lymphocytes were evaluated for 222 of 376 patients. Primary tumors (PT) from 186 TNT participants (13 matched recurrences) were profiled using total RNA sequencing. Four transcriptional DDR-related and 25 immune-related signatures were evaluated. We assessed their asso-ciation with objective response rate (ORR) and progression-free survival (PFS). Conditional inference forest clustering was applied to integrate multimodal data. The biology of subgroups was char-acterized by 693 gene expression modules and other markers.Results: Transcriptional DDR-related biomarkers were not pre-dictive of ORR to either treatment overall. Changes from PT to recurrence were demonstrated; in chemotherapy-naive patients, transcriptional DDR markers separated carboplatin responders from nonresponders (P values = 0.017; 0.046). High immune infiltration was associated with docetaxel ORR (interaction P values < 0.05). Six subgroups were identified; the immune-enriched cluster had preferential docetaxel response [62.5% (D) vs. 29.4% (C); P = 0.016]. The immune-depleted cluster had preferential carboplatin response [8.0% (D) vs. 40.0% (C); P = 0.011]. DDR-related subgroups were too small to assess ORR.Conclusions: High immune features predict docetaxel response, and high DDR signature scores predict carboplatin response in treatment-naive mTNBC. Integrating multimodal DDR and immune-related markers identifies subgroups with differential treatment sensitivity. Treatment options for patients with immune-low and DDR-proficient tumors remains an out -standing need. Caution is needed using PT-derived transcrip-tional signatures to direct treatment in mTNBC, particularly DDR-related markers following prior chemotherapy.

Automated summary

This study explored the predictive ability of DNA damage response (DDR) and immune markers in the treatment response of triple-negative breast cancer. High immune features predict response to docetaxel, while high DDR signature scores predict response to carboplatin. Patients can be divided into different subgroups based on their treatment sensitivity. Caution is needed when using transcriptional signatures derived from primary tumors to guide treatment.