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)

Tovey, H; Sipos, O; Parker, JS; Hoadley, KA; Quist, J; Kernaghan, S; Kilburn, L; Salgado, R; Loi, S; Kennedy, RD; Roxanis, I; Gazinska, P; Pinder, SE; Bliss, J; Perou, CM; Haider, S; Grigoriadis, A; Tutt, A; Cheang, MCU

Author(s): Tovey, H; Sipos, O; Parker, JS; Hoadley, KA; Quist, J; Kernaghan, S; Kilburn, L; Salgado, R; Loi, S; Kennedy, RD; Roxanis, I; Gazinska, P; Pinder, SE; Bliss, J; Perou, CM; Haider, S; Grigoriadis, A; Tutt, A; Cheang, MCU;
Details: Publication Year 2023-09-15,Volume 29,Issue #18,Page 3691-3705
Journal Title: Clinical Cancer Research
Publication Type: Research article
Abstract: 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 association 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 characterized by 693 gene expression modules and other markers. RESULTS: Transcriptional DDR-related biomarkers were not predictive 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 outstanding need. Caution is needed using PT-derived transcriptional signatures to direct treatment in mTNBC, particularly DDR-related markers following prior chemotherapy.
Publisher: American Association for Cancer Research
Keywords: Humans; Carboplatin; *BRCA1 Protein/genetics; Docetaxel/therapeutic use; *Triple Negative Breast Neoplasms/drug therapy/genetics/pathology; BRCA2 Protein/genetics; Biomarkers; DNA Damage; Antineoplastic Combined Chemotherapy Protocols/adverse effects
Department(s): Medical Oncology; Laboratory Research
PubMed ID: 37574209
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-23-0370
Open Access at Publisher's Site: https://doi.org/10.1158/1078-0432.Ccr-23-0370
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-21 05:54:39

Last Modified: 2023-11-21 05:55:40