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).

Autor:	Tovey H; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom., Sipos O; Breast Cancer Now Toby Robinsons Research Centre, The Institute of Cancer Research, London, United Kingdom., Parker JS; Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Hoadley KA; Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Quist J; The Breast Cancer Now Unit, King's College London Faculty of Life Sciences and Medicine, London, United Kingdom.; School of Cancer and Pharmaceutical Sciences, King's College London Faculty of Life Sciences and Medicine, London, United Kingdom., Kernaghan S; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom., Kilburn L; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom., Salgado R; Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium., Loi S; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia., Kennedy RD; ALMAC Diagnostic Services, Northern Ireland, United Kingdom., Roxanis I; Breast Cancer Now Toby Robinsons Research Centre, The Institute of Cancer Research, London, United Kingdom., Gazinska P; Breast Cancer Now Toby Robinsons Research Centre, The Institute of Cancer Research, London, United Kingdom.; Biobank Research Group, Lukasiewicz Research Network - PORT Polish Center for Technology Development, Wroclaw, Poland., Pinder SE; School of Cancer and Pharmaceutical Sciences, King's College London Faculty of Life Sciences and Medicine, London, United Kingdom., Bliss J; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom., Perou CM; Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Haider S; Breast Cancer Now Toby Robinsons Research Centre, The Institute of Cancer Research, London, United Kingdom., Grigoriadis A; The Breast Cancer Now Unit, King's College London Faculty of Life Sciences and Medicine, London, United Kingdom.; School of Cancer and Pharmaceutical Sciences, King's College London Faculty of Life Sciences and Medicine, London, United Kingdom., Tutt A; Breast Cancer Now Toby Robinsons Research Centre, The Institute of Cancer Research, London, United Kingdom.; The Breast Cancer Now Unit, King's College London Faculty of Life Sciences and Medicine, London, United Kingdom.; School of Cancer and Pharmaceutical Sciences, King's College London Faculty of Life Sciences and Medicine, London, United Kingdom., Cheang MCU; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Sep 15; Vol. 29 (18), pp. 3691-3705.
DOI:	10.1158/1078-0432.CCR-23-0370
Abstrakt:	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-naïve 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-naïve 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. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu