@article{fef62e770e354d2984abb477de5b2e45,
title = "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)",
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-na{\"i}ve 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-na{\"i}ve 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.",
author = "Holly Tovey and Orsolya Sipos and Parker, {Joel S} and Hoadley, {Katherine A} and Jelmar Quist and Sarah Kernaghan and Lucy Kilburn and Roberto Salgado and Sherene Loi and Kennedy, {Richard D} and Ioannis Roxanis and Patrycja Gazinska and Pinder, {Sarah E} and Judith Bliss and Perou, {Charles M} and Syed Haider and Anita Grigoriadis and Andrew Tutt and Cheang, {Maggie Chon U}",
note = "Funding Information: Grateful thanks to the patients and families of those who took part in the trial, and all involved staff at the participating centers. We also acknowledge past and present colleagues on the TNT Trial Management Group; the Independent Data Monitoring Committee and Trial Steering Committee, who oversaw the trial; the Response Evaluation Committee, who conducted the independent radiology review; Cancer Research UK and Breast Cancer Now (and their legacy charity Breakthrough Breast Cancer), who funded the study; and the National Institute for Health Research Cancer Research Networks in England and their equivalent NHS R&D-funded networks in Scotland, Wales, and Northern Ireland for “in-kind” support. The TNT study was funded by Cancer Research UK and Breast Cancer Now (and their legacy charity Breakthrough Breast Cancer) (Cancer Research UK grant number CRUK/07/012 to J. Bliss and A. Tutt). This work was also supported by funds from the NCI Breast SPORE program (P50-CA058223) and by NCI UG1-CA233333 (C.M. Perou), Breast Cancer Now (KCL-BCN-Q2/KCL-BCN-Q3 to A. Grigoriadis and A. Tutt and ICR-BCN-Q4/ ICR-BCN-Q5 to A. Tutt) and Cancer Research UK City of London Centre Award (CTRQQR-2021/100004 to A. Grigoriadis). Funding was provided from Myriad Genetics, Inc, to cover costs of nucleic extraction from tumor blocks appropriate for Next Generation Sequencing, and Prosigna reagent kits were provided by NanoString Technologies, Inc. ICR-CTSU also receives program grant funding from Cancer Research UK, grant number C1491–A15955 (J. Bliss). Funding Information: 2022, PAGE SAB, Gilead ASCO Educational event, and VHIO 2023; and personal fees and other support from Inbiomotion outside the submitted work. In addition, A. Tutt has a patent issued and with royalties paid from AstraZeneca. M.C.U. Cheang reports grants from Cancer Research UK, Breast Cancer Now, and Myriad Genetics and nonfinancial support from NanoString Technologies during the conduct of the study as well as other support from co-inventor of PAM50/Bioclassifier with royalties paid outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2023 The Authors; Published by the American Association for Cancer Research.",
year = "2023",
month = sep,
day = "15",
doi = "10.1158/1078-0432.CCR-23-0370",
language = "English",
volume = "29",
pages = "3691--3705",
journal = "Clinical cancer research : an official journal of the American Association for Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "18",
}