dc.contributor.author | Tovey, H | |
dc.contributor.author | Sipos, O | |
dc.contributor.author | Parker, JS | |
dc.contributor.author | Hoadley, KA | |
dc.contributor.author | Quist, J | |
dc.contributor.author | Kernaghan, S | |
dc.contributor.author | Kilburn, L | |
dc.contributor.author | Salgado, R | |
dc.contributor.author | Loi, S | |
dc.contributor.author | Kennedy, RD | |
dc.contributor.author | Roxanis, I | |
dc.contributor.author | Gazinska, P | |
dc.contributor.author | Pinder, SE | |
dc.contributor.author | Bliss, J | |
dc.contributor.author | Perou, CM | |
dc.contributor.author | Haider, S | |
dc.contributor.author | Grigoriadis, A | |
dc.contributor.author | Tutt, A | |
dc.contributor.author | Cheang, MCU | |
dc.date.accessioned | 2023-07-26T14:46:57Z | |
dc.date.available | 2023-07-26T14:46:57Z | |
dc.date.issued | 2023-09-15 | |
dc.identifier.citation | Clinical Cancer Research, | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5897 | |
dc.description.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-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. | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.relation.ispartof | Clinical Cancer Research | |
dc.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). | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-07-24 | |
dc.date.updated | 2023-07-25T12:23:29Z | |
rioxxterms.version | AM | |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.type | Journal Article/Review | |
pubs.organisational-group | /ICR | |
pubs.publication-status | Accepted | |
icr.researchteam | Directorate Breast Canc | |
dc.contributor.icrauthor | Tovey, Holly | |
dc.contributor.icrauthor | Kilburn, Lucy | |
dc.contributor.icrauthor | Bliss, Judith | |
dc.contributor.icrauthor | Haider, Syed | |
dc.contributor.icrauthor | Tutt, Andrew | |
dc.contributor.icrauthor | Cheang, Chon | |
icr.provenance | Deposited by Ms Alex Carroll (impersonating Prof Andrew Tutt) on 2023-07-25. Deposit type is initial. No. of files: 1. Files: DDR and immune paper v5 - CLEAN.docx | |