Browsing Over 180 Presentations
Potential new drugs with activity in metastatic TNBC (ID 287)
LBA2 - Impact of RNA expression signatures and tumor infiltrating lymphocytes (TILs) for pathological complete response (pCR) and survival after 12 week de-escalated neoadjuvant pertuzumab + trastuzumab ± paclitaxel in the WSG-HER2+/HR- ADAPT trial. (ID 319)
Abstract
Background
Limited data are available on predictive biomarkers for dual anti-HER2 blockade in HER2+/HR- early breast cancer (BC). The present analysis aimed to identify associations of biological signatures and stromal TILs (sTILs) with pCR and survival in phase II WSG-ADAPT HER2+/HR- trial (NCT01779206).
Methods
Patients (pts) with cT1-cT4c, cN0-3 HER2+/HR- BC were randomized to receive pertuzumab + trastuzumab (P+T) in Arm A (n=92) or P+T+paclitaxel in Arm B (n=42). Gene expression signatures were analyzed in baseline (BL) biopsies using NanoString Breast Cancer 360 panel (n=117); BL and on-treatment (week 3) sTIL levels were available in 119 and 76 pts, respectively. Impacts of standardized gene expression signatures on pCR (odds ratios, OR) and invasive disease-free survival (iDFS; hazard ratios, HR) were estimated by logistic and Cox regression, respectively; Spearman correlations were computed.
Results
In all pts, ERBB2 (OR 1.7; 95%CI 1.1-2.7) and estrogen receptor (ER) pathway signaling signatures (OR 1.7; 95%CI 1.1-2.6) were favorable, while PTEN signature (OR 0.6; 95%CI 0.4-0.9) was unfavorable for pCR. After 60 months median follow-up, 13 (A: 11, B: 2) invasive events occurred, none following pCR (ypT0 ypN0). Regarding iDFS, several gene signatures related to immune response (IR) as well as ER signaling were favorable, all with similar HR about 0.4 - 0.6. These patterns were even more prominent in the neoadjuvant chemotherapy-free Arm A, where additionally, BRCAness signature was unfavorable (HR 2.0; 95%CI 1.0-3.8). All significant IR signatures were strongly intercorrelated. sTILs (BL/week 3/change) were not significantly associated with pCR or iDFS, though BL-sTIL correlated positively with IR signatures.
Conclusions
The present translational analysis of the WSG-ADAPT HER2+/HR- trial suggests distinct (except for ER signaling) gene signatures associated with pCR vs iDFS. IR signatures can augment morphological data from sTILs; the potential role of IR in preventing recurrence suggests that pts with up-regulated IR signatures could be candidates for de-escalation concepts in HER2+ BC.
Clinical trial identification
EudraCT Number: 2011-001462-17.
Legal entity responsible for the study
Westdeutsche Studiengruppe GmbH.
Funding
Hoffmann la Roche.
Disclosure
All authors have declared no conflicts of interest.
PI3Kα inhibitors: Addressing unmet needs through precision medicine in HR+, HER2- ABC - From scientific breakthrough to clinical practice (ID 354)
Can imaging help tailor preoperative HER2-directed therapy? (ID 30)
Invited Discussant LBA2 and 3O (ID 250)
Challenges and opportunities: Key rules to get involved (ID 314)
Opening remarks (ID 349)
Molecular testing algorithms for metastatic BC (ID 25)
2O - Association of RAD51 with Homologous Recombination Deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial (ID 244)
Abstract
Background
Current genetic and genomic tests that measure HRD show limited predictive value. We compare the performance of a functional HRD test based on scoring RAD51 nuclear foci with genetic/genomic HRD tests, and assess its capacity to select patients (pts) with primary TNBC sensitive to platinum-based neoadjuvant chemotherapy (NACT).
Methods
A retrospective, blinded analysis from the GeparSixto randomized trial was conducted on TNBC pts who received neoadjuvant paclitaxel plus non-pegylated liposomal doxorubicin (Myocet®) and bevacizumab (PM) or PM plus carboplatin (PMCb). Functional HRD biomarkers (RAD51, BRCA1 and yH2AX nuclear foci) were quantified in formalin-fixed paraffin-embedded (FFPE) tumor samples on a tissue microarray format (TMA). Concordance analyses were performed between the RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (myChoice® CDx). Associations with clinical outcomes were studied by logistic (pathological complete response, pCR) and Cox (disease-free survival, DFS) regression models. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low).
Results
RAD51, BRCA1 and yH2AX were successfully scored in 133/200 TMA cores (67%). Functional HRD by RAD51-low was evidenced in 81/133 tumors (62%). The RAD51 test identified 93% of tBRCA-mutated tumors and 45% of the non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% (95%CI 79-93%). In pts with RAD51-high tumors, the pCR rate was similar between treatment arms (PMCb 31% vs PM 39%, odds ratio (OR) 0.71, 0.23-2.24, p=0.561). Pts with RAD51-low tumors benefited from PMCb (66% vs 33%, OR 3.96, 1.56-10.05, p=0.004; interaction test p=0.023). The addition of Cb showed a trend towards better DFS in both RAD51-high (hazard ratio (HR) 0.40, 0.12-1.29, p=0.125) and RAD51-low (HR 0.45, 0.16-1.25, p=0.124) groups.
Conclusions
The RAD51 test is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51-testing in the clinical decision making.
Clinical trial identification
NCT01426880.
Legal entity responsible for the study
Violeta Serra, ERAPERMED.
Funding
Has not received any funding.
Disclosure
A. Llop-Guevara: Research grant/Funding (self): AECC (INVES20095LLOP); Research grant/Funding (self): La Caixa Foundation and European Institute of Innovation and Technology/Horizon 2020 (LCF/TR/CC19/52470003). A. Schneeweiss: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, Medical writing grant: Roche; Research grant/Funding (institution): AbbVie; Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly. G. Villacampa: Honoraria (self): MSD; Honoraria (self): AstraZeneca. P. Jank: Research grant/Funding (institution): EU funding EraPerMed JTC2019 \"RAD51predict\"; Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Myriad Genetics, Inc. M. van Mackelenbergh: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Genomic Health; Honoraria (self): Mylan; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Roche. P.A. Fasching: Honoraria (self): Novartis; Research grant/Funding (institution): Biontech; Honoraria (self): Pfizer; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Merck Sharp & Dohme; Research grant/Funding (institution): Cepheid; Honoraria (self): Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Hexal. F. Marmé: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Clovis; Honoraria (self): GSK/Tesaro; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Seagen; Honoraria (self): Myriad Gen; Honoraria (self): PharmaMar; Honoraria (self): Eisai; Honoraria (self): Janssen-Cilag. R. Dienstmann: Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Merck Sharp Dohme; Honoraria (self): Amgen; Honoraria (self): Sanofi; Honoraria (self): Servier; Honoraria (self): Ipsen. J. Balmaña: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer. C. Denkert: Research grant/Funding (institution): European Commission H2020; Research grant/Funding (institution): German Cancer Aid Translational Oncology; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Research grant/Funding (institution): Myriad; Honoraria (self): Merck; Shareholder/Stockholder/Stock options: Sividon diagnostics; Licensing/Royalties, patent royalties: MScope digital pathology software; Licensing/Royalties, patent pending: WO2020109570A1 - cancer immunotherapy; Licensing/Royalties, patent issued: WO2015114146A1 and WO2010076322A1- therapy response. S. Loibl: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Honoraria (institution): Seagen; Research grant/Funding (institution): Immunomedics/Gilead Sciences Inc; Honoraria (institution): prIME/Medscape; Honoraria (institution): Eirgenix; Research grant/Funding (self), Research grant/Funding (institution): DSI; Honoraria (institution): BMS; Honoraria (institution): Merck; Honoraria (institution): Puma; Speaker Bureau/Expert testimony: Chugai; Licensing/Royalties, patent pending: EP14153692.0-Immunsignature in TNBC. V. Serra: Research grant/Funding (institution): ISCIII (CPII19/00033); Research grant/Funding (institution): TRANSCAN-2 (AC15/00063; Research grant/Funding (institution): AECC (LABAE16020PORTT); Research grant/Funding (institution): ERAPERMED2019-215. All other authors have declared no conflicts of interest.