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We evaluate therapy-induced molecular heterogeneity in longitudinal samples from high-risk, hormone-receptor positive/HER2-negative breast cancer patients with residual tumor after neoadjuvant chemotherapy from the Penelope-B trial (NCT01864746; EudraCT 2013-001040-62). Intrinsic subtypes are prognostic in pre-therapeutic (Tx) samples (n = 629, p < 0.0001) and post-Tx residual tumors (n = 782, p < 0.0001). After neoadjuvant chemotherapy, a shift of intrinsic subtypes is observed from pre-Tx luminal (Lum) B to post-Tx LumA, with reverse transition back to LumB in metastases. In a combined analysis of 540 paired pre-Tx and post-Tx samples, we identify five adaptive clusters (AC-1-5) based on transcriptomic changes before and after neoadjuvant chemotherapy. These AC-subtypes are prognostic beyond classical intrinsic subtyping, categorizing patients into groups with excellent prognosis (AC-1 and AC-2), poor prognosis (AC-3 and AC-4), and very poor prognosis (AC-5, enriched for basal-like subtype). Our analysis provides a basis for an extended molecular classification of breast cancer patients and improved identification of high-risk patient populations., Competing Interests: Declaration of interests C.D. reports grants from EU-H2020, BMBF, German Cancer Aid, and GBG, during the conduct of the study; personal fees from Novartis, Roche, MSD Oncology, DaiichiSankyo, Merck, AstraZeneca, and MolecularHealth; and institutional grants from Myriad, outside the submitted work. C.D. has a patent VMscope digital pathology software with royalties paid, a patent application related to prognostic subtypes in high-risk luminal breast cancer pending, as well as patents WO2020109570A1 and WO2015114146A1 pending and WO2010076322A1, issued. S.R., K.W., S.S., B.F., and V.N. report institutional grants from DaiichiSankyo, Gilead, Novartis, Pfizer, Roche, Seagen during the conduct of this work and from AbbVie, AstraZeneca, BMS, DaiichiSankyo, MolecularHealth, Novartis, Roche, Pfizer outside this work. S.R., K.W., S.S., B.F., and V.N. declare to be GBG Forschungs GmbH employees; GBG Forschungs GmbH royalties/patents: EP14153692.0, EP21152186.9, EP15702464.7, and EP19808852.8 and VM Scope GmbH as well as a patent application related to prognostic subtypes in high-risk luminal breast cancer pending. T.K. declares a patent application related to prognostic subtypes in high-risk luminal breast cancer pending. M.U. reports consulting fees to the institution from AstraZeneca, DaiichiSankyo, Lilly, MSD Merck, Myriad Genetics, Novartis, Pierre Fabre, Pfizer, Gilead, Roche, Sanofi Aventis, Seagen, Stemline, CD Pharma and honoraria to the institution from Astra Zeneca, Daiichi Sankyo, Lilly, Myriad Genetics, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi Aventis, Stemline, all outside the submitted work. S.-B.K. reports institutional grants from Novartis and Sanofi-Aventis, personal consulting fees from AstraZeneca, Beigene, DaeHwah Pharma, DaiichiSankyo, Ensol Bioscience Inc, ISU Abxis, Lilly, Novartis, OBI Pharma, and stock/stock options from Genopeaks and Neogene TC, all outside this work. H.D.B. reports stock ownership from Pfizer, Abbvie. and Viatris and research support from Merck Sharp & Dohme. N.McC. reports travel support from Novartis, AstraZeneca, Gilead, and Merck and participation in data safety or advisory board from Novartis, Gilead and Merck, outside the submitted work. C.C.W. is supported by the postdoctoral lecture qualification program of the Anneliese Pohl Foundation, Marburg. C.M.K. reports travel support from Novartis. T.R. reports institutional grants from German Cancer Aid, Else Kroener Fresenius Foundation, and German Society of Senology, outside this work and personal fees and travel support from Pfizer. M.M.O. reports travel support from Lilly and Novartis outside this work. E.S.K. reports institutional grants from NIH/NCI, Blueprint Medicine, and Bristol Meyer Squibb, personal consulting fees from Aleksia Pharmaceutical and Cancer Cell Cycle-LLC, and receipt of materials from Incyclix Pharma, all outside this work. N.T. reports consulting fees from Astra Zeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GlaxoSmithKline, Repare therapeutics, Relay therapeutics, Gilead, Inivata, Guardant, and Exact Sciences and grants from AstraZeneca, Pfizer, Roche/Genentech, Merck Sharpe and Dohme, Guardant Health, Invitae, Inivata, Personalis, and Natera, all outside of this work. F.R. reports consulting fees from BMS, Astra Zeneca, Roche, and MSD and honoraria and travel support from Novartis, Amgen, and Menarini, all outside this work. W.D.S. reports honoraria from AstraZeneca, GlaxoSmithKline, NOGGO, and Roche outside this work. P.A.F. reports institutional grants Biontech, Cepheid, and Pfizer; personal consulting fees and honoraria from Novartis, Pfizer, Roche, Daiichi-Sankyo, AstraZeneca, Lilly, Eisai, Merck Sharp & Dohme, Pierre Fabre, SeaGen, Agendia, Sanofi Aventis, Gilead, and Mylan; and participation in data safety monitoring boards or advisory boards for Novartis, Pfizer, Roche, Daiichi-Sankyo, AstraZeneca, Lilly, Eisai, Merck Sharp & Dohme, Pierre Fabre, SeaGen, Agendia, Sanofi Aventis, Gilead, and Mylan, all outside this work. M.T. reports research grants from Chugai, Takeda, Pfizer, Taiho, JBCRG assoc., KBCRN assoc., Eisai, Eli-Lilly and companies, Daiichi-Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon Kayaku, AFI technology, Luxonus, Shionogi, GL Science, and Sanwa Shurui and honoraria from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly, MSD, Exact Science, Novartis, Shimadzu, Yakult, Nippon Kayak, Devicore Medical Japan, Sysmex and participation in monitoring and advisory boards for Daiichi-Sankyo, Eli Lilly, BMS, Bertis, Terumo, Kansai Medical Net. He reports board membership for Assoc. JBCRG, Assoc. OOTR, Assoc. KBCRN, Assoc. JBCS and associate editorship for British Journal of Cancer, Scientific Reports, Breast Cancer Research and Treatment, Cancer Science, Asian Journal of Surgery, and Asian Journal of Breast Surgery, all outside this work. M.G. reports personal consulting fees for EliLilly, MSD, Novartis, Menarini-Stemline and honoraria from AstraZeneca, DaiichiSankyo, EliLilly, EPQHealth, Novartis, PierreFabre; payment for expert testimony from Veracyte and travel support from EliLilly and Novartis, leadership for ABCSG GmbH and ABCSG Research GmbH and other for Sandoz GmbH. A.M. reports honoraria for lectures from Pfizer. J.H. reports institutional grants from DaiichiSankyo, Gilead, Novartis, Pfizer, Roche, and Seagen during the conduct of this work and from AbbVie, AstraZeneca, BMS, DaiichiSankyo, MolecularHealth, Novartis, Roche, and Pfizer outside this work. J.H. reports personal consulting fees from MSD Oncology, Novartis, Palleos Health Care, Pfizer, Roche Pharma, and Seagen and honoraria from Daiichi-Sankyo, Gilead, Novartis, Pfizer, and Roche Pharma, Seagen and non-financial support from Hologic, all outside this work. J.H. declares to be GBG Forschungs GmbH employee; GBG Forschungs GmbH has royalties/patents: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8, and VM Scope GmbH. S.L. reports grants to the institution from AbbVie, AstraZeneca, Celgene, Daiichi-Sankyo, Immunomedics/Gilead, Molecular Health, Novartis, Roche, and Pfizer. S.L. declares to be GBG Forschungs GmbH employee; GBG Forschungs GmbH has following royalties/patents: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8, and VM Scope GmbH as well as a patent application related to prognostic subtypes in high-risk luminal breast cancer pending; honoraria for lectures and presentations from AstraZeneca, DSI, Gilead, Pfizer, Novartis, Roche, Seagen, and Medscape as well as honoraria for advisory boards from Abbvie, Amgen, AstraZeneca, BMS, Celgene, DSI, EirGenix, Gilead, GSK, Lilly, Novartis, Merck, Olema, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, and Seagen. S.L. reports non-financial interest as advisory role in AGO Kommission Mamma, as principal investigator (Aphinity), as member in AGO, ASCO, DKG, ESMO, and other non-financial interest from AstraZeneca, Daiichi-Sankyo, immunomedica/Gilead, Novartis, Pfizer, Roche, and Seagen., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Ovarian cancer patients with a Homologous Recombination Deficiency (HRD) often benefit from polyadenosine diphosphate-ribose polymerase (PARP) inhibitor maintenance therapy after response to platinum-based chemotherapy. HR status is currently analyzed via complex molecular tests. Predicting benefit from PARP inhibitors directly on histological whole slide images (WSIs) could be a fast and cheap alternative., Patients and Methods: We trained a Deep Learning (DL) model on H&E stained WSIs with "shrunken centroid" (SC) based HRD ground truth using the AGO-TR1 cohort (n = 208: 108 training, 100 test) and tested its ability to predict HRD as evaluated by the Myriad classifier and the benefit from olaparib in the PAOLA-1 cohort (n = 447) in a blinded manner., Results: In contrast to the HRD prediction AUROC of 72 % on hold-out, our model only yielded an AUROC of 57 % external. Kaplan-Meier analysis showed that progression free survival (PFS) in the PARP inhibitor treated PAOLA-1 patients was significantly improved in the HRD positive group as defined by our model, but not in the HRD negative group. PFS improvement in PARP inhibitor-treated patients was substantially longer in our HRD positive group, hinting at a biologically meaningful prediction of benefit from PARP inhibitors., Conclusion: Together, our results indicate that it might be possible to generate a predictor of benefit from PARP inhibitors based on the DL-mediated analysis of WSIs. However, further studies with larger cohorts and further methodological improvements will be necessary to generate a predictor with clinically useful accuracy across independent patient cohorts., Competing Interests: Declaration of Competing Interest TJB would like to disclose that he is the owner of Smart Health Heidelberg GmbH (Handschuhsheimer Landstr. 9/1, 69120 Heidelberg, Germany, https://smarthealth.de) which develops teledermatology mobile apps, outside of the submitted work. EPL is an employee of ARCAGY GINECO, has received honoraria from AstraZeneca, GSK and Agenus and has participated on Data Safety Monitoring Boards for Incyte, Roche and Pfizer. PH has received honoraria from Amgen, AstraZeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis, Eisai, Mersana, Exscientia, is a member of the Advisory Board for AstraZeneca, Roche, GSK, Clovis, Immunogen, MSD, Miltenyi, Novartis and Eisai and has received institutional research funding from AstraZeneca, Roche, GSK, Genmab, DFG, European Union, DKH, Immunogen, Seagen, Clovis, and Novartis. PCS is (one of the) named inventors on the patent 'Methods for assessing homologous recombination deficiency in ovarian cancer cells', EP4141127). IRC reports honoraria (self) from AbbVie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro, and Clovis; honoraria (institution) from GSK, MSD, Roche, and BMS; advisory/consulting fees from AbbVie, Agenus, Advaxis, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersena, Merck Serono, Novartis, Amgen, Tesaro, and Clovis; research grant/funding (self) from MSD, Roche, and BMS; research grant/funding (institution) from MSD, Roche, BMS, Novartis, AstraZeneca, and Merck Serono; travel support from Roche, AstraZeneca, and GSK. All other authors report no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To assess trial-level surrogacy value for overall survival (OS) of the pathologic complete response (pCR) and invasive disease-free survival (iDFS) in randomized clinical trials (RCTs) for early breast cancer (BC)., Methods: Individual patient data of neoadjuvant RCTs with available data on pCR, iDFS, and OS were included in the analysis. We used the coefficient of determination R 2 from weighted linear regression models to quantify the association between treatment effects on OS and on the surrogate end points., Results: Eleven RCTs, for a total of 15 treatment comparisons and 12,247 patients, were included in the analysis. There was a weak association between hazard ratios (HRs) for OS and odds ratio of pCR overall ( R 2 , 0.07; 95% CI, 0.00 to 0.48), as well as in all the subgroups explored. Overall, the R 2 for the association between HR OS and HR iDFS was 0.46 (95% CI, 0.08 to 0.71), which is just below the cutoff of 0.5 for moderate surrogacy. In the majority of subgroups explored, the R 2 ranged from 0.5 to <0.7, while in hormone receptor-/human epidermal growth factor receptor 2- subtype, histologic grade 1-2 tumors, and lobular tumors, surrogacy was strong (ie, R 2 ≥0.7). The surrogacy value of iDFS for OS was affected by follow-up (FUP) length: R 2 substantially increased up to 36 months of FUP, with little further improvement after 48 months of FUP., Conclusion: iDFS with sufficient FUP is an acceptable surrogate end point to confidently anticipate final OS results of neoadjuvant RCTs for early BC. This recommendation holds true across many subgroups, with the notable exception of HR+ disease. There is definite need to reassess whether OS is the optimal end point for treatment efficacy measurement in HR+ early BC.

Purpose: The CDK4/6 inhibitor palbociclib inhibits cyclin A, which is overexpressed in endometrial cancer. Combining palbociclib with endocrine therapy improves efficacy in hormone receptor-positive breast cancer. We investigated palbociclib combined with endocrine therapy for estrogen receptor-positive advanced/recurrent endometrial cancer., Patients and Methods: This placebo-controlled double-blind, randomized phase II screening trial (NCT02730429) enrolled women with measurable/evaluable estrogen receptor-positive endometrioid endometrial cancer that was primary metastatic or had relapsed after ≥1 prior systemic therapy. Patients were randomized in a 1:1 ratio, stratified by number of prior chemotherapy lines, measurable versus evaluable non-measurable disease, and prior medroxyprogesterone/megestrol acetate treatment, to receive oral letrozole 2.5 mg on days 1-28 plus either oral palbociclib 125 mg or placebo on days 1-21, repeated every 28 days until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS)., Results: Among 77 patients randomized between February 16, 2017, and December 21, 2018, 73 were treated (36 with palbociclib-letrozole, 37 with placebo-letrozole). Median follow-up was 21.9 (95 % CI, 16.7 to 22.3) months. Median PFS was 8.3 (95 % CI, 4.6 to 11.2) versus 3.1 (95 % CI, 2.7 to 6.8) months, respectively. In a landmark analysis at 12 months the PFS hazard ratio was 0.57 (95 % CI, 0.32 to 0.99; P = .044). Grade ≥ 3 adverse events were more common with palbociclib-letrozole (67 %) than placebo-letrozole (30 %), most commonly neutropenia (44 % v 0 %, respectively)., Conclusion: These results support a potential role of the palbociclib-letrozole combination as treatment for hormone receptor-positive advanced/recurrent endometrial cancer. Based on these encouraging results, phase III evaluation of letrozole combined with a CDK4/6 inhibitor is planned., Clinical Trial Information: NCT02730429., Competing Interests: Declaration of competing interest MRM reports leadership roles and stock for Karyopharm Therapeutics and Sera Prognostics; honoraria from Roche, AstraZeneca, Genmab/Seattle Genetics, GSK, Merck, Mersana, Takeda, Zai Lab, Geneos, and Allarity Therapeutics; consulting/advisory roles for AstraZeneca, Genmab, Karopharm Therapeutics, Pfizer, and GSK; research funding (to institution) from AstraZeneca, Boehringer Ingelheim, Pfizer, Tesaro, Clovis Oncology, Ultimovacs, Apexigen, and GSK; grants and personal fees from Tesaro, AstraZeneca, Pfizer, and Clovis Oncology; travel/accommodation/expenses from AstraZeneca, Karyopharm Therapeutics, Pfizer, Roche, Tesaro, and SeraCare; and other relationships with ENGOT, GCIG, and ESGO. LB reports speaker's bureau participation for GSK and MSD and research funding from AstraZeneca. FM reports honoraria from Roche/Genentech, Novartis, Pfizer, AstraZeneca, Clovis Oncology, Eisai, Genomic Health, PharmaMar, Amgen, MSD Oncology, Seagen, Myriad Genetics, Pierre Fabre, GSK, Agendia, Lilly, Gilead, Daiichi Sankyo, and Immunomedics; consulting/advisory roles for Pfizer, Genomic Health, CureVac, Amgen, Eisai, GSK, Gilead, Seagen, Clovis Oncology, AstraZeneca, Roche, Vaccibody, and Immunomedics; research funding from Roche/Genentech, Novartis, AstraZeneca, Tesaro, Clovis Oncology, MSD Oncology, Vaccibody, Gilead, and GSK; and travel/accommodation/expenses from Roche, Pfizer, AstraZeneca, and Gilead Sciences. RdPC reports employment and stock ownership from Y-mAbs Therapeutics and consulting/advisory role for Karyopharm. MGM reports consulting/advisory roles for AstraZeneca; speakers' bureau for GSK and MSD Oncology; and travel/accommodation/expenses from AstraZeneca, GSK, and MSD Oncology. AA reports consulting/advisory roles and travel/accommodation/expenses from GSK and MSD. BA reports honoraria from Roche, AstraZeneca, MSD, GSK, Eisai Europe, Novartis, Lilly, and Pfizer; consulting/advisory roles for Roche, MSD, Sanofi Aventis GmbH, GSK, and Eisai Europe; and travel/accommodation/expenses from Roche, AstraZeneca, GSK, Lilly, and Daiichi Sankyo/AstraZeneca. VS reports honoraria from AstraZeneca, MSD Oncology, GSK, PharmaMar, and Novocure; consulting/advisory roles for AstraZeneca and Novocure; and travel/accommodation/expenses from GSK and PharmaMar. AR reports consulting/advisory roles for AstraZeneca, GSK, Boehringer Ingelheim, MSD, and Pharma&; speakers' bureau for AstraZeneca, GSK, MSD, and Pharma&; and travel/accommodation/expenses from AstraZeneca. KL reports honoraria from AstraZeneca; consulting/advisory roles for Eisai, MSD, GSK, and Nycode; research funding (inst) from GSK; and is Deputy Medical Director of NSGO-CTU. FT reports research funding and personal fees from AstraZeneca, Clovis, Eisai, ImmunoGen, MSD, SAGA diagnostics, and Tesaro/GSK. MPBG reports consulting/advisory roles for AstraZeneca, GSK, MSD Oncology, Eisai Europe, Clovis Oncology, PharmaMar, and Pharma&; speakers' bureau for AstraZeneca Spain, GSK, Eisai Europe, and MSD Oncology; and travel/accommodation/expenses from AstraZeneca, GSK, and MSD Oncology. JEK reports employment (immediate family member) with MSD; consulting/advisory roles for AstraZeneca, MSD, and GSK; and travel/accommodation from AstraZeneca, Eisai, PharmaMar, and GSK. JS reports honoraria from AstraZeneca, Eisai, Clovis Oncology, Olympus Medical Systems, Johnson & Johnson, PharmaMar, Pfizer, Teva, Tesaro, MSD Oncology, GSK, and Bayer; consulting/advisory roles for AstraZeneca, Clovis Oncology, PharmaMar, Merck, Pfizer, Tesaro, MSD Oncology, Lilly, Novocure, Johnson & Johnson, Roche Diagnostics, NGRESS-Health, Riemser, Sobi, GSK, Novartis, and Alkermes; research funding (inst) from AstraZeneca, Clovis Oncology, Merck, Bayer, PharmaMar, Pfizer, Tesaro, MSD Oncology, and Roche; travel/accommodation/expenses from AstraZeneca, Clovis Oncology, PharmaMar, Roche Pharma AG, Tesaro, MSD Oncology, and Olympus. No other potential conflicts of interest were reported., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: No potential conflict of interest relevant to this article was reported.