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Background: Sentinel lymph node (SLN) status is a clinically important prognostic biomarker in breast cancer and is used to guide therapy, especially for hormone receptor-positive, HER2-negative cases. However, invasive lymph node staging is increasingly omitted before therapy, and studies such as the randomised Intergroup Sentinel Mamma (INSEMA) trial address the potential for further de-escalation of axillary surgery. Therefore, it would be helpful to accurately predict the pretherapeutic sentinel status using medical images., Methods: Using a ResNet 50 architecture pretrained on ImageNet and a previously successful strategy, we trained deep learning (DL)-based image analysis algorithms to predict sentinel status on hematoxylin/eosin-stained images of predominantly luminal, primary breast tumours from the INSEMA trial and three additional, independent cohorts (The Cancer Genome Atlas (TCGA) and cohorts from the University hospitals of Mannheim and Regensburg), and compared their performance with that of a logistic regression using clinical data only. Performance on an INSEMA hold-out set was investigated in a blinded manner., Results: None of the generated image analysis algorithms yielded significantly better than random areas under the receiver operating characteristic curves on the test sets, including the hold-out test set from INSEMA. In contrast, the logistic regression fitted on the Mannheim cohort retained a better than random performance on INSEMA and Regensburg. Including the image analysis model output in the logistic regression did not improve performance further on INSEMA., Conclusions: Employing DL-based image analysis on histological slides, we could not predict SLN status for unseen cases in the INSEMA trial and other predominantly luminal cohorts., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Titus Josef Brinker 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. DK received honoraria from Merck Sharp & Dohme, Pfizer, Medupdate, Onkowissen, best practice Onkologie, ESO, ESMO and Gilead as well as research funding from Merck KGaA, outside of the submitted work. Sibylle Loibl reports grants and other from Abbvie, other from Amgen, grants and other from AstraZeneca, other from BMS, grants and other from Celgene, grants, non-financial support and other from Daiichi-Sankyo, other from Eirgenix, other from Eisai Europe Ltd, other from GSK, grants, non-financial support and other from Immunomedics/Gilead, other from Lilly, other from Merck, grants from Molecular Health, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, other from Relay Therapeutics, grants, non-financial support and other from Roche, other from Sanofi, non-financial support and other from Seagen, other from Olema Pharmaceutics, other from VMscope GmbH, outside the submitted work. In addition, Sibylle Loibl has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. Valentina Nekljudova declares to be GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from Abbvie, Amgen, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Molecular Health, Novartis, Pfizer and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche, and Seagen (paid to the institution). GBG Forschungs GmbH has licensing fees from VMscope GmbH. In addition, GBG Forschungs GmbH has a patent EP21152186.9 pending, a patent EP19808852.8 pending, and a patent EP14153692.0 pending. All other authors have no conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The promising effect of antibody-drug conjugates on breast cancer with low expression of HER2 (HER2-low) raises many questions regarding the optimal selection of patients for this treatment. A key question is whether HER2 immunohistochemistry, an assay optimised to detect HER2 amplification, is reliable enough to assess HER2 protein levels to select patients with HER2-low breast cancer in daily pathology practices worldwide. Moreover, whether this assessment can be performed with sufficient reproducibility between pathologists in daily practices is debatable. Herein, we address the historical track record of the CAP-ASCO HER2 Guidelines, the reported limited reproducibility by pathologists of HER2 immunohistochemistry in the non-amplified cases, and the performance variation of different antibodies. Based on this summary, we propose solutions to improve the robustness to enable reliable identification of patients with HER2-low breast cancer., Competing Interests: Conflict of interest statement CvD received funding from AstraZeneca. The funder had no role in the design or writing of this manuscript. RS reports non-financial support from Merck and Bristol Myers Squibb (BMS), research support from Merck, Puma Biotechnology and Roche, and personal fees from Roche, BMS and Exact Sciences for advisory boards. JB reports consultancies from Insight Genetics, Inc. BioNTech AG Biotheranostics, Inc. Pfizer, Rna Diagnostics Inc., oncoXchange/MedcomXchange Communications Inc. Herbert Smith French Solicitors and OncoCyte Corporation. He is involved in a scientific advisory board of MedcomXchange Communications Inc. He received honoraria from NanoString Technologies, Inc. Oncology Education, Biotheranostics, Inc, MedcomXchange Communications Inc. and research funding from Thermo Fisher Scientific Genoptix, Agendia, NanoString Technologies, Inc. Stratifyer GmbH Biotheranostics, Inc. Travel, accommodation expenses were received from Biotheranostics, Inc., NanoString Technologies, Inc, and the Breast Cancer Society of Canada. He reports the following patents: 1) CIN4 predicts benefit from anthracycline, National Phase Application, (Canada, Jan. 11, 2017), 2) Systems, Devices and Methods for Constructing and Using a Biomarker, National Phase Application, 15/328,108 (United States, Jan. 23, 2017); 15824751.0 (Europe, Jan. 12, 2017); (Canada, Jan. 12, 2017), 3) Targeting the Histone Pathway to Detect and Overcome Anthracycline Resistance (IP Title), National Phase Application, PCT/CA2016/000247, Patent Application #: 3000858 (Country of filing: Canada – Patent Application Date: Apr. 4, 2018) and 4) Immune Gene Signature Predicts Anthracycline Benefit, PCT (international application), PCT/CA2016/000305, Filing date: Dec. 7, 2016. FPL reports personal fees from Astrazeneca, BMS, Daiichy-Sankyo, MSD, Roche, Seagen, Diaceutics, Veracyte, research support from Astrazeneca, Daiichy Sankyo, Roche, MSD and BMS. GV reports personal fees from AstraZeneca, BMS, Daiichy-Sankyo, MSD, Roche, Seagen, Pfizer, and research support from AstraZeneca and Roche. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: GeparOcto demonstrated that pathological complete response (pCR) of intense dose-dense epirubicin, paclitaxel and cyclophosphamide (iddEPC) was comparable to weekly paclitaxel/non-pegylated liposomal doxorubicin (plus carboplatin (PM(Cb) in triple-negative breast cancer [TNBC]) in high-risk early breast cancer (BC). Here, we report time-to-event secondary end-points., Patients and Methods: Patients were randomised to receive 18 weeks of E (150 mg/m 2 ) followed by P (225 mg/m 2 ) followed by C (2000 mg/m 2 ), each q2w or weekly P (80 mg/m 2 ) plus M (20 mg/m 2 ) plus, in TNBC, Cb (AUC 1.5). Patients with human epidermal growth factor receptor 2-positive (HER2+)BC received trastuzumab (6[loading dose 8]mg/kg q3w) and pertuzumab (420[840]mg q3w) with P and C cycles., Results: 945 patients started treatment (iddEPC n = 470; PM(Cb) n = 475). After a median follow-up of 47.0 (range 1.6-61.5) months, 162 (75 in iddEPC; 87 in PM(Cb)) invasive disease-free survival (iDFS) events and 79 (41 in iddEPC; 38 in PM(Cb)) deaths were reported. No significant difference was observed in 4-year iDFS (81.9% iddEPC versus 79.7% PM(Cb), HR = 1.16 [95%CI 0.85-1.59], log-rank p = 0.334) or 4-year overall survival (OS) (90.3% iddEPC versus 90.6% PM(Cb), HR = 0.90 [95%CI 0.58-1.40], log-rank p = 0.637) overall and in HER2+ and TNBC subgroups. HR+/HER2- BC patients, however, had significantly better 4-year iDFS (77.9% iddEPC versus 62.5% PM, HR = 2.11 [95%CI 1.08-4.10], log-rank p = 0.025) and 4-year OS with iddEPC (94.7% iddEPC versus 80.1% PM, HR = 3.26 [95%CI 1.06-10.00], log-rank p = 0.029)., Conclusion: While there was no difference in survival for the entire cohort, the HR+/HER2-subgroup significantly benefits from iddEPC. This supports the concept of an additional effect of NACT beyond pCR in patients with HR+/HER2- BC. CLINICALTRIALS., Gov Identifier: NCT02125344., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AS reports grants from Celgene, grants from Roche, grants from AbbVie, personal fees from Roche, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Roche, personal fees from Roche, personal fees from Celgene, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Novartis, personal fees from MSD, personal fees from Tesaro, personal fees from Lilly, personal fees from Pfizer, other from Roche, outside the submitted work; CD reports grants from European Commission H2020, grants from German Cancer Aid Translational Oncology, during the conduct of the study; personal fees from Novartis, personal fees from Roche, personal fees from MSD Oncology, personal fees from Daiichi Sankyo, personal fees from AstraZeneca, from Molecular Health, grants from Myriad, personal fees from Merck, other from Sividon diagnostics, outside the submitted work; In addition, Dr. Denkert has a patent VMScope digital pathology software with royalties paid, a patent WO2020109570A1-cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1-therapy response issued; CH reports a consulting or advisory role for Roche, AstraZeneca, Novartis, Lilly-Pharma, Celgene; CJ reports personal fees from Roche, personal fees from Celgene, personal fees from AstraZeneca, during the conduct of the study; CS reports a consulting or advisory role for Hologicm, MSD; reports travel, accommodations, or expenses from Pfizer, MSD, AstraZeneca, Roche; EH reports honoraria and a consulting or advisory role from AstraZeneca; HT reports other from Pierre Fabre, other from Pfizer Pharma, other from Mundipharma, other from ClinSol, other from Novartis, other from Lilly, other from AMGEN, other from Grünenthal, other from Vifor, other from AstraZeneca, other from Mylan, other from BMS, during the conduct of the study; JH reports personal fees from Lilly, personal fees from Novartis, personal fees from Pfizer, personal fees from Abbvie, personal fees from Astra Zeneca, personal fees from MSD, personal fees from Celgene, personal fees from Roche, other from Daichii, other from Roche, other from Pfizer, grants from Novartis, grants from Hexal, outside the submitted work; JUB reports honoraria, travel support and unrestricted grants from AMGEN, AstraZeneca, Lilly, Molecular Health, MSD, Novartis, Pfizer, Pierre-Fabre, Roche; KK reports other from MSD Sharpe amd Dome GmBH, personal fees from Roche, personal fees from Pfizer, personal fees from Astra Zeneca, outside the submitted work; KL reports a consulting or advisory role for Roche, Novartis, Pfizer, Lilly, Exact Science Eisai, MSD; reports travel, accommodations, or expenses from Roche; KR reports personal fees from AstraZeneca, personal fees from Pfizer, personal fees from MSD, outside the submitted work; LM reports honoraria from Pfizer, Eisai, AstraZeneca, Roche, Lilly; reports a consulting or advisory role for Pfizer, Roche, Eisai, AstraZeneca; reports travel, accommodations, or expenses from Eisai, Pfizer, AstraZeneca, Lilly, and Roche; MU reports honoraria to the employer/institution from Amgen, Astra Zeneca, Celgene, Daiichi Sankyo, Lilly, Roche, Pfizer, Pierre Fabre, Sanofi-Aventis, MSD; reports research funding to the employer/institution from Amgen, Astra Zeneca, Celgene, Daiichi Sankyo, Lilly, Pfizer, Roche, Sanofi Aventis, Pierre Fabre; PAF reports honoraria from Roche, Novartis, Pfizer, Daiichi-Sankyo, Eisai, Merck Sharp & Dohme, Astra Zeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Cepheid, BionTech; reports a consulting or advisory role for Roche, Novartis, Pfizer, Daiichi-Sankyo, Eisai, Merck Sharp & Dohme, Astra Zeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Lilly; reports research funding from Novartis, BioNTech AG, Cepheid; SL reports honoraria from Abbvie, Amgen, AstraZeneca, Bayer, BMS, Celgene, DSI, Eirgenix, GSK, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Prime/Medscape, Puma, Roche, Samsung, and Seagen; reports a consulting or advisory role for Abbvie, Amgen, AstraZeneca, Bayer, BMS, Celgene, DSI, Eirgenix, GSK, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Prime/Medscape, Puma, Roche, and Seagen; reports a speaker's bureau for AstraZeneca, DSI, Novartis, Pfizer, Pierre Fabre, Prime/Medscape, Roche, and Samsung; reports research funding from Abbvie, Amgen, AstraZeneca, Celgene, Cepheid, DSI, Immunomedics, Novartis, Pfizer, and Roche; reports a patent or intellectual property interest with VM Scope GmbH; reports another relationship with Roche; TL reports honoraria from Amgen, Roche, Clovis, MSD, Novartis, Pfizer, Lilly; reports a consulting or advisory role from Tesaro, Amgen, MSD, Roche, Pfizer, Lilly, Myriad, Esai, GSK; reports travel, accommodations, or expenses from MSD, Celgen, Clovis; VM reports and Speaker honoraria received from Amgen, AstraZeneca, Celgene, Roche, Teva. Consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutics; No other potential conflict of interest relevant to this article was reported., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The GAIN-2 trial was designed to identify a superior intense dose-dense (idd) strategy for high-risk patients with early breast cancer. Here, we report an interim analysis, at which the predefined futility boundary was crossed., Patients and Methods: GAIN-2 was an open-label, randomised, multicentre phase III trial. Two thousand eight hundred and eighty seven patients were randomised 1:1 between three courses each of idd epirubicin (E) 150 mg/m 2 , nab-paclitaxel (nP) 330 mg/m 2 and cyclophosphamide (C) 2000 mg/m 2 (iddEnPC) versus four cycles of leucocyte nadir-based tailored and dose-dense EC (dtEC) followed by four cycles of tailored and dose-dense docetaxel (dtD) (dtEC-dtD)., Results: The duration of median follow-up was 45.8 (range 0.0-88.3) months. Trial objectives included invasive disease-free survival (iDFS) as the primary end-point. A total of 593 patients received the treatment as neoadjuvant chemotherapy. At the time of futility interim analysis, 414 events for iDFS were reported. Overall, there was no difference in iDFS between iddEnPC and dtEC-dtD with 4-year iDFS rates of 84.3% (95% confidence interval (CI) 82.0-86.4%). Among all predefined subgroups, hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-), lobular cancer and ≤50 years subgroups predicted for better iDFS in the dtEC-dtD arm. Overall, 88.1% of patients completed all treatment in both arms. Haematological toxicity grade 3/4 and grade 3/4 non-haematological adverse events were significantly higher with iddEnPC (iddEnPC 50.8% vs dtEC-dtD 45.1%, P = 0.002), especially arthralgia and peripheral sensory neuropathy. Two treatment-related deaths occurred during dtEC-dtD, corresponding to a low mortality rate of 0.07%., Conclusions: iDFS is equal in both regimens, but tailoring dose-dense chemotherapy improved outcomes in HR+/HER2-, lobular cancer and patients ≤50 years., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AS reports grants from Celgene, grants from Roche, grants from AbbVie, personal fees from Roche, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Roche, personal fees from Roche, personal fees from Celgene, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Novartis, personal fees from MSD, personal fees from Tesaro, personal fees from Lilly, personal fees from Pfizer, other from Roche, outside the submitted work; CD reports personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, grants from Myriad Genetics, other from Sividon Diagnostics/Myriad, outside the submitted work and has a patent EP18209672 pending, a patent EP20150702464 pending and a patent Software (VMscope digital pathology) pending. CJ reports honoraria from Roche, Celgene, Novartis, Genomic Health and Amgen; compensation for consulting and advisory role from Roche, Novartis and Pfizer; travel expenses from Roche, Astra Zeneca and Genomic Health; CS reports compensation for consulting and advisory role from Olympus, Hologic; and travel expenses from imed, MedConcept, Medtronic, Diaglog Service, Mentor, mylan, GBG and Pfizer; ES reports honoraria from Roche, Astra Zeneca, Novartis, Pfizer, ESAI, Tesaro and MSD; compensation for consulting and advisory role from Roche and Tesaro; and travel expenses from Roche and Pfizer; FM reports personal fees from Roche, AstraZeneca, Pfizer, Tesaro, Novartis, Amgen, PharmaMar, GenomicHealth, CureVac, EISAI, Celgene, Clovis, Janssen-Cilag, Immunomedics, GSK, MSD, Seagen and Lilly outside the submitted work; JH reports grants and personal fees from Novartis, personal fees from Lilly, personal fees and other from Pfizer, personal fees and other from Roche, personal fees from Abbvie, personal fees from Astra Zeneca, personal fees from Eisai, other from Daichii, grants, personal fees and other from Celgene, personal fees from MSD, grants and personal fees from Hexal, outside the submitted work; JUB reports personal fees from AMGEN, personal fees from ASTRA Zeneca, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from SonoScape, from Sysmex, outside the submitted work; MR reports honoraria from MSD, Astra Zeneca, Lilly, Novartis and SOMATEX; compensation for consulting and advisory role from Roche, Novartis, MSD, Astra Zeneca and Lilly; and travel expenses from Pfizer, Novartis and Celgene; MU reports honoraria paid to his employer by Amgen, Astra Zeneca, Celgene, Daiji Sankyo, Eisai, Lilly, MSD, Mundipharma, Pfizer, Novartis, Roche, Sanofi Aventis and PUMA Biotechnology; compensation for consulting and advisory role to the employer from Amgen, Abbvie, Astra Zeneca, Celgene, Daiji Sankyo, Eisai, Lilly, MSD, Mundipharma, Novartis, Odonate, Pfizer, Roche, PUMA Biotechnology, Sanofi Aventis and Teva; SL reports grants and other from Roche during the conduct of the study; grants and other from Abbvie, grants and other from Amgen, grants and other from Celgene, grants and non-financial support from Immunomedics, grants and other from Novartis, grants and other from Pfizer, other from Seattle Genetics, other from PriME/Medscape, personal fees from Chugai, grants from Teva, grants from Vifor, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from EirGenix, other from BMS, other from Puma, other from MSD and grants and other from AstraZeneca outside the submitted work; In addition, SL has a patent EP14153692.0 pending. TL reports honoraria from Lilly, Teva, Tesaro, Roche, Novartis, Pfizer, MSD, Amgen and Clovis; compensation for consulting and advisory role from Lilly, Roche, Tesaro, Amgen and MSD; travel expenses from Roche, Pfizer and Celgene; VM reports speaker honoraria from Amgen, Astra Zeneca, Celgene, Roche, TEVA and consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutics; WJ reports grants and personal fees from Sanofi-Aventis, Novartis, Lilly, Pfizer, Roche, Chugai and AstraZeneca during the conduct of the study; No other potential conflict of interest relevant to this article was reported., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) is associated with superior survival. This association is strongest in triple-negative breast cancer (TNBC). The CPS + EG system, based on pre-treatment clinical (CS) and post-treatment pathological stage (PS), oestrogen-receptor status (E) and grade (G), leads to a refined estimate of prognosis after NACT in all-comers and hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here, we investigate if CPS + EG scoring provides a superior estimate of prognosis in TNBC to select patients for postneoadjuvant therapy., Methods: We calculated the CPS + EG score for 1795 patients with TNBC from 8 prospective German trials. Five-year disease-free survival (DFS) and overall survival estimates were calculated using the Kaplan-Meier method., Results: In TNBC, patients with pCR (ypT0/is ypN0, n = 822, 45.8%) had a 5-year DFS of 86%, whereas patients with residual American Joint Committee on Cancer stage I disease (n = 383; 21.3%) had a 5-year DFS of 77.5%.CPS + EG led to superior prognostic information compared with that provided by the clinical stage, but it was inferior to the prognostic information provided by the pathological stage (c-index statistics, p < 0.001). CPS + EG did not discriminate prognosis within the two best prognostic groups (score 1 and 2; n = 362; 37.2%). In contrast, pCR status added prognostic information beyond CPS + EG. Patients with a CPS + EG score of 3 had a 5-year DFS rate of 64% overall, but those with pCR had a 5-year DFS rate of 84%, and those without pCR had a 5-year DFS rate of only 49.7%., Conclusions: In TNBC, CPS + EG scoring provided inferior prognostic information compared with the pathological stage and was unable to identify patients without pCR and with a sufficiently good prognosis, who could avoid postneoadjuvant therapy. pCR remains the strongest and most clinically useful prognostic factor after NACT. Other biologic factors beyond pCR are needed in TNBC., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Young women receiving chemotherapy for early breast cancer (EBC) have a high probability for ovarian failure, defined by chemotherapy-induced amenorrhea (CIA) as a surrogate. CIA is insufficiently reliable and reproducible. We analysed chemotherapy-induced ovarian failure (CIOF) by assessing hormone parameters, CIA, and antral follicle count (AFC)., Methods: Blood samples of women aged ≤45 years treated with anthracycline/taxane-based chemotherapy for EBC from four neoadjuvant/adjuvant trials were collected at baseline, at the end of treatment (EOT), and at 6, 12, 18, and 24 months after EOT. Centrally assessed oestradiol (cutoff <52.2 ng/L) and follicle-stimulating hormone (cutoff >12.4IU/L) were used to define CIOF for patients with baseline premenopausal hormone levels, anti-Müllerian hormone (AMH), and AFC to assess ovarian reserve. Further analyses included CIA, regain of premenopausal hormone levels, and disease-free survival (DFS) also in subgroups., Results: Six hundred ninety-six patients aged ≤45 years had premenopausal hormone levels at baseline. Overall, 85.1% (592/696) experienced CIOF at EOT, and 147 of 592 had further hormone measurements after EOT. Of those, 32.7% (48/147) regained premenopausal hormone levels after 6 months, 57.9% (66/114) regained premenopausal hormone levels after 12 months, 83.0% (73/88) regained premenopausal hormone levels after 18 months, and 89.2% (74/83) regained premenopausal hormone levels after 24 months. After 24 months, 72.4% (21/29) of patients without CIOF and 100% (14/14) with CIOF had low AMH levels. Four-year DFS without CIOF versus CIOF was 65.9% versus 84.6% (hazard ratio [HR] = 2.09, 95% confidence interval [CI]: 1.37-3.19; P < 0.001); in hormone receptor positive 61.8% versus 87.5% (HR = 2.69, 95% CI: 1.57-4.60; P < 0.001); in <30 years 68.3% versus 92.6% (HR = 4.87, 95% CI: 1.05-22.63; P = 0.026)., Conclusion: Most premenopausal women experienced CIOF after chemotherapy for EBC. After 2 years, nearly all regain premenopausal hormone levels. CIOF was associated with better DFS, especially in patients with hormone receptor-positive EBC or aged <30 years., Competing Interests: Conflict of interest statement M.F. reports personal fees from Roche, AstraZeneca, Pfizer, Tesaro, Novartis, Amgen, PharmaMar, GenomicHealth, CureVac, EISAI, Celgene, Clovis, Janssen-Cilag, Immunomedics, GSK, MSD, Lilly, outside the submitted work. U.M. reports personal fees and non-financial support from Abbvie, Amgen GmbH, Astra Zeneca, BMS, Celgene GmbH, Daiji Sankyo, Eisai GmbH, Lilly Deutschland, Lilly Int., MSD Merck, Mundipharma, Myriad Genetics, Odonate, and Pfizer GmbH; personal fees from PUMA Biotechnology; personal fees and non-financial support from Roche Pharma AG, Sanofi Aventis Deutschland GmbH, TEVA Pharmaceuticals Ind Ltd, Novartis; personal fees from Pierre Fabre; and personal fees and non-financial support from Clovis Oncology, outside the submitted work. S.A. reports grants from Celgene, Roche, and AbbVie; personal fees from Roche, AstraZeneca, Celgene, Pfizer, Novartis, MSD, Tesaro, Lilly; and others from Roche, outside the submitted work. F.P.A. reports personal fees from Novartis; grants from BioNTech; personal fees from Roche, Pfizer, Daiichi-Sankyo, Astra Zeneca, Eisai, and Merck Sharp & Dohme; grants from Cepheid; personal fees from Lilly, Pierre Fabre, and Seattle Genetics, during the conduct of the study. D.C. reports personal fees from Novartis, Roche, MSD Oncology, and Daiichi Sankyo; grants from Myriad Genetics; and others from Sividon Diagnostics/Myriad, outside the submitted work. In addition, D.C. has a patent EP18209672 pending, a patent EP20150702464 pending, and a patent software (VMscope digital pathology) pending. V.M.M. reports personal fees from AstraZeneca, Amgen, Novartis, Genomic Health, Lilly, Pfizer, and Roche, outside the submitted work. M.V. reports grants and personal fees from Roche, during the conduct of the study; personal fees from Amgen, Astra Zeneca, Daiichi-Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, and Seattle Genetics; consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro, and Nektar; personal fees from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro, and Nektar; and others from Novartis, Roche, Seattle Genetics, Genentech, outside the submitted work. L.S. reports grants and others from Abbvie, Amgen, Celgene, Novartis, and Roche; others from Seattle Genetics, PriME/Medscape; personal fees from Chugai; grants and others from Daiichi-Sankyo; others from Lilly, Samsung, BMS, and Puma; others from MSD; grants from Immunomedics; grants and others from AstraZeneca and Pfizer; others from Pierre Fabre; and others from Merck outside the submitted work. In addition, L.S. has a patent EP14153692.0 pending. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: To evaluate HER2-negative breast cancer (BC) with a low hormone receptor (HR) expression, with regard to pathological complete response (pCR) and survival, in comparison to triple-negative BC (TNBC) and strong HR-positive BC., Methods: We compared negative [oestrogen (ER) and progesterone receptor (PR) <1%], low-positive (ER and/or PR 1-9%) and strong-positive (ER or PR 10-100%) HR-expression in neoadjuvant clinical trial cohorts (n = 2765) of BC patients. End-points were disease-free survival (DFS), distant-disease free survival (DDFS) and overall survival (OS). We performed RNA sequencing on available tumour tissue samples from patients with low-HR expression (n = 38)., Results: Ninety-four (3.4%) patients had low HR-positive tumours, 1769 (64.0%) had strong HR-positive tumours, and 902 (32.6%) had TNBC. There were no significant differences in pCR rates between women with low HR-positive tumours (27.7%) and women with TNBC (35.5%). DFS and DDFS were also not different [for DFS, hazard ratio 1.26, 95%-CI (confidence interval) : 0.87-1.83, log-rank test p = 0.951; for DDFS, hazard ratio 1.17, 95%-CI: 0.78-1.76, log-rank test p = 0.774]. Patients with strong HR-positive tumours had a significantly lower pCR rate (pCR 9.4%; odds ratio 0.38, 95%-CI: 0.23-0.63), but better DFS (hazard ratio 0.48, 95%-CI: 0.33-0.70) and DDFS (hazard ratio 0.49, 95%-CI: 0.33-0.74) than patients with low HR-positive tumours. Molecular subtyping (RNA sequencing) of low HR-positive tumours classified these predominantly into a basal subtype (86.8%)., Conclusion: Low HR-positive, HER2-negative tumours have a similar clinical behaviour to TNBC showing high pCR rates and poor survival and also a basal-like gene expression signature. Patients with low HR-positive tumours should be regarded as candidates for therapy strategies targeting TNBC., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AS reports grants from Celgene, grants from Roche, grants from AbbVie, grants from Molecular Partner, personal fees from Roche, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Roche, personal fees from Roche, personal fees from Celgene, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Novartis, personal fees from MSD, personal fees from Tesaro, personal fees from Lilly, personal fees from Pfizer, other from Roche, outside the submitted work. CD reports grant support from the European Commission (Responsify and Oncobiome project) as well as from the German Cancer Aid (Deutsche Krebshilfe, TransLuminal-B and Integrate-TN project) during the conduct of the study; ownership interest in Sividon Diagnostics outside the submitted work; and honoraria from Pfizer, Merck, Sharp & Dohme, Amgen, Myriad, Teva, Celgene, Roche, and AstraZeneca outside the submitted work. CH reports personal fees from Novartis, personal fees from Celgene, personal fees from Lilly, personal fees from Astra Zeneca, personal fees from Amgen, outside the submitted work. CJ reports personal fees from Roche, personal fees from Celegen, personal fees from Amgen, outside the submitted work. FM reports personal fees from Roche, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Tesaro, personal fees from Novartis, personal fees from Amgen, personal fees from PharmaMar, personal fees from GenomicHealth, personal fees from CureVac, personal fees from EISAI, personal fees from Clovis, personal fees from Celgene, outside the submitted work. HT reports personal fees and non-financial support from Roche, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Novartis, personal fees and non-financial support from AstraZeneca, outside the submitted work. JH reports grants and personal fees from Novartis, personal fees from Lilly, personal fees from Abbvie, personal fees from Pfizer, personal fees from Roche, personal fees from MSD, personal fees from Astra Zeneca, grants and personal fees from Celgene, outside the submitted work. KEW reports personal fees and other from Myriad, outside the submitted work. MK reports grants from Deutsche Krebshilfe (German Cancer Aid), grants from DFG/BMBF, grants from Senator Roesner Foundation, grants from Dr. Pommer-Jung Foundation, personal fees from Springer Press, personal fees from Biermann Press, personal fees from Celgene, personal fees from Astra Zeneca, personal fees from Myriad Genetics, personal fees from TEVA, personal fees from Bavarian KVB, personal fees from DKMS Life, personal fees from BLÄK, other from Therawis Diagnostics GmbH, other from Busenfreundin GmbH, outside the submitted work. MU reports personal fees and non-financial support from Abbvie, personal fees and non-financial support from Amgen GmbH, personal fees and non-financial support from Astra Zeneca, personal fees from BMS, personal fees and non-financial support from Celgene GmbH, personal fees and non-financial support from Daiji Sankyo, personal fees and non-financial support from Eisai GmbH, personal fees from Lilly Deutschland, personal fees and non-financial support from Lilly Int., personal fees and non-financial support from MSD Merck, personal fees and non-financial support from Mundipharma, personal fees and non-financial support from Myriad Genetics, personal fees and non-financial support from Odonate, personal fees and non-financial support from Pfizer GmbH, personal fees from PUMA Biotechnology, personal fees and non-financial support from Roche Pharma AG, personal fees and non-financial support from Sanofi Aventis Deutschland GmbH, personal fees and non-financial support from TEVA Pharmaceuticals Ind Ltd, personal fees and non-financial support from Novartis, personal fees from Pierre Fabre, outside the submitted work. MVM reports personal fees from Amgen, personal fees from AstraZeneca, personal fees from Genomic Health, non-financial support from Novartis, non-financial support from Lilly, outside the submitted work. NP reports personal fees from Roche, personal fees from Novartis, outside the submitted work. PAF reports grants from Novartis, grants from BioNTech, personal fees from Novartis, personal fees from Roche, personal fees from Pfizer, personal fees from Celgene, personal fees from Daiichi-Sankyo, personal fees from TEVA, personal fees from Astra Zeneca, personal fees from Merck Sharp & Dohme, personal fees from Myelo Therapeutics, personal fees from Macrogenics, personal fees from Eisai, personal fees from Puma, grants from Cepheid, personal fees from Lilly, during the conduct of the study. SL reports grants and other from Abbvie, grants and other from Amgen, grants and other from AstraZeneca, grants and other from Celgene, grants and other from Novartis, grants and other from Pfizer, grants and other from Roche, other from Seattle Genetics, other from Prime/Medscape, personal fees from Chugai, grants from Teva, grants from Vifor, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from Eirgenix, outside the submitted work; In addition, Dr. Loibl has a patent EP14153692.0 pending. WDS reports personal fees from AstraZeneca, outside the submitted work. WW reports personal fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Amgen, Astellas and grants from Roche, MSD, BMS, Bruker outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: This pooled analysis aimed to evaluate locoregional recurrence (LRR) rates of breast cancer (BC) after neoadjuvant chemotherapy (NACT) and to identify independent LRR predictors., Methods: 10,075 women with primary BC from nine neoadjuvant trials were included. The primary outcome was the cumulative incidence rate of LRR as the first event after NACT. Distant recurrence, secondary malignancy or death were defined as competing events. For identifying LRR predictors, surgery type, pathological complete response (pCR), BC subtypes and other potential risk factors were evaluated., Results: Median followup was 67 months (range 0-215), overall LRR rate was 9.5%, 4.1% in pCR versus 9.5% in non-pCR patients. Younger age, clinically positive lymph nodes, G3 tumours, non-pCR and TNBC but not surgery type were independent LRR predictors in multivariate analysis. Among BC subtypes, 5-year cumulative LRR rates were associated with higher risk in non-pCR versus pCR patients, which was significant for HR+/HER2- (5.9% vs 3.9%; HR = 2.32 [95%CI 1.22-4.43]; p = 0.011); HR-/HER2+ (14.8% vs 3.1%; HR = 4.26 [94%CI 2.35-7.71]; p < 0.001) and TNBC (18.5% vs 4.2%; HR = 4.10 [95%CI 2.88-5.82]; p < 0.001) but not for HR+/HER2+ (8.1% vs 4.8%; HR = 1.56 [95%CI 0.85-2.85]; p = 0.150). Within non-pCR subgroup, LRR risk was higher for HR-/HER2+ and TNBC vs HR+/HER2- (HR = 2.05 [95%CI 1.54-2.73]; p < 0.001 and HR = 2.77 [95%CI 2.27-3.39]; p < 0.001, respectively)., Conclusions: This pooled analysis demonstrated that young age, node-positive and G3 tumours, as well as TNBC, and non-pCR significantly increased the risk of LRR after NACT. Hence, there is a clear need to investigate better multimodality therapies in the post-neoadjuvant setting for high-risk patients., Competing Interests: Conflict of interest statement H. Tesch reported nonfinancial support, honoraria and travel grants from Lilly, Amgen, Roche and Novartis outside the submitted work. J. Huober reported honoraria und advice board from Lilly, Novartis, Roche, Pfizer, Hexal, Astra Zeneca, MSD, Celgene; research funding from Novartis, Celgene and Travel expenses from Roche, Pfizer, Novartis, Celgene. C. Hanusch reported personal fees from AstraZeneca, Pfizer, Celgene, Lilly, Novartis and Roche outside the submitted work. C. Denkert reported stock and ownership interests from Sividon Diagnostics; honoraria from TEVA, Novartis, Pfizer, Roche, Amgen; consulting or advisor role from MSD Oncology, Amgen, Daiichi Sankyo and patents or other intellectual property from VMScope: digital pathology software, patent application: EP18209672 - cancer immunotherapy, patent application EP20150702464 - therapy response outside the submitted work. D. Krug reported personal fees from Merck Sharp & Dome outside the submitted work. A. Schneeweiss reported grants from Celgene, Roche, AbbVie, Molecular Partner, personal fees from Roche, AstraZeneca, Celgene, Roche, Pfizer, Novartis, MSD, Tesaro, Lilly, outside the submitted work. M. Untch reported personal fees and nonfinancial support to the institute from Lilly, MSD Merck, Mundipharma, Myriad Genetics, Odonate, Pfizer, Roche, Sanofi Aventis Deutschland GmbH, TEVA, Novartis, and personal fee to the institute from PUMA Biotechnology outside the submitted work. C. Jackisch reported personal fees from Roche and Amgen during the conduct of the study. T. Link reported personal fees from Amgen, nonfinancial support from AstraZeneca, personal fees and nonfinancial support from Pfizer, nonfinancial support from Pharma Mar, nonfinancial support from Daiichi Sankyo, personal fees from MSD, personal fees from Novartis, TEVA, Tesaro, personal fees and nonfinancial support from Roche outside the submitted work. S. Loibl reported research grant from Roche during the conduct of the study; honoraria paid to the institute from AbbVie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche, Seattle Genetics, TEVA, Vifor, PRIME, Daiichi Sankyo outside the submitted work and patent P14153692.0 pending. P.A. Fasching reported grants from Novartis, Biontech, personal fees from Novartis, Roche, Pfizer, Celgene, Daiichi Sankyo, TEVA, Astra Zeneca, Merck Sharp & Dohme, Myelo Therapeutics, Macrogenics, Eisai, Puma, grants from Cepheid during the conduct of the study. K. Rhiem reported personal fees from Tesaro, Pfizer and AstraZeneca outside the submitted work. All remaining authors declare that they have no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Immune cell infiltration in breast cancer is important for the patient's prognosis and response to systemic therapies including immunotherapy. We sought to investigate the prevalence of tumour-infiltrating lymphocytes (TILs) and their association with immune checkpoints such as programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in high-risk, node-positive breast cancer of the adjuvant German Adjuvant Intergroup Node-positive (GAIN-1) trial., Patients and Methods: We evaluated TILs by haematoxylin and eosin staining and PD-1 and PD-L1 (SP263 assay) expression by immunohistochemistry in 1318 formalin-fixed, paraffin-embedded breast carcinomas. The association of TILs with PD-1, PD-L1, molecular intrinsic subtypes, outcome and therapy regimens (dose-dense [dd] epirubicin, paclitaxel and cyclophosphamide [EPC] and dd epirubicin, cyclophosphamide, paclitaxel and capecitabine [EC-PwX]) was statistically tested., Results: Overall TILs density was significantly associated with the expression of PD-1 and PD-L1 in immune cells (each p < 0.0001) and PD-L1 in tumour cells (p = 0.0051). TILs were more common in triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive tumours (each p < 0.0001). On multivariate Cox regression analyses, patients with breast cancer without TILs had an unfavourable disease-free survival (DFS) in the EPC arm compared with the EC-PwX arm (hazard ratio [HR] = 0.69 [0.44-1.06], p = 0.0915); but no differences were seen in tumours with TILs (HR = 1.24 [0.92-1.67], p = 0.1566, interaction p = 0.0336). PD-1-positive immune cells in TNBC were associated with a significantly better DFS (HR = 0.50 [0.25-0.99], p = 0.0457). PD-L1 expression had no impact on patient outcome., Conclusions: TILs predict the benefit of intensified ddEPC compared with ddEC-PwX therapy in node-positive, high-risk breast cancer. TILs, PD-1 and PD-L1 are linked to each other indicating tumour immunogenicity. Moreover, PD-1-positive immune cells have a positive prognostic impact in TNBC., Clinical Trial: NCT00196872., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: GeparOcto compared efficacy and safety of two chemotherapy regimens in high-risk early breast cancer (BC): sequential treatment with intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly treatment with paclitaxel plus non-pegylated liposomal doxorubicin (M, Myocet®) with additional carboplatin (PM(Cb)) in triple-negative BC (TNBC)., Patients and Methods: Patients with cT1c-cT4a-d and centrally assessed human epidermal growth factor receptor (HER)2-positive BC or TNBC were eligible, irrespective of nodal status, luminal B-like tumours only if pN+. Patients were randomised (stratified by BC subtype, Ki67, lymphocyte-predominant BC) to receive 18 weeks of E (150 mg/m 2 ) followed by P (225 mg/m 2 ) followed by C (2000 mg/m 2 ), each q2w for 3 cycles or weekly P (80 mg/m 2 ) plus M (20 mg/m 2 ) plus, in TNBC, Cb (area under curve (AUC) 1.5). HER2-positive BC patients additionally received trastuzumab (6 [loading dose 8]mg/kg q3w) and pertuzumab (420 [840]mg q3w) with all P and C cycles. Primary end-point was pathological complete response (pCR, ypT0/is ypN0), secondary end-points included other pCR definitions, pCR in stratified subpopulations, tolerability and compliance. This trial is registered with ClinicalTrials.gov number NCT02125344., Results: 945/961 randomised patients started treatment. The median age was 48 years; 7.6% had cT3-4, 46% cN+, 66% G3, 40% HER2-positive, 43% TNBC. pCR rate with iddEPC was 48.3%, with PM(Cb) 48.0%, respectively (PM(Cb) versus iddEPC odds ratio 0.99; 95% confidence interval 0.77-1.28, P = 0.979) with no significant differences observed in TNBC, HER2-positive, luminal B-like subtypes. 16.4% with iddEPC and 34.1% with PM(Cb) discontinued treatment (P < 0.001), mainly due to adverse events; two patients on PM(Cb) died., Conclusions: In high-risk early BC there is no difference in pCR rates following neoadjuvant treatment with iddEPC or weekly PM(Cb), respectively. iddEPC is one of the effective dose-dense regimens feasible in daily practice., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer., Methods: NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15., Results: Recruitment was suspended mainly due to liver toxicity after enrolment of 50 of the planned 256 patients. In each arm (buparlisib n = 25; placebo n = 25) 21 patients (84%) had wild type PIK3CA and 4 patients (16%) had mutant PIK3CA. Overall, pCR rate was similar between buparlisib and placebo arms (32.0% versus 40%; one-sided P = 0.811). A trend towards higher ORR (68.8% versus 33.3%; P = 0.053) and a significant decrease in Ki67 (75% versus 26.7%; P = 0.021) was observed in buparlisib versus placebo arm in the ER+ subgroup (P interaction  = 0.03)., Conclusions: Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors., Trial Registration Identifier: NCT01816594., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The UICC TNM (tumour-node-metastasis) staging system for pancreatic ductal adenocarcinoma (PDAC) has been a matter of debate over decades because survival prediction based on T stages was weak and unreliable. To improve staging, the recently published 8th TNM edition (2016) introduced a conceptually completely changed strictly size-based T staging system and a refined N stage for PDAC. To investigate the clinical value of the novel TNM classification, we compared the prognostic impact of pT and pN stage between the 7th and 8th edition in two well-characterised independent German PDAC cohorts from different decades, including a total number of 523 patients. Former UICC T staging (7th edition 2009) resulted in a clustering of pT3 cases (72% and 85% of cases per cohort, respectively) and failed to show significant prognostic differences between the four stages in one of the investigated cohorts (p = 0.074). Application of the novel size-based T stage system resulted in a more equal distribution of cases between the four T categories with a predominance of pT2 tumours (65% and 60% of cases). The novel pT staging algorithm showed greatly improved discriminative power with highly significant overall differences between the four pT stages in both investigated cohorts in univariate and multivariate analyses (p < 0.001, each). In contrast, no prognostic differences were observed between the recently introduced pN1 and pN2 categories in both cohorts (p = 0.970 and p = 0.061). pT stage of resected PDAC patients according to the novel UICC staging protocol (8th edition) significantly improves patient stratification, whereas introduction of an extended N stage protocol does not demonstrate high clinical relevance in our cohorts., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The GENEVIEVE study compared the pathological complete response (pCR) rate (ypT0/is ypN0/+) in patients with operable human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) treated with either cabazitaxel or paclitaxel., Methods: GENEVIEVE was a prospective, multicentre, randomised, open-label, phase II study comparing the efficacy and the safety of four 3-weekly cycles cabazitaxel versus 12 weeks of paclitaxel given as neoadjuvant treatment. Primary end-point was the pCR rate defined as the complete absence of invasive carcinoma on histological examination of the breast irrespective of lymph node involvement (ypT0/is, ypN0/+) after the taxane treatment. Patients could receive an anthracycline-based therapy thereafter., Results: Overall, 333 patients were randomised and started treatment with 74.7% and 83.2% of patients completing treatment in the cabazitaxel and paclitaxel arms, respectively. Patients in cabazitaxel arm had a significantly lower pCR rate compared to the paclitaxel arm (1.2% versus 10.8%; p = 0.001). A total of 42 (25.3%) patients in the cabazitaxel arm and 17 (10.2%) in the paclitaxel arm had at least one serious adverse event (p < 0.001). Dose reductions were observed in 9.6% patients in the cabazitaxel arm compared to 11.4% in the paclitaxel arm (p = 0.721). Main reason for dose reductions was non-haematological toxicities in 3.0% versus 7.8% (p = 0.087), respectively., Conclusions: The GENEVIEVE study showed no short-term effect of cabazitaxel in triple-negative or luminal B/HER2-negative primary BC, while there seemed to be no differences in drug exposure and patient compliance between the two arms., Clinical Trials Registration: ClinicalTrials.gov NCT01779479., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: We studied the prognostic effect of CD3-, CD8- and CD103-positive T lymphocytes in a cohort of 165 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the treatment group (adjuvant gemcitabine) and the untreated control group of the CONKO-001 study., Methods: Immunohistochemical stainings on tissue microarrays (TMAs) against CD3, CD8 and CD103 were performed according to standard procedures., Results: A high number of CD8-positive lymphocytes were significantly and independently associated with longer disease-free survival (DFS) and overall survival (OS) in the overall study population. Median DFS/OS were 7.4/18.1 months for patients with a low number of CD8-positive intratumoural lymphocytes (≤42 per 1 mm tissue core) and 12.7/25.2 months for patients with high numbers (>42 per 1-mm tissue core; p = 0.008/0.020; HR 0.62/0.65). The ratio of intraepithelial to total CD103-positive lymphocytes, but not total numbers of CD103-positive lymphocytes or CD103-positive intraepithelial lymphocytes, was associated with significantly improved DFS and OS in the overall study population (p = 0.022/0.009). Median DFS/OS was 5.9/15.7 for patients with a ratio of intraepithelial to total CD103-positive intratumoural lymphocytes higher than 0.3 and 11.6/24.7 for patients with a lower ratio., Conclusion: T-lymphocyte subpopulations might be prognostic in resectable PDAC but need standardization and verification by further studies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Patients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer., Patients and Methods: Patients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival., Results: After a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709-1.30, log rank P=0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant (P=0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79-1.79; log rank P=0.408). Zoledronate was well tolerated and no new toxicity signal was identified., Conclusion: Postneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Pathologic complete response after neoadjuvant chemotherapy (NACT) correlates with overall survival (OS) in primary breast cancer. A recently described staging system based on pre-treatment clinical stage (CS), final pathological stage (PS), estrogen receptor (ER) status and nuclear grade (NG) leads to a refined estimation of prognosis in unselected patients. Its performance in luminal type breast cancers has not been determined. This study investigates the clinical utility of this CPS+EG score when restricted to hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) patients and compares the results to a cohort of unselected patients., Methods: The CPS+EG score was calculated for 6637 unselected patients and 2454 patients with HR+/HER2- tumours who received anthracycline/taxane-based NACT within 8 prospective German trials., Results: Five-year disease-free survival (DFS) and OS were 75.6% and 84.1% for the unselected cohort and 80.6% and 87.8% for the HR+/HER2- subgroup, respectively. The CPS+EG system distinguished different prognostic groups with 5-year DFS ranging from 0% to 91%. The CPS+EG system leads to an improved categorisation of patients by outcome compared to CS, PS, ER or NG alone. When applying the CPS+EG score to the HR+/HER2- subgroup, a shift to lower scores was observed compared to the overall population, but 5-year DFS and OS for the individual scores were identical to that observed in the overall population., Conclusions: In HR+/HER2- patients, the CPS+EG staging system retains its ability to facilitate a refined stratification of patients according to outcome. It can help to select candidates for post-neoadjuvant clinical trials in luminal breast cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: High expression of human equilibrative nucleoside transporter 1 (hENT1) is considered to predict survival in patients treated with adjuvant gemcitabine for pancreatic cancer. A standard evaluation system for immunohistochemical analysis (antibody, scoring system) has not yet been established., Methods: CONKO-001, a prospective randomised phase III study investigated the role of adjuvant gemcitabine (gem) as compared to observation (obs). Tumour samples of 156 patients were analysed by immunohistochemistry with the rabbit monoclonal antibody SP120 (Ventana Medical Systems) for expression of hENT1. Kaplan-Meier analyses for median disease-free survival (DFS) and overall survival (OS) were performed in dependence of hENT1 expression measured analogously to Farrell et al. 2009 and Poplin et al. 2013., Results: For the 88 gem and 68 obs patients, median DFS/OS was 12.9/22.7 months and 6.2/19.1 months. High hENT1 expression was not associated with improved median DFS (Farrell: no hENT1 22.2 months, low hENT1 13.7 months, high hENT1 12.1 months, p=0.248; Poplin: low hENT1 13.2 months versus high hENT1 11.5 months, p=0.5) or median OS (Farrell: no hENT1 21.7 months, low hENT1 24.7 months, high hENT1 19.5, p=0.571; Poplin: low hENT1 24.4 months versus high hENT1 19.7 months, p=0.92;) in the gem group or in the obs group (median DFS Farrell: no hENT1 5.1 months, low hENT1 6.2 months, high hENT1 7.5 months, p=0.375; Poplin: low hENT1 6.2 months versus high hENT1 5.9 months, p=0.83; median OS Farrell: no hENT1 20.2months, low hENT1 17.7 months, high HENT1 19.1 months, p=0.738; Poplin: low hENT1 17.7 months versus high hENT1 20.4 months, p=0.65) measured by the Farrell or Poplin Score., Conclusions: We cannot confirm a predictive role of hENT1 measured by the clone SP120 rabbit antibody in our study population. Reproducible standard procedures are urgently needed prior to the implementation or exclusion of hENT1 as a predictive biomarker in the treatment of pancreatic cancer., Trial Registration: ISRCTN34802808., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The ubiquitously expressed actin-binding protein, gelsolin, is known to play a role in the modulation of the actin network and in the regulation of cell growth and cell motility. In the present study, we analysed the expression of gelsolin in 241 matched cDNA pairs from human normal and tumour tissues using a Cancer Profiling Array. We found a decreased expression of gelsolin in cancer tissue from female reproductive organs, including the ovary. On a protein level, we examined the expression of gelsolin in human ovarian cancer cell lines and in a set of 110 cases of human benign and malignant ovarian tumours. Low levels of gelsolin protein were observed in four of six ovarian carcinoma cell lines, in contrast to its expression in normal ovarian surface epithelial cells. In addition, we found a reduced expression of gelsolin in borderline tumours and ovarian carcinomas compared with the epithelium of normal ovaries and benign adenomas. Decreased gelsolin expression was associated with poorly differentiated carcinomas (p=0.014). No significant association between gelsolin expression and other clinicopathological markers or patient survival could be established. In addition, we investigated the growth regulatory function of gelsolin in human ovarian cancer cell lines using cDNA transfections. Re-expression of gelsolin in OAW42 and ES-2 cells resulted in a suppression of tumour cell survival in vitro. To explore the mechanism responsible for the downregulation of gelsolin expression in ovarian carcinoma cells, we treated cells with inhibitors of DNA methylation and histone deacetylation. We observed an upregulation of gelsolin in ovarian cancer cells after treatment with both types of inhibitor. Our results suggest that gelsolin might be involved in the growth regulation of human ovarian cancer.