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The role of adaptive immunity in long-term outcomes in early breast cancer is increasingly recognised. Standard (neo)adjuvant chemotherapy can have adverse effects on immune cells. We conducted a retrospective longitudinal study of full blood counts (FBC) of 200 patients receiving (neo)adjuvant chemotherapy for early breast cancer at a single institution. FBC results at four time points from pre-treatment to 12 months post-chemotherapy were analysed. Flow cytometry was performed for patients with matched pre- and post-chemotherapy peripheral blood mononuclear cell samples. A significant decrease in absolute lymphocyte count at 12 months post-chemotherapy was observed (p < 0.01), most pronounced in pre-menopausal patients (n = 73; p < 0.01), patients receiving dose-dense chemotherapy regimens (n = 60; p < 0.01) and patients receiving adjuvant radiotherapy (n = 147, p < 0.01). In pre-menopausal patients, significant changes in CD4 + T cells subsets post-chemotherapy were observed. Further investigation, including long-term clinical outcomes, is needed to meaningfully improve long-term anti-tumour immunity., (© 2024. The Author(s).)

Importance: Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking., Objective: To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer., Design, Setting, and Participants: This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022., Main Outcomes and Measures: Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses., Results: Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively., Conclusions and Relevance: In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

Physical exercise both during and after curative cancer treatment has been shown to reduce side effects. Evidence in the metastatic cancer setting is scarce, and interventions that improve health-related quality of life (HRQOL) are much needed for patients with metastatic breast cancer (MBC). The multinational randomized controlled PREFERABLE-EFFECT trial assessed the effects of exercise on fatigue and HRQOL in patients with MBC. In total, 357 patients with MBC and a life expectancy of ≥6 months but without unstable bone metastases were recruited at eight study centers across five European countries and Australia. Participants were randomly assigned (1:1) to usual care (control group, n = 179) or a 9-month supervised exercise program (exercise group, n = 178). Intervention effects on physical fatigue (European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-FA12 scale) and HRQOL (EORTC QLQ-C30 summary score) were determined by comparing the change from baseline to 3, 6 (primary timepoint) and 9 months between groups using mixed models for repeated measures, adjusted for baseline values of the outcome, line of treatment (first or second versus third or higher) and study center. Exercise resulted in significant positive effects on both primary outcomes. Physical fatigue was significantly lower (-5.3 (95% confidence interval (CI), -10.0 to -0.6), Bonferroni-Holm-adjusted P = 0.027; Cohen's effect size, 0.22) and HRQOL significantly higher (4.8 (95% CI, 2.2-7.4), Bonferroni-Holm-adjusted P = 0.0003; effect size, 0.33) in the exercise group than in the control group at 6 months. Two serious adverse events occurred (that is, fractures), but both were not related to bone metastases. These results demonstrate that supervised exercise has positive effects on physical fatigue and HRQOL in patients with MBC and should be recommended as part of supportive care.ClinicalTrials.gov Identifier: NCT04120298 ., (© 2024. The Author(s).)

Context: Menopause is associated with changes in musculoskeletal, body composition, and metabolic parameters that may be amplified in premenopausal women receiving estradiol suppression for breast cancer. Denosumab offsets deleterious skeletal effects of estradiol suppression and has been reported to have effects on body composition and metabolic parameters in preclinical and observational studies, but evidence from double-blind randomized controlled trials is limited., Objective: To assess the effect of denosumab on body composition and metabolic parameters., Methods: In a prespecified secondary analysis of a 12-month randomized, double-blind, placebo-controlled trial, 68 premenopausal women with breast cancer initiating ovarian function suppression and aromatase inhibition were randomized to denosumab 60-mg or placebo administered at baseline and 6 months. Outcome measures were total and regional fat and lean mass (DXA), body mass index (BMI), waist and hip circumference, fasting glucose, HOMA-IR, and lipid profile. Using a mixed model, between-group mean adjusted differences over time are reported., Results: Over 12 months, relative to placebo, android and gynoid fat mass decreased in the denosumab group (-266 g [95% CI -453 to -79], P = .02, and -452 g [-783 to -122], P = .03, respectively). Total fat mass and waist circumference were lower in the denosumab group but not significantly (-1792 g [-3346 to -240], P = .08 and (- 3.77 cm [-6.76 to -0.79], P = .06, respectively). No significant treatment effects were detected in lean mass, BMI, hip circumference, fasting glucose, HOMA-IR, or lipid profile., Conclusion: In premenopausal women receiving estradiol suppression, denosumab decreases some measures of fat mass with no detectable effects on other measures of body composition or metabolic parameters., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

This manuscript describes the Advanced Breast Cancer (ABC) international consensus guidelines updated at the last two ABC international consensus conferences (ABC 6 in 2021, virtual, and ABC 7 in 2023, in Lisbon, Portugal), organized by the ABC Global Alliance. It provides the main recommendations on how to best manage patients with advanced breast cancer (inoperable locally advanced or metastatic), of all breast cancer subtypes, as well as palliative and supportive care. These guidelines are based on available evidence or on expert opinion when a higher level of evidence is lacking. Each guideline is accompanied by the level of evidence (LoE), grade of recommendation (GoR) and percentage of consensus reached at the consensus conferences. Updated diagnostic and treatment algorithms are also provided. The guidelines represent the best management options for patients living with ABC globally, assuming accessibility to all available therapies. Their adaptation (i.e. resource-stratified guidelines) is often needed in settings where access to care is limited., Competing Interests: Declaration of competing interest Matti S. Aapro: Consultant for Accord Pharmaceuticals, Amgen, BMS, Celgene, Clinigen Group, Daiichi Sankyo, Eisai Co.Ltd, Eli Lilly, Genomic Health (Exact Sciences), G1 Therapeutics, Inc., GlaxoSmithKline (GSK), Helsinn Healthcare SA, Hospira (Pfizer), Johnson & Johnson, Merck, Merck Serono (Merck KGaA), Mundipharma International Limited, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Tesaro (GSK), Teva Pharmaceuticals Industries Ltd., Vifor Pharma. Received honoraria for lectures at symposia of Accord Pharmaceuticals, Amgen, Astellas, Bayer HealthCare Pharmaceuticals (Schering), Biocon, Boeringer Ingelheim, Cephalon, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Dr Reddy's Laboratories, Genomic Health (Exact Sciences), Glenmark Pharmaceuticals Limited, GSK, Helsinn Healthcare SA, Hospira (Pfizer), Ipsen, Janssen Biotech, Kyowa Kirin Group, Merck, Merck Serono (Merck KGaA), Mundipharma International Limited, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi, Tesaro (GSK), Taiho Pharmaceutical, Teva Pharmaceutical Industries Ltd., Vifor Pharma. Grant/Research supports: Amgen, Eisai, Genomic Health (Exact Sciences), Helsinn, Hospira, Novartis, Merck, Mundipharma, Pfizer, Roche, Sandoz, Tesaro, Teva, Vifor. Jyoti Bajpai: Institutional financial interests for conducting research: Eli Lilly, MSD, Novartis, Roche, Paxman Coolers Ltd, Samsung Bioepis co. Ltd, Sun Pharma. Carlos H. Barrios: Receipt of grants/research supports: (to the institution) Nektar, Pfizer, Polyphor, Amgen, Daiichi Sankyo, Sanofi, Exelixis, Regeneron, Novartis, GSK, Janssen, OBI Pharma, Lilly, Seagen, Roche, BMS, MSD, Merck Serono, AstraZeneca, Novocure, Aveo Oncology, Takeda, TRIO, PharmaMar, Celgene, PPD, Syneos Health, Labcorp, ICON, IQVIA, Parexel, Nuvisan, PSI, Worldwide, Gilead Sciences, Bayer, Servier. Receipt of honoraria or consultation fees: Advisory Boards and Consulting: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Lilly, Sanofi, Daiichi. Stock shareholder: Ownership or stocks: Tummi, MEDSir. Jonas Bergh: Receipt of grants/research supports: Research grants from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche & Sanofi-Aventis to Karolinska Institutet and/or University Hospital. No personal payments. Other support: Payment for a chapter in UpToDate on breast cancer prediction to Asklepios Medicin HB. Laura Biganzoli: Personal financial interests (Honoraria, consultancy or advisory role): Amgen, AstraZeneca, Boehringer-Ingelheim, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead, Lilly, Menarini, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, SeaGen. Institutional financial interests: Celgene, Genomic Health, Novartis. Travel grants: AstraZeneca, Daiichi-Sankyo. Fatima Cardoso: Receipt of honoraria or consultation fees: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, Gilead, GlaxoSmithKline, Iqvia, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva, Touchime. Maria-Joao Cardoso: Receipt of honoraria or consultation fees: AstraZeneca, Merck-Sharp, Novartis and Roche. Lisa A. Carey: Other support: Research funding (institution): NanoString Technologies, Seagen, Veracyte, AstraZeneca. Uncompensated relationships: Lilly, Seagen, Novartis, Genentech/Roche, GlaxoSmithKline. Mariana Chavez-MacGregor: Receipt of grants/research supports: BCRF, Susan G Komen. Receipt of honoraria or consultation fees: Astra Zeneca, Pfizer, Lilly, Roche, Merck. Javier Cortés: Receipt of grants/research supports: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies. Receipt of honoraria or consultation fees: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo, Astrazeneca. Stock shareholder: MedSIR, Nektar Pharmaceuticals, Leuko (relative). Other support: Research funding to the Institution: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London. Travel, accommodation, expenses: Roche, Novartis, Eisai, pfizer, Daiichi Sankyo, Astrazeneca, Gilead. Patents: Pharmaceutical Combinations of a Pi3k Inhibitor and A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED. Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés.US 2019/0338368 A1. LICENSED. Giuseppe Curigliano: Receipt of grants/research supports: Merck. Receipt of honoraria or consultation fees: Merck, Lilly, Pfizer, Daichi Sankyo, Seagen, Novartis, Roche, Astra Zeneca, Ellipsis. Participation in a sponsored speakers' bureau: Seagen, Novartis, Lilly, Pfizer, Daichii Sankyo. Rebecca A. Dent: Receipt of grants/research supports: AstraZeneca, Roche. Receipt of honoraria or consultation fees: AstraZeneca, DKSH, Eisai, Merck, Novartis, Pfizer, Roche. Nagi S. El Saghir: Receipt of honoraria or consultation fees: Roche, Novartis, Lilly. Alexandru Eniu: Receipt of honoraria or consultation fees: Astra Zeneca, Daiichi Sankyo, Gilead, Janssen, MSD, Novartis, SeaGen. Receipt of grants/research supports: AstraZeneca. Full or part-time employment: European School of Oncology (ESO). Lesley Fallowfield: Receipt of grants/research supports: Novartis, Bristol-Myers Squibb, Lilly. Receipt of honoraria or consultation fees: Voluntis, Genomic Health, NanoString Technologies, Novartis, Pfizer, MSD, Novartis, Abbvie, Clovis Oncology, Puma Biotechnology, AstraZeneca, Takeda, Genomic Health/Exact Sciences, Lilly, Seagen, Roche. Sandra X. Franco Millan: Receipt of honoraria or consultation fees: Novartis, Pfizer, Eli Lilly. Participation in a sponsored speakers' bureau: Novartis, Pfizer, Eli Lilly. Karen Gelmon: Receipt of grants/research supports: Pfizer, AstraZeneca. Receipt of honoraria or consultation fees: Pfizer, Lilly, Novartis, AstraZeneca, Merck, Gilead, Seagen. Jenny Gilchrist: Receipt of honoraria or consultation fees: Eli-Lilly, AstraZeneca, Novartis, Pfizer, MSD, Gilead, Juniper Biologics. Joseph Gligorov: Receipt of grants/research supports: Eisai, Exact Science, Guardant, Roche Genentech. Receipt of honoraria or consultation fees: Astra Zeneca, Daiichi, Eisai, Evapharma, Exact Science, Gilead, Guardant Lilly, Merck, Novartis, Onxeo, Pfizer, Roche Genentech, Seattle Genetics. Participation in a sponsored speakers' bureau: Eisai, Eva Pharm, Novartis, Roche Genentech, Seattle Genetics. Other support (please specify): Institutional: Institut Universitaire de Cancérologie AP-HP Sorbonne Université; French breast cancer guidelines St Paul. Nadia Harbeck: Receipt of grants/research supports: all to institution. Receipt of honoraria or consultation fees: AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, MSD, Novartis, PierreFabre, Pfizer, Roche, Sandoz, Seagen, Viatris, Zuelligpharma. Participation on a sponsored speakers' bureau: EPG Communication, MEDSCAPE, Springer. Stock shareholder: WSG minority ownership. Spouse/Partner: Consulting for WSG. Ranjit Kaur: Receipt of grants/research supports: Novartis, Roche, Pfizer, Astrazeneca. Receipt of honoraria or consultation fees: Novartis, Roche, Pfizer, Astrazeneca. Participation in a sponsored speakers' bureau: Novartis, Roche, Pfizer, Astrazeneca. Belinda Kiely: Receipt of honoraria or consultation fees: Speakers fees: Novartis, Eisai. Advisory boards: Roche, Gilead, Novartis. Other support (please specify): meeting registrations fees: Novartis, Pfizer, MSD. Sung-Bae Kim: Receipt of grants/research supports: Novartis, Sanofi-Aventis, and DongKook Pharm Co. Receipt of honoraria or consultation fees: Novartis, AstraZeneca, Lilly, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, OBI pharma, Beigene and Daiichi-Sankyo. Stock shareholder: Genopeaks. Smruti Koppikar: Receipt of honoraria or consultation fees: Eli Lilly, Novartis, Cipla, Roche. Participation in a sponsored speakers' bureau: Eli Lilly, Novartis, Cipla, Roche. Marion Kuper-Hommel: Receipt of honoraria or consulting fees: Astra Zeneca. Ginny Mason: Participation in a sponsored speakers' bureau: Novartis. Volkmar Mueller: Receipt of grants/research supports: Institutional research support from Novartis, Roche, Seagen, Genentech, Astra Zeneca. Receipt of honoraria or consultation fees: Speaker honoraria: Astra Zeneca, Daiichi-Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, Pierre Fabre. Consultancy honoraria from Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, DaiichiSankyo, Eisai, Lilly, Sanofi, Seagen, Gilead, Stemline, ClinSol. Other support (please specify): Travel grants: Roche, Pfizer, Daiichi Sankyo, Gilead. Claire Myerson: Receipt of honoraria or consultation fees: Novartis Pharma. Silvia Neciosup: Receipt of grants/research supports: Roche, Pfizer. Participation in a sponsored speakers' bureau: Tecnofarma, AZ, Roche, Pfizer. Larry Norton: Receipt of honoraria or consultation fees: Blackrock QLS Advisors, Cold Spring Harbor Laboratory, UNC Breast Spore EAB Meeting, Codagenix Scientific Advisory Board Meeting, Martell Diagnostic Laboratories, Inc., Celgene, Agenus, Immix Biopharma, Inc. Shinji Ohno: Participation in a sponsored speakers' bureau: Chugai, Lilly, MSD, Nippon Kayaku. Shani Paluch-Shimon: Receipt of grants/research supports: Pfizer. Receipt of honoraria or consultation fees: Pfizer, Lily, Novartis, Astra Zeneca, Roche, MSD, Gilead, Rhenium/Exact Sciences, Stemline, Daichi Sankyo. Participation in a sponsored speakers' bureau: Pfizer, Lily, Novartis, Astra Zeneca, Roche, MSD, Gilead. Ann H. Partridge: Uptodate Royalties. Aleix Prat: Receipt of grants/research supports: Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, Medica Scientia inno. Research, SL, Celgene, Astellas and Pzifer. Receipt of honoraria or consultation fees: Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardan Health, Peptomyc and Lilly, Nanostring Technologies and Daiichi Sankyo. Other support: Clinical trials: Boehringer, Lilly, Roche, Novartis, Amgen and Daiichi Sankyo. Hope S. Rugo: Receipt of grants/research supports: Astellas Pharma Inc.; AstraZeneca; Daiichi Sankyo, Inc.; F. Hoffmann-La Roche AG/Genentech, Inc.; Gilead Sciences, Inc.; GlaxoSmithKline; Lilly; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer; Pionyr Immunotherapeutics; Sermonix Pharmaceuticals Inc.; Taiho Oncology, Inc. and Veru Inc. Receipt of honoraria or consultation fees: Puma, NAPO, Blueprint, and Scorpion Therapeutics Daichi Sankyo. Elzbieta Senkus: Receipt of honoraria or consultation fees: AstraZeneca, Curio Science, Egis, Eli Lilly, Gilead, high5md, MSD, Novartis, Pfizer, Roche, Swixx. Other support: travel support: AstraZeneca, Egis, Gilead, Novartis, Roche. Contracted research: Amgen, AstraZeneca, Eli Lilly, Gilead, Novartis, OBI Pharma, Roche, Samsung, Seagen. Medical writing: AstraZeneca, Eli Lilly. Royalties: Springer. Sandra M. Swain: Receipt of grants/research supports: Kailos Genetics, Genentech/Roche. Receipt of honoraria or consultation fees: Athenex, AstraZeneca, Biotheranostics, Natera, Exact Sciences, Lilly, Merck, Genentech/Roche, Sanofi, Daiichi Sankyo, Molecular Templates, Napo Pharmaceuticals. Stock shareholder: SEAGEN. Other support: CO- PI of INAVO 122 Genentech/Roche with in-kind travel to investigator meetings, Travel related expenses in kind Sanofi and Daiichi Sankyo. Peter Vuylsteke: Receipt of grants/research supports: UICC grant. Receipt of honoraria or consultation fees: Roche, Novartis and MSD. Theresa Wiseman: Receipt of grants/research supports: Receiver of SPCC Pfizer grant. Binghe Xu: Receipt of grants/research supports: sponsored research to my institution from Roche, AstraZeneca and Pfizer. Receipt of honoraria or consultation fees: advisory or consultancy fees from Novartis and Roche. Participation in a sponsored speakers' bureau: speakers’ bureau fees from AstraZeneca, Pfizer, Roche, Eisai. Elizabeth Bergsten-Nordström, Alberto Costa, Runcie C. W. Chidebe, Prudence A. Francis, Xichun Hu, Renate Haidinger, Leonor Matos, Shirley A. Mertz, Birgitte V. Offersen, Olivia Pagani, Eva Schumacher-Wulf, Daniel A. Vorobiof, Frédéric E. Lecouvet, and Eric P. Winer reported no significant relationships. William J. Gradishar, George W. Sledge and Christoph Thomssen have not submitted a disclosure of interests’ form., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Suppression of ovarian function and aromatase inhibition (AI) increases disease-free survival in premenopausal women with estrogen receptor (ER)-positive early-stage breast cancer but accelerates bone loss. We therefore hypothesized that suppressing bone remodeling using denosumab (DMAB) would prevent bone loss in these women., Methods: In a 12-month double-blind randomized trial, 68 women with ER-positive early-stage breast cancer commencing ovarian function suppression and AI were randomly assigned to 60 mg DMAB (n = 34) or placebo (PBO; n = 34) once every 6 months (at 0 and 6 months). Volumetric bone mineral density (BMD), microarchitecture, and estimated bone strength of the distal tibia and distal radius were measured using high-resolution peripheral quantitative computed tomography, and spine and hip BMD were measured using dual-energy X-ray absorptiometry at 0, 6, and 12 months. The primary end point and treatment effect was the mean adjusted between group difference (MAD; [95% CI]) in distal tibial total volumetric BMD over 12 months, with a single P value tested over all time points. The study is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; identifier: ACTRN12616001051437)., Results: Intention-to-treat analysis included all 68 randomly assigned women. Over 12 months, compared with PBO, DMAB prevented the decrease in distal tibial total BMD (MAD, 20.8 mg HA/cm 3 [95% CI, 17.3 to 24.2]), cortical BMD (42.9 mg HA/cm 3 [95% CI, 32.1 to 53.9]), trabecular BMD (3.32 mg HA/cm 3 [95% CI, 1.45 to 5.20], P = .004), estimated stiffness (11.6 kN/m [95% CI, 7.6 to 15.6]), and failure load (563 N [95% CI, 388 to 736]). Findings were similar at the distal radius. Decreases in BMD at the lumbar spine (MAD, 0.13 g/cm 2 [95% CI, 0.11 to 0.15]), total hip (0.08 g/cm 2 [95% CI, 0.07 to 0.09], and femoral neck (0.06 g/cm 2 [95% CI, 0.05 to 0.07]) were also prevented. All P < .001 unless otherwise noted., Conclusion: Treatment with DMAB at commencement of estradiol suppression therapy preserves BMD, bone microarchitecture, and estimated strength, and is likely to increase fracture-free survival.

Competing Interests: Declaration of interests CEC reports grants from Breast Cancer Now, Cancer Research UK (CRUK), Addenbrooke's Charitable Trust, and the National Institute for Health and Care Research (NIHR); participation in the Independent Data Monitoring Committees for the UK PivotalBoost trial (chair), the PROTIS phase III sinonasal proton versus IMRT trial (member), the TORPEdO Proton Beam Therapy trial (member); and a leadership role for the Lancet Breast Cancer Commission (chair). CHB reports grants and research support from AbbVie, Nektar Therapeutics, Pfizer, Polyphor, Amgen, Daiichi Sankyo, Sanofi, Exelixis, Regeneron, Novartis, Henlius, Shanghai Henlius Biotech, GSK, Janssen, OBI Pharma, Eli Lilly, Seagen, Checkpoint Therapeutics, Roche, Bristol Myers Squibb, MSD, Merck Serono, AstraZeneca, Novocure, Aveo Oncology, Takeda Pharmaceuticals, TRIO Pharmaceuticals, PharmaMar, Celgene, Myovant, PPD, Syneos Health, DOCS, Labcorp, ICON, IQVIA, Parexel, Nuvisan, PSI, and Medpace; ownership or stocks in Tummi and MEDSir; and participation in advisory boards and consulting activities for Boehringer Ingelheim, GSK, Novartis, Pfizer, Genentech, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Eli Lilly, Sanofi, and Daiichi Sankyo. DAC reports research grants and support from Exact Sciences and Novartis; consulting fees from Eli Lilly, Novartis, Seagen, Daiichi Sankyo, Erytech Pharma, Carnall Farrar, Sapience, and Sanofi; payment or honoraria for lectures and presentations from Exact Sciences, Gilead, Eli Lilly, and Pfizer; participation on data safety monitoring or advisory boards for Novartis, AstraZeneca, and Grail; unremunerated leadership roles for Make Seconds Count (chair of charity trustees) and the Breast International Group (chair of board of not-for-profit research organisation); and receipt of funding for analysis and medical writing for Eli Lilly and Novartis. FC reports payment or honoraria for lectures and presentations and support for attending meetings and travel from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, Gilead, GSK, IQVIA, Macrogenics, Medscape, MSD, Merus, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva Pharmaceuticals, and Touch Independent Medical Education; institutional financial support for clinical trials from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Fresenius, Genentech, Gilead, GSK, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, MediGene, MedImmune, MSD, Millenium, Pfizer, Pierre Fabre, Roche, Sanofi, Sonus, Tesaro, Tigris, Wilex, and Wyeth; a leadership role for the ABC Global Alliance and ABC Consensus Conference and Guidelines (president); and membership of ESMO, ESO, EORTC-BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, and ASPIC. WC reports honoraria from AstraZeneca, Pfizer, MSD, and Eisai. PAF reports a former role in the scientific advisory committee of Breast Cancer Trials Australia and New Zealand cooperative group (chair). RJ reports support from the Susan G Komen Foundation; grants from the National Institutes of Health (NIH), the Doris Duke Charitable Foundation, the Greenwall Foundation, and the American Cancer Society; serving as an expert witness for Kleinbard and Hawks Quindel Law; roles in the Board of Directors of ASCO (former member), ASTRO's Ethics Committee (chair), and the Women in Radiation Oncology Affinity Group (chair); membership on the Medical Advisory Board for Blue Cross Blue Shield Association; stock options for their advisory board role in Equity Quotient; and personal fees from the NIH, Doris Duke Charitable Foundation, and the Greenwall Foundation. FMK reports research grants from the ABC Global Alliance, Breast Cancer Now, Merck Serono WHO, MSD, Avon Cosmetics, the US Cancer Pain Relief Committee, and the Medical Research Council; consulting fees from Merck Serono and Instituto Tecnológico y de Estudios Superiores de Monterrey Mexico; and leadership roles for the Board of Directors of Women in Global Health (unpaid member), Tómatelo a Pecho (unpaid president and founder), the Mexican Health Foundation (unpaid Senior Economist), and the Board of Directors of the International Association for Hospice and Palliative Care (unpaid member). SAMcI reports grant funding from the NIHR, CRUK, and Breast Cancer Now; honoraria from Roche, MSD, AstraZeneca, Becton, Dickinson and Company; travel and conference support from Roche, Eli Lilly, and MSD; membership of advisory boards for Eli Lilly, MSD, Roche, and Novartis; and roles for the UK National Cancer Research Institute Breast Research Group (unpaid chair) and the Royal College of Surgeons Breast Surgical Specialty Lead (unpaid). K-AP reports clinical trial funding from AstraZeneca (paid to institution) and unremunerated previous participation in AstraZeneca advisory boards. LR reports grants from the European Commission Horizon 2020 and the German Research Foundation and a role in the International Association for Hospice and Palliative Care (Chair of Board of Directors). MKT reports grants from Addenbrooke's Charitable Trust and CRUK. FA reports grants from Novartis, Pfizer, AstraZeneca, Eli Lilly, Daiichi Sankyo, and Roche and consulting fees from MedImmune, Gilead, Relay Therapeutics, and Guardant Health. JEA reports speaker honoraria from AstraZeneca, Pfizer, Novartis, and Eisai and conference travel support from AstraZeneca. ISB reports participation in the Roche advisory board for ESMO. JMB reports research grants from Breast Cancer Now, AstraZeneca, MSD, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis, Eli Lilly, Roche, CRUK, and the NIHR. MAF is funded by a Conquer Cancer Breast Cancer Research Foundation Career Development Award for Diversity and Inclusion supported by the Breast Cancer Research Foundation and reports financial support from the WeShare project. AF reports consultancy work for Oxford Immune Algorithmics; grants from Addenbrooke's Charitable Trust and the Ann McLaren Building Preclinical Imaging Suite of the University of Cambridge; and travel support from the University of Cambridge. DIR reports support from the University of Chicago Center for Global Health. DN reports research support from Cepheid; a grant from the US National Cancer Institute; and an unpaid leadership role with the WHO Global Breast Cancer Initiative. WER reports grants from the Cambia Health Foundation, the Robert Wood Johnson Foundation, and the Rita and Alex Hillman Foundation; and book royalties from Springer Publishing and Jones & Bartlett Learning. JR reports funding from the NIHR and support from AstraZeneca for attendance at a teaching event. DS reports a leadership role at the Jamaica Cancer Care and Research Institute (co-director). HS reports membership of the Breast Cancer Now Tissue Bank Advisory Board and voluntary patient membership of the Independent Cancer Patients' Voice charity; an honorarium from the CRUK Precision Grand Challenge; and support for travel expenses from Breast Cancer Now, CRUK, the Association of Breast Surgeons UK, and Breast International Group. IV-L reports grants from Resilience; consulting fees from Novartis, AstraZeneca, and Amgen; payment or honoraria for lectures and presentations from Novartis, Sandoz, Amgen, AstraZeneca, and Pfizer; and support for travel and attending meetings from Novartis. CV-G reports grants from AstraZeneca and Roche; consulting fees from Roche, Novartis, Pfizer, and Eli Lilly; honoraria from Roche, Myriad Genetics, and Novartis; and support for attending meetings and travel from Roche, MSD Oncology, and Pfizer. All other authors declare no competing interests.

Objective: Determine the incidence of vestibular disorders in patients with SARS-CoV-2 compared to the control population., Study Design: Retrospective., Setting: Clinical data in the National COVID Cohort Collaborative database (N3C)., Methods: Deidentified patient data from the National COVID Cohort Collaborative database (N3C) were queried based on variant peak prevalence (untyped, alpha, delta, omicron 21K, and omicron 23A) from covariants.org to retrospectively analyze the incidence of vestibular disorders in patients with SARS-CoV-2 compared to control population, consisting of patients without documented evidence of COVID infection during the same period., Results: Patients testing positive for COVID-19 were significantly more likely to have a vestibular disorder compared to the control population. Compared to control patients, the odds ratio of vestibular disorders was significantly elevated in patients with untyped (odds ratio [OR], 2.39; confidence intervals [CI], 2.29-2.50; P < 0.001), alpha (OR, 3.63; CI, 3.48-3.78; P < 0.001), delta (OR, 3.03; CI, 2.94-3.12; P < 0.001), omicron 21K variant (OR, 2.97; CI, 2.90-3.04; P < 0.001), and omicron 23A variant (OR, 8.80; CI, 8.35-9.27; P < 0.001)., Conclusions: The incidence of vestibular disorders differed between COVID-19 variants and was significantly elevated in COVID-19-positive patients compared to the control population. These findings have implications for patient counseling and further research is needed to discern the long-term effects of these findings., Competing Interests: None declared., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

Aim: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme., Methods and Results: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1-3) compared with non-carriers (median n = 9, range = 1-7) (P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3-8) than non-carriers (median n = 5, range = 3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging., Conclusion: Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Study Objectives: This study aimed to investigate the mechanisms of a combined brief cognitive behavioral plus bright light therapy (CBT-I+Light) in women receiving chemotherapy., Methods: Women (N = 101) were randomly assigned to CBT-I+Light or treatment as usual plus relaxation audios (TAU+). Participants completed sleep diaries and wore an actigraph during the 6-week intervention period. Patient-reported outcomes were assessed at baseline, mid-point (week 3), and later (week 6). Cognitive (i.e., dysfunctional sleep beliefs, pre-sleep cognitions, and arousal) and behavioral (i.e., time in bed awake and day-to-day out-of-bedtime variability) mechanisms were examined., Results: Cognitively, both groups declined significantly in overall dysfunctional sleep beliefs from pre- to post-intervention (both p < .04); however, they did not differ on sleep-related beliefs nor pre-sleep cognitions and arousal at post-intervention (both p > .50). Dysfunctional beliefs sleep expectations subscale was lower in CBT-I+Light versus TAU+ ( p = .01). Behaviorally, CBT-I+Light reported less overall time in bed awake after the start of the intervention ( p < .05) and significantly less time in bed during the morning until the final week of the intervention period. Out-of-bedtime day-to-day variability was lower in the CBT-+Light vs TAU+ at the final intervention day., Conclusion: Mechanisms of CBT-I+Light during chemotherapy remain to be shown. Our results suggest that changes in behavioral mechanisms may be associated with sleep improvements within this cohort. Future studies should assess the role of additional mechanisms (e.g., sleep effort) within larger samples. Whilst intervention brevity is important, more potent interventions may be required to achieve robust changes in target mechanisms.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The Suppression of Ovarian Function Trial (SOFT; ClinicalTrials.gov identifier: NCT00066690) randomly assigned premenopausal women with hormone receptor-positive breast cancer to 5 years of adjuvant tamoxifen, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. The primary analysis compared disease-free survival (DFS) between tamoxifen plus OFS versus tamoxifen alone; exemestane plus OFS versus tamoxifen was a secondary objective. After 8 years, SOFT reported a significant reduction in recurrence and improved overall survival (OS) with adjuvant tamoxifen plus OFS versus tamoxifen alone. Here, we report outcomes after median follow-up of 12 years. DFS remained significantly improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.82; 95% CI, 0.69 to 0.98) with a 12-year DFS of 71.9% with tamoxifen, 76.1% with tamoxifen plus OFS, and 79.0% with exemestane plus OFS. OS was improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.78; 95% CI, 0.60 to 1.01) and was 86.8% with tamoxifen, 89.0% with tamoxifen plus OFS, and 89.4% with exemestane plus OFS at 12 years. Among those who received prior chemotherapy for human epidermal growth factor receptor-2-negative tumors, OS was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS. In conclusion, after 12 years, there remains a benefit from including OFS in adjuvant endocrine therapy, with an absolute improvement in OS more apparent with higher baseline risk of recurrence.[Media: see text].

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The combined analysis of SOFT-TEXT compared outcomes in 4,690 premenopausal women with estrogen/progesterone receptor-positive (ER/PgR+) early breast cancer randomly assigned to 5 years of exemestane + ovarian function suppression (OFS) versus tamoxifen + OFS. After a median follow-up of 9 years, exemestane + OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI), but not overall survival, compared with tamoxifen + OFS. We now report DFS, DRFI, and overall survival after a median follow-up of 13 years. In the intention-to-treat (ITT) population, the 12-year DFS (4.6% absolute improvement, hazard ratio [HR], 0.79; 95% CI, 0.70 to 0.90; P < .001) and DRFI (1.8% absolute improvement, HR, 0.83; 95% CI, 0.70 to 0.98; P = .03), but not overall survival (90.1% v 89.1%, HR, 0.93; 95% CI, 0.78 to 1.11), continued to be significantly improved for patients assigned exemestane + OFS over tamoxifen + OFS. Among patients with human epidermal growth factor receptor 2-negative tumors (86.0% of the ITT population), the absolute improvement in 12-year overall survival with exemestane + OFS was 2.0% (HR, 0.85; 95% CI, 0.70 to 1.04) and 3.3% in those who received chemotherapy (45.9% of the ITT population). Overall survival benefit was clinically significant in high-risk patients, eg, women age < 35 years (4.0%) and those with > 2 cm (4.5%) or grade 3 tumors (5.5%). These sustained reductions of the risk of recurrence with adjuvant exemestane + OFS, compared with tamoxifen + OFS, provide guidance for selecting patients for whom exemestane should be preferred over tamoxifen in the setting of OFS.[Media: see text].

The benefit from removing ovaries to control premenopausal breast cancer growth was identified more than 100 years ago. Subsequent identification of estrogen receptor (ER) enabled targeting of this approach. Development of gonadotropin-releasing hormone agonists facilitated a reversible method of ovarian function suppression, suitable for young women with early breast cancer. Clinical trials have established the value of including ovarian suppression to reduce recurrence of ER-positive premenopausal early breast cancer. Ovarian suppression administered with chemotherapy can reduce the risk of premature menopause in ER-negative cancer, and increase the prospect of future pregnancy in premenopausal women, regardless of tumor hormone receptor status., Competing Interests: Disclosure The author has nothing to disclose. Support for conduct of SOFT and TEXT trials by Breast Cancer Trials Australia & New Zealand from National Health and Medical Research Council of Australia (grant numbers 351161, 510788 and 1105058)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Very young premenopausal women diagnosed with hormone receptor-positive, HER2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained., Patients and Methods: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the SOFT clinical trial to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1,276 patients (deep targeted sequencing, N=1258; whole-exome sequencing in a young-age, case-control subsample, N=82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI), and overall survival (OS)., Results: Younger women (<40 years, N=359) compared with older women (≥40 years, N=917) had significantly higher frequencies of mutations in GATA3 (19%vs16%) and CN-amplifications (47%vs26%), but significantly lower frequencies of mutations in PIK3CA (32%vs47%), CDH1 (3%vs9%), and MAP3K1 (7%vs12%). Additionally, significantly higher frequencies of features suggestive of HRD (27%vs21%), and a higher proportion of PIK3CA mutations with concurrent CN-amplifications (23%vs11%).Genomic features suggestive of HRD, PIK3CA mutations with CN-amplifications, and CN-amplifications associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% ≥40 years. Poor prognostic features (N=584[46%]) vs none (N=692[54%]) had an 8-year DRFI of 84%vs94% and OS of 88%vs96%. Younger women (<40) had the poorest outcomes: 8-year DRFI 74%vs85% and OS of 80%vs93% respectively., Conclusion: These results provide insights into genomic alterations that are enriched in young women with HR+HER2-EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Clinical trial endpoints are fundamental for evaluating the safety and efficacy of cancer therapies, yet it is not well understood how they are selected or the role of stakeholder groups in deciding endpoints. This study aimed to explore how clinical trial endpoints are selected in breast cancer trials of anti-cancer drugs through semi structured interviews with purposively selected stakeholders involved in breast cancer clinical trials (clinicians, consumers, pharmaceutical company representatives, and members of drug regulatory agencies). Participants were asked to describe the process of selecting trial endpoints. Interviews were transcribed verbatim and analysed using inductive thematic analysis supported by NVivo software. Saturation of the main themes was reached and the final sample included 25 participants from 14 countries (9 clinicians, 7 consumers, 5 members of regulatory agencies, 4 pharmaceutical company representatives). Pharmaceutical companies were almost always identified as the main decision maker. While most consumers and pharmaceutical company representatives felt clinicians and consumers influenced trial design, some clinicians and regulators reported consumers and clinicians had little influence. Factors identified as important considerations in determining trial endpoints included the main goal of the trial, established standardised endpoints, resources, and the investigational agent studied. All pharmaceutical advisors reported that meeting the requirements for regulatory approval was the major factor considered. Clinical trial endpoint selection is largely decided by the pharmaceutical industry, driven by requirements for regulatory approval. Given the limited influence from clinicians and consumers, guidance by regulatory agencies will be important for future inclusion of novel endpoints in clinical trials., Competing Interests: W Cui: Dr. Cui reports honoraria from AstraZeneca, Pfizer, Janssen and Merck. KA Phillips: Professor Phillips reports two unpaid Advisory Boards for AstraZeneca in 2021. Breast Cancer trials Scientific Advisory Committee member. Breast Cancer Network Australia Strategic Advisory Committee member. RA Anderson: Professor Anderson reports personal fees and non-financial support from Roche Diagnostics, outside the submitted work. PA Francis: Professor Francis is the Breast Cancer Trials Australia & New Zealand Chair Scientific Advisory Committee. She reports travel to lecture overseas: Novartis, Ipsen. S Loi: Professor Loi receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics Astra Zeneca, Roche-Genentech and Seattle Genetics. She has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Meyers Squibb, Merck, AstraZeneca and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, Astra Zeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Seattle Genetics and Bristol Meyers Squibb. Professor Loi is a Scientific Advisory Board Member of Akamara Therapeutics. She is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. S Loibl: Professor Loibl reports grants and other from Abbvie, other from Amgen, grants and other from AstraZeneca, other from Bayer, other from BMS, grants and other from Celgene, grants, non-financial support and other from Daiichi-Sankyo, other from Eirgenix, other from GSK, grants, non-financial support and other from Immunomedics/Gilead, other from Lilly, other from Merck, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, other from Prime/Medscape, non-financial support and other from Puma, grants, non-financial support and other from Roche, other from Samsung, non-financial support and other from Seagen, outside the submitted work; In addition, Professor Loibl has a patent EP14153692.0 pending, a patent EP2115-2186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending, and a patent Digital Ki67 Evaluator with royalties paid. AH Partridge: Professor Partridge reports travel to lecture overseas: Novartis., (AJCR Copyright © 2022.)

There is limited knowledge on the benefit of the α-subunit-specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor-positive (ER+) HER2- and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2- and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083-0.67, P = 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078-0.60, P = 0.003)., Significance: Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. This article is highlighted in the In This Issue feature, p. 2007., (©2022 American Association for Cancer Research.)

Background: Insomnia and fatigue symptoms are common in breast cancer. Active cancer treatment, such as chemotherapy, appears to be particularly disruptive to sleep. Yet, sleep complaints often go unrecognised and under treated within routine cancer care. The abbreviated delivery of cognitive behavioral therapy for Insomnia (CBTI) and bright light therapy (BLT) may offer accessible and cost-effective sleep treatments in women receiving chemotherapy for breast cancer., Methods: The Sleep, Cancer and Rest (SleepCaRe) Trial is a 6-month multicentre, randomized, controlled, 2 × 2 factorial, superiority, parallel group trial. Women receiving cytotoxic chemotherapy for breast cancer at tertiary Australian hospitals will be randomly assigned 1:1:1:1 to one of four, non-pharmacological sleep interventions: (a) Sleep Hygiene and Education (SHE); (b) CBTI; (c) BLT; (d) CBT-I + BLT combined and simultaneously delivered. Each sleep intervention is delivered over 6 weeks, and will comprise an introductory session, a mid-point phone call, and regular emails. The primary (insomnia, fatigue) and secondary (health-related quality of life, rest activity rhythms, sleep-related impairment) outcomes will be assessed via online questionnaires at five time-points: baseline (t0, prior to intervention), mid-point intervention (t2, Week 4), post-intervention (t3, Week 7), 3-months (t4, Week 18), and 6-months follow-up (t5, Week 30)., Conclusions: This study will report novel data concerning the comparative and combined efficacy of CBT-I and BLT during chemotherapy. Findings will contribute to the development of evidence-based early sleep and fatigue intervention during chemotherapy for breast cancer. Clinical trial information Registered with the Australian New Zealand Clinical Trials Registry (http://anzctr.org.au/), Registration Number: ACTRN12620001133921., Competing Interests: Declaration of Competing Interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Detailed toxicity data are routinely collected in breast cancer (BC) clinical trials. However, ovarian toxicity is infrequently assessed, despite the adverse impacts on fertility and long-term health from treatment-induced ovarian insufficiency., Objectives: To determine the barriers to and facilitators of ovarian toxicity assessment in BC trials of anti-cancer drugs., Methods: Semi-structured interviews were conducted with purposively selected stakeholders from multiple countries involved in BC clinical trials (clinicians, consumers, pharmaceutical company representatives, members of drug-regulatory agencies). Participants were asked to describe the perceived benefits and barriers to evaluating ovarian toxicity. Interviews were transcribed verbatim, coded in NVivo software and analysed using inductive thematic analysis., Results: Saturation of the main themes was reached and the final sample size included 25 participants from 14 countries (9 clinicians, 7 consumers, 5 members of regulatory agencies, 4 pharmaceutical company representatives); half were female. The main reported barrier to ovarian toxicity assessment was that the issue was rarely considered. Reasons included that these data are less important than survival data and are not required for regulatory approval. Overall, most participants believed evaluating the impact of BC treatments on ovarian function is valuable. Suggested strategies to increase ovarian toxicity assessment were to include it in clinical trial design guidelines and stakeholder advocacy., Conclusion: Lack of consideration about measuring ovarian toxicity in BC clinical trials that include premenopausal women suggest that guidelines and stronger advocacy from stakeholders, including regulators, would facilitate its more frequent inclusion in future trials, allowing women to make better informed treatment decisions., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diet and lifestyle-related illnesses including functional gastrointestinal disorders (FGIDs) and obesity are rapidly emerging health issues worldwide. Research has focused on addressing FGIDs via in-person cognitive-behavioral therapies, diet modulation and pharmaceutical intervention. Yet, there is paucity of research reporting on digital therapeutics care delivering weight loss and reduction of FGID symptom severity, and on modeling FGID status and symptom severity reduction including personalized genomic SNPs and gut microbiome signals. Our aim for this study was to assess how effective a digital therapeutics intervention personalized on genomic SNPs and gut microbiome signals was at reducing symptomatology of FGIDs on individuals that successfully lost body weight. We also aimed at modeling FGID status and FGID symptom severity reduction using demographics, genomic SNPs, and gut microbiome variables. This study sought to train a logistic regression model to differentiate the FGID status of subjects enrolled in a digital therapeutics care program using demographic, genetic, and baseline microbiome data. We also trained linear regression models to ascertain changes in FGID symptom severity of subjects at the time of achieving 5% or more of body weight loss compared to baseline. For this we utilized a cohort of 177 adults who reached 5% or more weight loss on the Digbi Health personalized digital care program, who were retrospectively surveyed about changes in symptom severity of their FGIDs and other comorbidities before and after the program. Gut microbiome taxa and demographics were the strongest predictors of FGID status. The digital therapeutics program implemented, reduced the summative severity of symptoms for 89.42% (93/104) of users who reported FGIDs. Reduction in summative FGID symptom severity and IBS symptom severity were best modeled by a mixture of genomic and microbiome predictors, whereas reduction in diarrhea and constipation symptom severity were best modeled by microbiome predictors only. This preliminary retrospective study generated diagnostic models for FGID status as well as therapeutic models for reduction of FGID symptom severity. Moreover, these therapeutic models generate testable hypotheses for associations of a number of biomarkers in the prognosis of FGIDs symptomatology., Competing Interests: All authors except JU and PD were employees of Digbi Health. JU did contractual work for Digbi Health. PD was an advisor to Digbi Health. The authors declare that this study received funding from Digbi Health. The funder Digbi Health was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. SK, DA, and RS had a patent-pending concerning this work: US Application No. 63/246,348, Methods and systems for multi-omic interventions as diagnostics for personalized care of functional gastrointestinal disorders. The digital therapeutics program provided to study participants in this work is a commercially available program developed and marketed by Digbi Health., (Copyright © 2022 Kumbhare, Francis-Lyon, Kachru, Uday, Irudayanathan, Muthukumar, Ricchetti, Singh-Rambiritch, Ugalde, Dulai, Almonacid and Sinha.)

Study Objectives: Sleep problems are common during chemotherapy for breast cancer (BC). We evaluated whether combined brief cognitive behavioral and bright light therapy (CBT-I + Light) is superior to treatment as usual with relaxation audio (TAU+) for insomnia symptoms and sleep efficiency (primary outcomes)., Methods: We randomized women receiving intravenous chemotherapy, stratified by tumor stage and insomnia severity index, to 6-week CBT-I + Light or TAU+. CBT-I + Light included 1 in-person session, 1 telephone call, 7 emails, and 20 min bright light (BL) each morning. TAU+ comprised usual treatment and two emails with relaxation audio tracks. Patient-reported outcomes were assessed at baseline, midpoint (week 3), post (week 6), and 3-month follow-up., Results: Women (N = 101) were randomly assigned to CBT-I + Light or TAU+. The CBT-I + Light group showed significantly greater improvement in insomnia symptoms than the TAU+ group (-5.06 vs -1.93, p = .009; between-group effect size [ES] = .69). At 3-month follow-up, both groups were lower than baseline but did not differ from each other (between-group ES = .18, p = .56). CBT-I + Light had higher patient-reported sleep efficiency than TAU+ immediately after the start of intervention (p = .05) and significantly greater improvement in fatigue (between-group ES = .59, p = .013) and daytime sleep-related impairment (between-group ES = .61, p = .009) than the TAU+ group., Conclusions: CBT-I + Light had a clinically significant impact on insomnia and fatigue with moderate ESs. Results support offering cognitive behavioral therapy for insomnia and BL therapy during chemotherapy for BC to help manage sleep and fatigue., Clinical Trial: Australian New Zealand Clinical Trials Registry (http://anzctr.org.au/). Registration number: ACTRN12618001255279., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The importance of integrating biomarkers into the TNM staging has been emphasized in the 8 th Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Prognostic Stage Groups from the AJJC 8 th edition Cancer Staging System. This suggest that clinical and research studies on TNBC should take TILs into account in addition to stage, as for example patients with stage II TNBC and high TILs have a better outcome than patients with stage I and low TILs., (© 2022. The Author(s).)

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC., (© 2021. The Author(s).)

Background: Loss of ovarian function is a recognized adverse effect of chemotherapy for breast cancer and of great importance to patients. Little is known about the ovarian toxicity of newer cancer treatments. This study examined whether breast cancer clinical trials include assessment of the impact of trial interventions on ovarian function., Methods: Eligible trials were phase III (neo)adjuvant trials of pharmacologic treatments for breast cancer, recruiting between June 2008 and October 2019, which included premenopausal women. MEDLINE, EMBASE, Clinicaltrials.gov, and EudraCT were searched. Data were extracted from trial publications, protocols, databases, and a survey sent to all trial chairs. Tests of statistical significance were 2-sided., Results: Of 2354 records identified, 141 trials were eligible. Investigational treatments included chemotherapy (36.9%), HER2 targeted (24.8%), endocrine (12.8%), immunotherapy (7.8%), cyclin-dependent kinase 4/6 inhibitors (5.0%), and poly-ADP-ribose polymerase inhibitors (2.8%). Ovarian function was a prespecified endpoint in 13 (9.2%) trials. Forty-five (31.9%) trials collected ovarian function data, but only 33 (23.4%) collected posttrial-intervention data. Common postintervention data collected included menstruation (15.6%), pregnancy (13.5%), estradiol (9.9%), and follicle-stimulating hormone levels (8.5%). Only 4 (2.8%) trials collected postintervention anti-müllerian hormone levels, and 3 (2.1%) trials collected antral follicle count. Of 22 trials investigating immunotherapy, cyclin-dependent kinase 4/6 inhibitors, or poly-ADP-ribose polymerase inhibitors, none specified ovarian function as an endpoint, but 4 (18.2%) collected postintervention ovarian function data., Conclusions: The impact of pharmacologic interventions on ovarian function is infrequently assessed in phase III breast cancer (neo)adjuvant trials that include premenopausal women. Trialists should consider inclusion of ovarian function endpoints when designing clinical trials, given its importance for informed decision making., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Heparanase promotes tumor growth in breast tumors. We now evaluated heparanase protein and gene-expression status and investigated its impact on disease-free survival in order to gain better insight into the role of heparanase in ER-positive (ER+) breast cancer prognosis and to clarify its role in cell survival following chemotherapy. Using pooled analysis of gene-expression data, we found that heparanase was associated with a worse prognosis in estrogen receptor-positive (ER+) tumors (log-rank p < 10 -10 ) and predictive to chemotherapy resistance (interaction p = 0.0001) but not hormonal therapy (Interaction p = 0.62). These results were confirmed by analysis of data from a phase III, prospective randomized trial which showed that heparanase protein expression is associated with increased risk of recurrence in ER+ breast tumors (log-rank p = 0.004). In vitro experiments showed that heparanase promoted tumor progression and increased cell viability via epithelial-mesenchymal transition, stemness, and anti-apoptosis pathways in luminal breast cancer. Taken together, our results demonstrated that heparanase is associated with worse outcomes and increased cell viability in ER+ BC.

Background: The COVID-19 pandemic has highlighted the urgency of addressing an epidemic of obesity and associated inflammatory illnesses. Previous studies have demonstrated that interactions between single-nucleotide polymorphisms (SNPs) and lifestyle interventions such as food and exercise may vary metabolic outcomes, contributing to obesity. However, there is a paucity of research relating outcomes from digital therapeutics to the inclusion of genetic data in care interventions., Objective: This study aims to describe and model the weight loss of participants enrolled in a precision digital weight loss program informed by the machine learning analysis of their data, including genomic data. It was hypothesized that weight loss models would exhibit a better fit when incorporating genomic data versus demographic and engagement variables alone., Methods: A cohort of 393 participants enrolled in Digbi Health's personalized digital care program for 120 days was analyzed retrospectively. The care protocol used participant data to inform precision coaching by mobile app and personal coach. Linear regression models were fit of weight loss (pounds lost and percentage lost) as a function of demographic and behavioral engagement variables. Genomic-enhanced models were built by adding 197 SNPs from participant genomic data as predictors and refitted using Lasso regression on SNPs for variable selection. Success or failure logistic regression models were also fit with and without genomic data., Results: Overall, 72.0% (n=283) of the 393 participants in this cohort lost weight, whereas 17.3% (n=68) maintained stable weight. A total of 142 participants lost 5% bodyweight within 120 days. Models described the impact of demographic and clinical factors, behavioral engagement, and genomic risk on weight loss. Incorporating genomic predictors improved the mean squared error of weight loss models (pounds lost and percent) from 70 to 60 and 16 to 13, respectively. The logistic model improved the pseudo R 2 value from 0.193 to 0.285. Gender, engagement, and specific SNPs were significantly associated with weight loss. SNPs within genes involved in metabolic pathways processing food and regulating fat storage were associated with weight loss in this cohort: rs17300539&#95;G (insulin resistance and monounsaturated fat metabolism), rs2016520&#95;C (BMI, waist circumference, and cholesterol metabolism), and rs4074995&#95;A (calcium-potassium transport and serum calcium levels). The models described greater average weight loss for participants with more risk alleles. Notably, coaching for dietary modification was personalized to these genetic risks., Conclusions: Including genomic information when modeling outcomes of a digital precision weight loss program greatly enhanced the model accuracy. Interpretable weight loss models indicated the efficacy of coaching informed by participants' genomic risk, accompanied by active engagement of participants in their own success. Although large-scale validation is needed, our study preliminarily supports precision dietary interventions for weight loss using genetic risk, with digitally delivered recommendations alongside health coaching to improve intervention efficacy., (©Ranjan Sinha, Dashyanng Kachru, Roshni Ray Ricchetti, Simitha Singh-Rambiritch, Karthik Marimuthu Muthukumar, Vidhya Singaravel, Carmel Irudayanathan, Chandana Reddy-Sinha, Imran Junaid, Garima Sharma, Patricia Alice Francis-Lyon. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 19.05.2021.)

More than 90% of women with newly diagnosed breast cancer present with stage I to III disease and, with optimal multidisciplinary therapy, are likely to survive their disease. Of these patients, 70% are hormone receptor-positive and candidates for adjuvant endocrine therapy. The adoption of cumulatively better adjuvant treatments contributed to improved outcomes in patients with hormone receptor-positive, early-stage breast cancer. Premenopausal women with hormone receptor-positive breast cancer often present with complex disease and have inferior survival outcomes compared with their postmenopausal counterparts. Risk stratification strategies, including classic clinicopathologic features and newer gene expression assays, can assist in treatment decisions, including adjuvant chemotherapy use and type or duration of endocrine therapy. Gene expression assays may help identify patients who can safely forgo chemotherapy, although to a lesser extent among premenopausal patients, in whom they may play a role only in node-negative disease. Patients at lower risk of recurrence can be adequately treated with tamoxifen alone, whereas higher-risk patients benefit from ovarian function suppression with tamoxifen or an aromatase inhibitor. The role of adding newer therapies such as CDK4/6 inhibitors to adjuvant endocrine therapy is not yet clear. Breast cancer treatments are associated with several side effects, with major impact on patients' quality of life and treatment adherence, particularly in premenopausal women for whom these side effects may be more prominent as the result of the abrupt decrease in estrogen concentrations. Personalized management of treatment side effects, addressing patients' concerns, and health promotion should be an integral part of the care of premenopausal women diagnosed with luminal breast cancers.

Objective: Coronavirus disease 2019 (COVID-19) poses societal challenges that require expeditious data and knowledge sharing. Though organizational clinical data are abundant, these are largely inaccessible to outside researchers. Statistical, machine learning, and causal analyses are most successful with large-scale data beyond what is available in any given organization. Here, we introduce the National COVID Cohort Collaborative (N3C), an open science community focused on analyzing patient-level data from many centers., Materials and Methods: The Clinical and Translational Science Award Program and scientific community created N3C to overcome technical, regulatory, policy, and governance barriers to sharing and harmonizing individual-level clinical data. We developed solutions to extract, aggregate, and harmonize data across organizations and data models, and created a secure data enclave to enable efficient, transparent, and reproducible collaborative analytics., Results: Organized in inclusive workstreams, we created legal agreements and governance for organizations and researchers; data extraction scripts to identify and ingest positive, negative, and possible COVID-19 cases; a data quality assurance and harmonization pipeline to create a single harmonized dataset; population of the secure data enclave with data, machine learning, and statistical analytics tools; dissemination mechanisms; and a synthetic data pilot to democratize data access., Conclusions: The N3C has demonstrated that a multisite collaborative learning health network can overcome barriers to rapidly build a scalable infrastructure incorporating multiorganizational clinical data for COVID-19 analytics. We expect this effort to save lives by enabling rapid collaboration among clinicians, researchers, and data scientists to identify treatments and specialized care and thereby reduce the immediate and long-term impacts of COVID-19., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Competing Interests: Disclosure MSA reports receipt of consultation fees from Amgen, BMS, Celgene, Clinigen, Eisai, Genomic Health, GSK, Helsinn, Hospira, JnJ, Novartis, Merck, Merck Serono, Mundipharma, Pfizer, Pierre Fabre, Roche, Sandoz, Tesaro, Tevam Vifor, G1 Therapeutics and Lilly; receipt of honoraria for symposia lectures from Amgen, Bayer, Schering, Cephalon, Chugai, Eisai, Genomic Health, GSK, Helsinn, Hospira, Ipsen, JnJ Ortho Biotech, Kyowa Hakko Kirin, Merck, Merck Serono, Mundipharma, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi, Tesaro, Taiho, Tevam Vifor, G1 Therapeutics and Lilly. CHB reports receipt of honoraria or consultation fees from Boehringer Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, MSD, AstraZeneca and Bayer; receipt of grants/research support to the institution from AbbVie, Amgen, Astellas Pharma, AstraZeneca, BMS, Celgene, Covance, Lilly, Medivation, Merck Serono, MSD, Novartis, Pfizer, PharmaMar and Roche/Genentech. JB reports receipt of grants/research support grants to Karolinska Institute and University Hospital from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, Sanofi-Aventis; no personal payments; payment from UpToDate to Asklepios Medicine HB for a chapter on breast cancer prediction. LB reports receipt of grants/research support from Celgene, Genomic Health and Novartis; receipt of honoraria or consultation fees from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Genomic Health, Ipsen, Lilly, Novartis, Pfizer, Pierre Fabre and Roche. FC reports receipt of honoraria or consultation fees from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GSK, MacroGenics, Medscape, MSD, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Sanofi, Seattle Genetics and Teva. JC reports acting as a consultant/advisor for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, MSD, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim and Kyowa Kirin; received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MSD and Daiichi Sankyo; received research funding to the institution from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffmann-La Roche, Guardant Health, MSD, Pfizer, PIQUR Therapeutics, Puma C and Queen Mary University of London; holds stock, patents and intellectual property for MEDSIR; received travel, accommodation and expenses from Roche, Novartis, Eisai, Pfizer and Daiichi Sankyo. GC reports receipt of honoraria or consultation fees from Roche, Pfizer, Lilly, Novartis and SeaGen; participation in a sponsored speakers' bureau for SeaGen, Pfizer, Lilly and Novartis. NSES reports receipt of grants/research support to institution from Novartis; receipt of honoraria or consultation fees from Novartis, Roche, Pfizer, Lilly and AstraZeneca. ME reports acting in an advisory role for Novartis and Roche. AE reports receipt of grants/research support from AstraZeneca, Roche, Celltrion, Pfizer and Novartis. LF reports receipt of grants/research support from BMS, GSK, Myriad and Novartis; receipt of honoraria or consultation fees from BMS, AstraZeneca, Teva, Novartis, Eisai, Takeda, Pfizer, Lilly, Genomic Health and Myriad. PAF reports receipt of honoraria or consultation fees from AstraZeneca and Novartis; travel for lecture for Pfizer and Ipsen. KG reports receipt of grants/research support from AstraZeneca, Pfizer and BMS; receipt of honoraria or consultation fees from Pfizer, AstraZeneca, Novartis, Nanostring, Merck, Mylan, Genomic Health, Roche and BMS. JG reports receipt of grants/research support from Amgen, Eisai, Genomic Health, Novartis, Pfizer and Roche/Genentech; receipt of honoraria or consultation fees from Daiichi, Eisai, Genomic Health, Ipsen, MacroGenics, MSD, Mylan, Novartis, Onxeo, Pfizer and Roche/Genentech; participation in a sponsored speakers' bureau for Eisai, Genomic Health, Ipsen, Novartis, Pfizer and Roche/Genentech. NH reports receipt of honoraria or consultation fees from Amgen, AstraZeneca, Celgene, Daiichi Sakyo, Lilly, MSD, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal and Seattle Genetics. RK reports receipt of grants/research support from Pfizer Malaysia. BEK reports receipt of grants/research support to institution from Roche; receipt of honoraria for advisory boards and educational presentations as well as travel and meeting expenses from Roche; receipt of honoraria for advisory boards and educational presentations from Novartis. SBK reports receipt of grants/research support to institution from Novartis, Sanofi-Aventis, Kyowa Kirin Inc. and DongKook Pharm Co.; receipt of consultancy fees from Novartis, AstraZeneca, Lilly, Enzychem, Daehwa Pharmaceutical Co. Ltd, ISU ABXIS and Daiichi Sankyo. NUL reports receipt of grants/research support from Genentech and Seattle Genetics; receipt of honoraria or consultation fees from Seattle Genetics, Daiichi Sankyo and Puma. SAM reports receipt of honoraria from Pfizer and Lilly; SN reports receipt of grants/research support from Roche, Pfizer, BMS and Novartis; participation in a sponsored speakers' bureau for Roche, Pfizer, BMS, Merck and Novartis. LN reports receipt of honoraria from Sermonix Oncology Ad Board, Prime Oncology, Sarah Lawrence Lecture, Context advisory board, Oncology Pioneers Science Lecture Series, BCRF programmatic review meeting and CSHL external advisory board meeting. SO reports receipt of grants/research support from Chugai, Eisai, Taiho, Daiichi Sankyo; participation in a sponsored speakers' bureau for Chugai, AstraZeneca, Eisai, Taiho, Pfizer and Lilly. OP reports participation in a sponsored speakers' bureau for Takeda, Roche, Pfizer, Novartis and Lilly. SPS has participated in a speakers' bureau and received honoraria from Roche, AstraZeneca, Novartis, Pfizer, Nanostring and Teva; reports consultancy for Roche, AstraZeneca, Novartis and Pfizer. FPL reports receipt of grants/research support from Roche; receipt of honoraria or consultation fees from Roche, Puma, Pierre Fabre and AstraZeneca. AP reports personal financial interests and lecture fees for Roche, Pfizer, Novartis, Amgen, BMS and Daiichi Sankyo; participation in an advisory role/consultancy for Roche, Pfizer, Novartis, Amgen, BMS, Puma and Oncolytics Biotech; institutional financial interests include contracted research for Novartis, Nanostring, Roche and Boehringer; lecture fees from Nanostring technologies; clinical trials for Novartis, Roche, Boehringer, Daiichi Sankyo, Pfizer, Lilly and Amgen. HSR reports receipt of grants/research support from Pfizer, Merck, Novartis, Lilly, Genentech, OBI, Odonate, Daiichi Sankyo, Eisai, Seattle Genetics, MacroGenics and Immunomedics. ES reports receipt of honoraria or consultation fees from Amgen, AstraZeneca, Clinigen, Egis, Eli Lilly, Genomic Health, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz and TLC Biopharmaceuticals; travel support from Amgen, AstraZeneca, Egis, Novartis, Pfizer and Roche; contracted research for Amgen, AstraZeneca, Boehringer, Eli Lilly, Merck, Novartis, Pfizer, Roche and Samsung; holds stock in Eli Lilly. EPW reports receipt of grants/research support from Merck and Genentech/Roche; receipt of honoraria or consultation fees from Carrick Therapeutics, Genentech/Roche, Genomic Health, GSK, Jounce, Leap, Lilly, Merck and Seattle Genetics; research fees to institute from Genentech/Roche and Merck; participation in a scientific advisory board for Leap. BX reports receipt of advisory fees from Novartis and Roche; fees for serving on a speakers' bureau from AstraZeneca, Pfizer, Roche and Eisai. FA, FB, BK, FEL, GWS, CT and TW have not reported any potential conflict of interest. GSB, MJC, LAC, AC, RH, XH, BVO and DAV have declared no significant conflict of interest.

Purpose: Lipophilic drugs, such as taxanes, have a high affinity for adipose tissue and a resulting higher volume of distribution. Here, we reanalyzed clinical trial data to investigate whether the efficacy of docetaxel-based chemotherapy differs from non-docetaxel-based chemotherapy in patients with breast cancer according to their baseline body mass index (BMI)., Patients and Methods: We retrospectively analyzed data from all of the patients in the adjuvant BIG 2-98 trial (ClinicalTrials.gov identifier: NCT00174655; N = 2,887) comparing non-docetaxel- to docetaxel-containing chemotherapy. BMI (kg/m 2 ) was categorized as follows: 18.5 to < 25, lean; 25 to < 30, overweight; and ≥ 30, obese. Disease-free survival (DFS) was the primary endpoint, and overall survival (OS) was the secondary endpoint. A second-order interaction was assessed among treatment, BMI, and estrogen receptor (ER) status., Results: There was no difference in DFS or OS according to BMI in the non-docetaxel group, while reduced DFS and OS were observed with increasing BMI category in the docetaxel group. Adjusted hazard ratios for DFS and OS were, respectively, 1.12 (95% CI, 0.98 to 1.50; P = .21) and 1.27 (95% CI, 1.01 to 1.60; P = .04) for overweight versus lean groups and were 1.32 (95% CI, 1.08 to 1.62; P = .007) and 1.63 (95% CI, 1.27 to 2.09; P < .001), respectively, for obese versus lean groups. Similar results were obtained when considering ER-negative and ER-positive tumors separately and when considering only patients who received a relative dose intensity ≥ 85% for docetaxel. A joint modifying role of BMI and ER status on treatment effect was evident for DFS (adjusted P = .06) and OS (adjusted P = .04)., Conclusion: This retrospective analysis of a large adjuvant trial highlights a differential response to docetaxel according to BMI, which calls for a body composition-based re-evaluation of the risk-benefit ratio of the use of taxanes in breast cancer. These results now must be confirmed in additional series.

Background: Metastatic breast cancer remains incurable. Next-generation sequencing (NGS) offers the ability to identify actionable genomic alterations in tumours which may then be matched with targeted therapies, but the implementation and utility of this approach is not well defined for patients with metastatic breast cancer., Methods: We recruited patients with advanced breast cancer of any subtype for prospective targeted NGS of their most recent tumour samples, using a panel of 108 breast cancer-specific genes. Genes were classified as actionable or non-actionable using the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) guidelines., Results: Between February 2014 and May 2019, 322 patients were enrolled onto the study, with 72% (n = 234) of patients successfully sequenced (n = 357 samples). The majority (74%, n = 171) of sequenced patients were found to carry a potentially actionable alteration, the most common being a PIK3CA mutation. Forty-three percent (n = 74) of patients with actionable alterations were referred for a clinical trial or referred for confirmatory germline testing or had a change in therapy outside of clinical trials. We found alterations in AKT1, BRCA2, CHEK2, ESR1, FGFR1, KMT2C, NCOR1, PIK3CA and TSC2 to be significantly enriched in our metastatic population compared with primary breast cancers. Concordance between primary and metastatic samples for key driver genes (TP53, ERBB2 amplification) was > 75%. Additionally, we found that patients with a higher number of mutations had a significantly worse overall survival., Conclusion: Genomic profiling of patients with metastatic breast cancer can have clinical implications and should be considered in all suitable patients.