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Background: Despite treatment advances for patients with early-stage triple-negative breast cancer (TNBC) and hormone receptor (HR)-low/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, treatments that improve clinical outcomes while mitigating toxicity are needed. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate consisting of a humanized IgG1 monoclonal antibody attached via a plasma-stable cleavable linker to a topoisomerase-I inhibitor payload, has shown efficacy alone or in combination with durvalumab, a selective, high-affinity anti-programmed cell death ligand 1 antibody, in early-phase clinical studies., Objectives: The primary objective of TROPION-Breast04 is to evaluate the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2- breast cancer., Design: This is an ongoing, international, phase III, open-label, randomized controlled study., Methods and Analysis: Approximately 1728 patients (aged ⩾18 years) will be randomized 1:1 to eight cycles of neoadjuvant Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) followed by nine cycles of adjuvant durvalumab (1120 mg IV Q3W) with or without chemotherapy versus eight cycles of pembrolizumab (200 mg IV Q3W) plus chemotherapy followed by nine cycles of adjuvant pembrolizumab (200 mg IV Q3W) with or without chemotherapy. Dual primary endpoints are pathological complete response by blinded central review and event-free survival by investigator assessment. Secondary endpoints include overall survival (key), distant disease-free survival, patient-reported outcomes, and safety., Ethics: The study is approved by independent ethics committees and/or institutional review boards at each study site. All patients will provide written informed consent., Discussion: This study will evaluate the potential use of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2- breast cancer. The findings of this trial could lead to promising treatment options for these patients., Trial Registration: ClinicalTrials.gov identifier: NCT06112379., Competing Interests: H.L.M. has participated in advisory boards with Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi-Sankyo, Seattle Genetics, AstraZeneca, Gilead, Crown Bioscience, and TapImmune; has received research grants (institution) from Bristol-Myers Squibb, BTG/Boston Scientific, and Merck. S.M.T. has acted as a consultant or advisor for Novartis, Pfizer (SeaGen), Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, CytomX Therapeutics, Daiichi-Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, and Arvinas; has received research funding (institution) from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Gilead, Seattle Genetics, OncoPep, Daiichi-Sankyo; has received travel or accommodation expenses from Eli Lilly, Sanofi, Gilead, and Jazz Pharmaceuticals. R.D. has received consulting fees from AstraZeneca, MSD, Roche, Pfizer, Eisai, Novartis, and Lilly. P.S. has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Eisai, and Celgene; conducted contracted research for Astellas, AstraZeneca, Genentech, Novartis, OncoGenex Pharmaceuticals, Roche, and Medivation. J.A. has no conflicts of interest to declare. Q.L. has acted as a speaker for Roche, AstraZeneca, Pfizer, Eisai, and Novartis; reports participation in speakers’ bureaus for Roche, AstraZeneca, Pfizer, Eisai, and Novartis; participated in advisory boards with AstraZeneca and Pfizer; has received funding from Eisai. J.L.M. has acted as a speaker for Prime Oncology and Targeted Oncology; participated in advisory boards with Sermonix; has acted as a Principal Investigator with Olema, Sermonix, and Seagen (now Pfizer); has acted as an advisor for Pfizer, Novartis, Puma, Seagen (now Pfizer), Olema, Genentech, GSK, AstraZeneca, and Sermonix. N.N. has received honoraria from AstraZeneca, Chugai Pharma, Daiichi-Sankyo/UCB Japan, Eisai, Kyowa Kirin, Lilly Japan, MSD, Novartis, Pfizer, and Taiho Pharmaceutical; has received research funding from Boehringer Ingelheim, Chugai Pharma, Daiichi-Sankyo, Eisai, Kyowa Kirin, Lilly Japan, Mochida Pharmaceutical Co. Ltd, Nihon Medi-Physics, Nippon Kayaku, Pfizer, Puma Biotechnology, Taiho Pharmaceutical, and Takeda. Y.H.P. has received honoraria from AstraZeneca, Daiichi-Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, and Roche; has acted as a consultant or advisor for AstraZeneca, Boryung, Daiichi-Sankyo, Eisai, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, and Roche; has received research funding from AstraZeneca, Gencurix, Genome Insight, NGeneBio, Pfizer, and Roche; has received travel and accommodation expenses from Gilead Sciences. G.W. has acted as a speaker for AstraZeneca, MSD, Pfizer, and Roche; participated in advisory boards with Novartis, Organon, Roche, MSD, and Daiichi-Sankyo; has received research grants from Astellas Pharma, AstraZeneca, Ipsen, Janssen, Novartis, Pfizer, Roche, Takeda, GlaxoSmithKline, Bayer, and Libbs; has acted as a Principal Investigator with AstraZeneca, BMS, Lilly, and MSD. G.B. has received honoraria from AstraZeneca/Daiichi-Sankyo, Eisai, Exact Sciences, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, Roche, and Seagen; has acted as a consultant or advisor for Agendia, AstraZeneca, AstraZeneca/Daiichi-Sankyo, Daiichi-Sankyo Europe GmbH, Eisai, Exact Sciences, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen; has received research funding (institution) from Gilead Sciences; has received travel or accommodations expenses from AstraZeneca/Daiichi-Sankyo, Gilead Sciences, Novartis, Pfizer, and Roche. J.C.A. has received honoraria from AstraZeneca, Genentech, Genomic Health, Novartis, and Puma Biotechnology; has acted as a consultant or advisor for AstraZeneca, Athenex, Daiichi-Sankyo Pharmaceutical, Genentech, Genomic Health, Immunomedics, Myriad Genetic Laboratories, Novartis, Pfizer, Puma Biotechnology, and Seagen; has participated in speakers’ bureaus with AstraZeneca, Genentech, Genomic Health, Novartis, and Puma Biotechnology. R.K. is an employee of AstraZeneca. N.R. is an employee of AstraZeneca. B.P. has received consulting fees (institutional) from AstraZeneca, Seagen, Gilead, Novartis, Lilly, MSD, Pierre Fabre (personal), and Daiichi-Sankyo (institutional/personal); has received research funding (institutional) from AstraZeneca, Daiichi-Sankyo, Gilead, Seagen, and MSD; has received travel support from AstraZeneca, Pierre Fabre, Lilly, Daiichi-Sankyo, and MSD. S.L. has acted as a consultant or advisor for AbbVie, Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, Celgene, Daiichi-Sankyo, EirGenix, Eisai Europe, GlaxoSmithKline, Lilly, Menarini Group, Merck KGaA, MSD Oncology, Novartis, Olema Pharmaceuticals, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi, and Seagen; reports participation in speakers’ bureaus for AstraZeneca, Daiichi-Sankyo Europe GmbH, Gilead Sciences, Novartis, Pfizer, Roche, and Seagen; has received research funding from AbbVie, AstraZeneca, Celgene, Daiichi-Sankyo, Gilead Sciences, Menarini Group, Molecular Health, Novartis, Pfizer, and Roche; reports patents, royalties, or other intellectual property: Digital Ki67 Evaluator, VM Scope GmbH, Patent Issued EP15702464.7, Patent Pending EP14153692.0, Patent Pending EP19808852.8, Patent Pending EP21152186.9., (© The Author(s), 2025.)

Background: Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy., Methods: We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety., Results: Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively., Conclusions: Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: In patients with early-stage triple-negative breast cancer, the phase 3 KEYNOTE-522 trial showed significant improvements in pathological complete response and event-free survival with the addition of pembrolizumab to platinum-containing chemotherapy. Here we report the final results for overall survival., Methods: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response and event-free survival. Overall survival was a secondary end point., Results: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. At the data-cutoff date (March 22, 2024), the median follow-up was 75.1 months (range, 65.9 to 84.0). The estimated overall survival at 60 months was 86.6% (95% confidence interval [CI], 84.0 to 88.8) in the pembrolizumab-chemotherapy group, as compared with 81.7% (95% CI, 77.5 to 85.2) in the placebo-chemotherapy group (P = 0.002). Adverse events were consistent with the established safety profiles of pembrolizumab and chemotherapy., Conclusions: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab resulted in a significant improvement, as compared with neoadjuvant chemotherapy alone, in overall survival among patients with early-stage triple-negative breast cancer. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Sacituzumab govitecan (SG) is a promising Trop-2-targeted antibody-drug conjugate (ADC) approved for the treatment of metastatic triple-negative breast cancer (TNBC). Early phase clinical trials have demonstrated good clinical activity and safety profile of SG in various tumor types, albeit with differing response rates and durations. The aim of this systematic review and meta-analysis was to evaluate the clinical efficacy and toxicity of SG and the influence of UGT1A1*28 genotype in clinical trials involving solid tumors., Methods: A systematic review of the literature from publicly available databases was performed on February 15, 2024 whereby studies published till 15 February 2024 were retrieved according to PRISMA guidelines [PROSPERO #CRD42022359943]. Data extracted included tumor type, sample size, demographic information, SG dose, UGT1A1*28 status, toxicity events, duration of follow-up, response, and survival outcomes. Risks of bias analysis was refereed using the Joanna Briggs Institute quality assessment tool for the cohort and RCT studies using 11 and 13 parameters, respectively. Statistical analysis was performed using the DerSimonian and Laird inverse variance methods. Heterogeneity was assessed using the I 2 statistic and Χ 2 tests. P value < 0.05 was considered as statistical significance., Results: Eleven eligible clinical trials comprised of 1578 patients harboring various tumor types including TNBC, lung, genitourinary and gastrointestinal malignancies were included in the systematic review and meta-analysis. Pooled incidences of severe adverse events were minimal at <10%, with the exception of grade 3-4 neutropenia at 37.4%. The median PFS and OS across all studies were 4.9 (95%CI: 4.0-5.8) months and 9.6 (95%CI: 7.6-11.6) months, respectively. Objective response rate across all studies evaluated was 17.1% (95%CI: 12.0-22.1)., Conclusion: Our systematic review and meta-analysis confirmed that SG confers good clinical activity in certain solid tumor types and was tolerable with minimal adverse events. The potential utility of UGT1A1*28 genotyping in predicting clinical response and outcomes could not be determined due to the limited number of studies with available UGT1A1 genotype data., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab plus chemotherapy and then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522., Methods: Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel plus carboplatin and then 4 cycles of doxorubicin (or epirubicin) plus cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23) were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1 of cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with at least 60% completion and at least 80% compliance were assessed using a longitudinal model (no alpha error assigned)., Results: Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab plus chemotherapy [n = 762] vs placebo plus chemotherapy [n = 383]) in LS mean change from baseline to week 21 in QLQ-C30 global health status/quality of life (GHS/QoL), emotional functioning, and physical functioning were -1.04 (95% confidence interval = -3.46 to 1.38), -0.69 (95% CI = -3.13 to 1.75), and -2.85 (95% CI = -5.11 to -0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [n = 539] vs placebo [n = 308]) in LS mean change from baseline to week 24 were -0.41 (95% CI = -2.60 to 1.77), -0.60 (95% CI = -2.99 to 1.79), and -1.57 (95% CI = -3.36 to 0.21)., Conclusions: No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo plus chemotherapy in early-stage TNBC., Trial Registration: ClinicalTrials.gov, NCT03036488., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Burnout and moral injury are among the most pressing issues facing healthcare and public safety today. In 2021, Congress provided $120 million through the American Rescue Plan Act for 44 Health Resources and Services Administration grants to implement evidence-informed strategies to address burnout and improve mental health among the health workforce. This article examines facilitators and barriers to implementation and reported impact of grantees' interventions., Method: Key informant interviews (n = 39) and surveys (n = 36) with grantees were conducted between May and August 2023 and qualitatively analyzed using inductive and deductive approaches., Results: This study found grantees were adapting their program modality, timing, and content to meet the needs of their workforce. Many grantees were increasingly focused on training/engaging leadership, establishing structures for worker engagement, and allowing worker voice and priorities to guide operational changes. Though many grantees could not yet report program impact, those who could provide early data documented decreases in staff turnover, burnout, and moral distress. A common challenge was ongoing resource constraints, including staff and leadership turnover., Discussion: Findings suggest health and public safety organizations continued to struggle with staffing post-COVID, increasing the challenges of implementing their programs to improve burnout and well-being. However, just 18 months into their activities, grantees reported their efforts were leading to changes in organizations, culture, and the experiences of individuals. Key lessons include the importance of engaging workers, building trust, and developing intentional communication, evaluation, and feedback strategies to advance organizational-level efforts to improve worker and learner well-being. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce., Patients and Methods: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety., Results: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure., Conclusions: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group., Patients and Methods: A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model., Results: Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group., Conclusions: Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR., Competing Interests: Disclosure All authors’ institutions received research funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, for the conduct of this study. YZ, WP, and KT are full-time employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and hold stock and/or restricted stock units in Merck & Co., Inc., Rahway, NJ, USA., (Copyright © 2024 European Society for Medical Oncology. All rights reserved.)

Approximately 60% of traditionally defined human epidermal growth factor receptor 2 (HER2)-negative breast cancers express low levels of HER2 [HER2-low; defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization (ISH)-]. HER2-low breast cancers encompass a large percentage of both hormone receptor-positive (up to 85%) and triple-negative (up to 63%) breast cancers. The DESTINY-Breast04 trial established that HER2-low tumors are targetable, leading to the approval of trastuzumab deruxtecan (T-DXd) as the first HER2-directed therapy for the treatment of HER2-low breast cancer in the United States and Europe. This change in the clinical landscape results in a number of questions and challenges-including those related to HER2 assessment and patient identification-and highlights the need for careful assessment of HER2 expression to identify patients eligible for T-DXd. This review provides context for understanding how to identify patients with HER2-low breast cancer with respect to sample types, scoring and reporting HER2 status, and testing methods and assays. It also discusses management of important T-DXd-related adverse events. Available evidence supports the efficacy of T-DXd in patients with any history of IHC 1+ or IHC 2+/ISH- scores; however, future research may further refine the population who could benefit from T-DXd or other HER2-directed therapies and identify novel methods for patient identification. Because HER2 expression can change with disease progression or treatment, and variability exists in scoring and interpretation of HER2 status, careful re-evaluation in certain scenarios may help to identify more patients who may benefit from T-DXd., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: We explored the efficacy of PARP inhibition with or without programmed death ligand-1 (PD-L1) blockade as chemotherapy-free maintenance therapy for advanced triple-negative breast cancer (aTNBC) sensitive to platinum-based chemotherapy., Patients and Methods: In the phase II non-comparative DORA trial (NCT03167619), patients with ongoing stable disease (SD) or complete/partial response (CR/PR) to first- or second-line platinum-based chemotherapy for TNBC (≤10% estrogen/progesterone receptor expression) were randomized 1:1 to receive olaparib 300 mg twice daily with or without durvalumab 1,500 mg on day 1 every 4 weeks. The primary objective was to compare progression-free survival (PFS) versus a historical control of continued platinum-based therapy., Results: 45 patients were randomized (23 to olaparib alone, 22 to the combination; 3 with estrogen/progesterone receptor expression 1%-10%). At 9.8 months' median follow-up, median PFS from randomization was 4.0 [95% confidence interval (CI), 2.6-6.1] months with olaparib and 6.1 (95% CI, 3.7-10.1) months with the combination, both significantly longer than the historical control (P = 0.0023 and P < 0.0001, respectively). Clinical benefit rates (SD ≥24 weeks or CR/PR) were 44% (95% CI, 23%-66%) and 36% (95% CI, 17%-59%) in the monotherapy and combination arms, respectively. Sustained clinical benefit was seen irrespective of germline BRCA mutation or PD-L1 status, but tended to be associated with CR/PR to prior platinum, particularly in the olaparib-alone arm. No new safety signals were reported., Conclusions: PFS was longer than expected with both regimens. A patient subset with wild-type BRCA platinum-sensitive aTNBC had durable disease control with chemotherapy-free maintenance., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC)., Patients and Methods: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance., Results: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels., Conclusions: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: In KEYNOTE-119 (ClinicalTrials.gov, NCT02555657), overall survival (primary end-point) was similar between pembrolizumab and chemotherapy in patients with previously treated metastatic triple-negative breast cancer (TNBC), although the pembrolizumab treatment effect increased with tumour PD-L1 expression. We report results of prespecified health-related quality of life (HRQoL) analyses from KEYNOTE-119., Methods: Eligible patients were randomised 1:1 to pembrolizumab 200 mg Q3W intravenously for up to 35 cycles or treatment of physician's choice per local/country guidelines. Prespecified exploratory end-points were the change from baseline in HRQoL (EORTC QLQ-C30, QLQ-BR23) and to characterise utilities (EQ-5D-3L). Time to deterioration (TTD) was the time from start of treatment to first onset of a ≥10-point worsening from baseline., Results: HRQoL analyses included 187 patients with tumour PD-L1 combined positive score (CPS) ≥10. Changes from baseline at 6 weeks (primary analysis time point) were directionally better with pembrolizumab versus chemotherapy for QLQ-C30 GHS/QoL (between-group difference in least-squares mean scores of 4.21 [95% CI, -1.38 to 9.80]), QLQ-C30 functional scales (physical, role, cognitive, social), QLQ-C30 symptom scales/items (fatigue, nausea/vomiting, dyspnoea, appetite loss), and QLQ-BR23 symptom scales/items (systemic therapy side-effects, upset by hair loss). Median TTD was directionally longer for pembrolizumab versus chemotherapy for QLQ-C30 QHS/QoL (4.3 versus 1.7 months), QLQ-C30 nausea/vomiting (7.7 versus 4.8 months), and QLQ-BR23 systemic therapy side-effects (6.1 versus 3.4 months). Minimal treatment differences were observed for other HRQoL end-points., Conclusions: HRQoL results were consistent with clinical outcomes and appeared to be driven by results for patients with tumour PD-L1 CPS ≥10., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter Schmid: Consultant/Honoraria: AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Merck Sharp, and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Puma, and Roche; grant funding to institution: Astellas, AstraZeneca, Genentech, Medivation, Novartis, Oncogenex, and Roche. Oleg Lipatov: Nothing to disclose. Seock-Ah Im: consulting/advisory role: AstraZeneca, Novartis, Roche/Genentech, Pfizer, Amgen, Hanmi, Lilly, GlaxoSmithKline, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Daiichi Sankyo, Idience Co. Ltd., and Bertis; research funding to institution: AstraZeneca, Pfizer, Roche/Genentech, Daewoong Pharmaceutical, Eisai Korea, and Boryung Pharm. Anthony Goncalves: Nonfinancial support/consultant (compensated to hospital): AstraZeneca, Novartis, Astellas, Pfizer, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Lilly, Mylan, Parexel, and Roche. Eva Muñoz-Couselo: Nothing to disclose. Keun Seok Lee: Consultant: Lilly, Novartis, Pfizer, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Bixink, Everest Medicine, Daiichi Sankyo, and Roche; drug supplies: Dong-A Pharm. Kenji Tamura: Nothing to disclose. Laura Testa: Funding for the current trial conduct, provision of study materials, medical writing, and article processing charges: Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; research grant: Novartis; payment or honoraria for medical education: Lilly, Novartis, Pfizer, AstraZeneca, Daiichi-Sankyo, and Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; support for attending meetings and/or travel: Roche, Gilead, and AstraZeneca; Data Safety Monitoring/Advisory board: AstraZeneca, Lilly, Novartis, Merck Sharp, and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Daichi-Sankyo, and Pfizer; steering committee for trials: AstraZeneca and Lilly. Isabell Witzel: Research funding to institution: Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; personal fees: Daiichi Sankyo, Merck Sharp, and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, and Roche. Shoichiro Ohtani: Lecture fees: AstraZeneca, Chugai, Lilly, and Pfizer. Nicholas Turner: Advisory board honoraria: AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GlaxoSmithKline, Repare Therapeutics, Relay Therapeutics, Zentalis, Gilead, Inivata, Guardant, and Exact Sciences; research funding: AstraZeneca, Pfizer, Roche/Genentech, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Guardant Health, Invitae, Inivata, Personalis, and Natera. Stefania Zambelli: Nothing to disclose. Nadia Harbeck: Consulting/Lecture fees: AstraZeneca, Daiichi Sankyo, Lilly, Merck Sharp, and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, and Seattle Genetics. Fabrice Andre: Research grants to institution: AstraZeneca, Daiichi Sankyo, Lilly, Novartis, Pfizer, and Roche; Advisory board or speaker (compensation to institution): AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, and Guardant Health; and personal fees (advisory board): Lilly. Rebecca Dent: Advisory board: AstraZeneca, Eisai, Eli Lilly and Company, Genentech, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, and Pfizer; Consultant: Genentech; Travel: Genentech, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Pfizer. Jaime A. Mejia: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; owns stock in Merck & Co., Inc., Rahway, NJ, USA. Xuan Zhou: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; owns stock in Merck & Co., Inc., Rahway, NJ, USA. Amin Haiderali: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; owns stock in Merck & Co., Inc., Rahway, NJ, USA. Allison Martin Nguyen: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; owns stock in Merck & Co., Inc., Rahway, NJ, USA. Javier Cortes: Consulting fees: AstraZeneca, Athenex, Bioasis, BioInvent, Boehringer Ingelheim, Celgene, Cellestia, Clovis Oncology, Daiichi Sankyo, Ellipses, Erytech, Gemoab, Gilead, GSK, Hibercell, Leuko, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Polyphor, Roche, and Seattle Genetics; fees for non-CME services received directly from commercial interest or their agents (e.g., speakers' bureaus): Celgene, Daiichi Sankyo, Eisai, Lilly, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Pfizer, Roche, and Samsung Bioepis; contracted research: Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Pfizer, Piqur Therapeutics, Puma, Queen Mary University of London, and Roche; Ownership interest (stock, stock options, or other ownership interest excluding diversified mutual funds): MedSIR; Travel/Accommodation: Daiichi Sankyo, Eisai, Novartis, Pfizer, and Roche; Patent: HER2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Eric P. Winer: Advisory board member: LEAP; Consultant: G1 Therapeutics, Garrick Therapeutics, Genomic Health, GlaxoSmithKline, Jounce, Lilly, Novartis, Roche Genentech, Seattle Genetics, and Syros., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Importance: In the phase 3 KEYNOTE-522 study, addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab significantly increased pathologic complete response (pCR) and event-free survival (EFS) vs neoadjuvant chemotherapy in patients with early triple-negative breast cancer., Objective: To evaluate efficacy and safety outcomes for patients enrolled in East/Southeast Asia (Asia) in KEYNOTE-522., Design, Setting, and Participants: KEYNOTE-522, a multicenter, double-blind, randomized clinical trial, enrolled 1174 patients between March 7, 2017, and September 13, 2018. For interim EFS and overall survival (OS) analyses (data cutoff, March 23, 2021), median follow-up was 39.8 months (range, 30.4-46.9 months) for pembrolizumab plus chemotherapy and 40.8 months (range, 30.1-46.9 months) for placebo plus chemotherapy. Data cutoff for pCR analysis was September 24, 2018. This secondary analysis included adults enrolled in Asia with newly diagnosed, previously untreated, nonmetastatic triple-negative breast cancer (tumor stage T1c and nodal stage N1-2 or tumor stage T2-4 and nodal stage N0-2) and Eastern Cooperative Oncology Group performance status of 0 to 1, regardless of programmed cell death ligand 1 (PD-L1) status., Intervention: Patients were randomized 2:1 to 4 cycles of pembrolizumab (200 mg every 3 weeks) or placebo plus carboplatin and paclitaxel and another 4 cycles of pembrolizumab or placebo plus doxorubicin or epirubicin and cyclophosphamide before surgery. After definitive surgery, patients received pembrolizumab or placebo every 3 weeks for 9 cycles or until recurrence or unacceptable toxic effects., Main Outcomes and Measures: The main outcome was pCR (no evidence of primary tumor after neoadjuvant therapy or carcinoma in situ after neoadjuvant therapy and no regional lymph node involvement after neoadjuvant therapy) at the time of definitive surgery and EFS., Results: A total of 216 of 1174 randomized patients (all female; median [range] age, 46.0 [24.0-71.0] years) were from Korea, Japan, Taiwan, and Singapore (136 in the pembrolizumab plus chemotherapy group and 80 in the placebo plus chemotherapy group). Of these patients, 104 (76.5%) in the pembrolizumab plus chemotherapy group and 60 (75.0%) in the placebo plus chemotherapy group had a tumor PD-L1 combined positive score of 1 or greater. Pathologic complete response was 58.7% (95% CI, 46.7%-69.9%) with pembrolizumab plus chemotherapy and 40.0% (95% CI, 26.4%-54.8%) with placebo plus chemotherapy; benefit was observed regardless of PD-L1 status. Thirteen patients (9.6%) in the pembrolizumab plus chemotherapy group and 20 patients (25.0%) in the placebo plus chemotherapy group had EFS events (hazard ratio, 0.35; 95% CI, 0.17-0.71). The 36-month EFS rate was 91.2% (95% CI, 85.0%-94.9%) with pembrolizumab plus chemotherapy and 77.2% (95% CI, 66.3%-85.0%) with placebo plus chemotherapy. Grade 3 to 4 treatment-related adverse events occurred in 109 patients (80.1%) receiving pembrolizumab plus chemotherapy and 64 patients (81.0%) receiving placebo plus chemotherapy., Conclusions and Relevance: In this subgroup analysis of patients enrolled in Asia in KEYNOTE-522, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab led to clinically meaningful improvements in pCR and EFS vs neoadjuvant chemotherapy alone. These findings support the use of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab as a standard-of-care therapy for patients in Asian countries with early triple-negative breast cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT03036488.

Objective: Full meal replacement (FMR) Intensive Lifestyle Interventions (ILI) have been used for weight management. However, predictors of efficacy with these programs are less clear. The primary objective was to assess weight loss predictors in a community-based FMR ILI program. A secondary objective was to determine if weight loss was different between virtual and in person ILI., Methods: This was a retrospective cohort study involving 234 patients who started the program between 1 January 2016 and 3 March 2021. In the 24-week program, patients spent 12 weeks on FMR and then transitioned back to food for the remainder, with weekly follow up with a physician and group sessions with a dietitian. Visits were in person prior to March 2020 and virtual afterward., Results: Patients' average age was 47.5 years (SD = 12.0) and 73.5% were female. Average weight loss was 14.3% (SD = 6.2%). There was no significant difference in weight loss between virtual and in person programs. Patients on a Glucagon-like Peptide-1 Receptor Agonist prior lost less weight. Other significant associations between groups were baseline Hemoglobin A 1 C, classes attended, as well as the age since peak weight., Conclusion: Weight loss from virtual ILI was not significantly different from person ILI. More research is needed to determine how to best stratify care as virtual or in person using FMR programs., Competing Interests: We have no conflicts of interest to disclose., (© 2023 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Trastuzumab deruxtecan (T-DXd)-an antibody-drug conjugate targeting the human epidermal growth factor receptor 2 (HER2)-improved outcomes of patients with HER2-positive and HER2-low metastatic breast cancer. Guidance on monitoring and managing T-DXd-related adverse events (AEs) is an emerging unmet need as translating clinical trial experience into real-world practice may be difficult due to practical and cultural considerations and differences in health care infrastructure. Thus, 13 experts including oncologists, pulmonologists and a radiologist from the Asia-Pacific region gathered to provide recommendations for T-DXd-related AE monitoring and management by using the latest evidence from the DESTINY-Breast trials, our own clinical trial experience and loco-regional health care considerations. While subgroup analysis of Asian (excluding Japanese) versus overall population in the DESTINY-Breast03 uncovered no major differences in the AE profile, we concluded that proactive monitoring and management are essential in maximising the benefits with T-DXd. As interstitial lung disease (ILD)/pneumonitis is a serious AE, patients should undergo regular computed tomography scans, but the frequency may have to account for the median time of ILD/pneumonitis onset and access. Trastuzumab deruxtecan appears to be a highly emetic regimen, and prophylaxis with serotonin receptor antagonists and dexamethasone (with or without neurokinin-1 receptor antagonist) should be considered. Health care professionals should be vigilant for treatable causes of fatigue, and patients should be encouraged to use support groups and practice low-intensity exercises. To increase treatment acceptance, patients should be made aware of alopecia risk prior to starting T-DXd. Detailed monitoring and management recommendations for T-DXd-related AEs are discussed further., (© 2023. The Author(s).)

Models predicting individual body weights over time clarify patient expectations in weight loss programs. The accuracy of two commonly used weight prediction models in community living people is unclear. All eligible people entering a weight management program between 1992 and 2015 were included. Patients' diet was 1200 kcal/day for week 0 followed by 900 kcal/day for weeks 1-7 and were excluded from the analysis if they were nonadherent. We generated expected weights using the National Institutes of Health Body Weight Planner (NIH-BWP) and the Pennington Biomedical Research Center Weight Loss Predictor (PBRC-WLP). 3703 adherent people were included (mean age 46 years, 72.6% women, mean [SD] weight 262.3 pounds [54.2], mean [SD] BMI 42.4 [7.6]). Mean (SD) relative body weight differences (100*[observed-expected]/expected) for NIH-BWP and PBRC-WLP models was - 1.5% (3.8) and - 2.9% (3.2), respectively. At week 7, mean squared error with NIH-BWP (98.8, 83%CI 89.7-108.8) was significantly lower than that with PBRC-WLP (117.7, 83%CI 112.4-123.4). Notable variation in relative weight difference were seen (for NIH-BWP, 5th-95th percentile was - 6.2%, + 3.7%; Δ 9.9%). During the first 7 weeks of a weight loss program, both weight prediction models returned expected weights that were very close to observed values with the NIH-BWP being more accurate. However, notable variability between expected and observed weights in individual patients were seen. Clinicians can monitor patients in weight loss programs by comparing their progress with these data., (© 2023. The Author(s).)

Stratification of recurrence risk is a cornerstone of early breast cancer diagnosis that informs a patient's optimal treatment pathway. Several tools exist that combine clinicopathological and molecular information, including multigene assays, which can estimate risk of recurrence and quantify the potential benefit of different adjuvant treatment modalities. While the tools endorsed by treatment guidelines are supported by level I and II evidence and provide similar prognostic accuracy at the population level, they can yield discordant risk prediction at the individual patient level. This review examines the evidence for these tools in clinical practice and offers a perspective of potential future risk stratification strategies. Experience from clinical trials with cyclin D kinase 4/6 (CDK4/6) inhibitors in the setting of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer is provided as an illustrative example of risk stratification., (© 2023. The Author(s).)

Background: Following a European Society for Medical Oncology Women for Oncology (ESMO W4O) survey in 2016 showing severe under-representation of female oncologists in leadership roles, ESMO launched a series of initiatives to address obstacles to gender equity. A follow-up survey in October 2021 investigated progress achieved., Materials and Methods: The W4O questionnaire 2021 expanded on the 2016 survey, with additional questions on the impact of ethnicity, sexual orientation and religion on career development. Results were analysed according to respondent gender and age., Results: The survey sample was larger than in 2016 (n = 1473 versus 482), especially among men. Significantly fewer respondents had managerial or leadership roles than in 2016 (31.8% versus 51.7%). Lack of leadership development for women and unconscious bias were considered more important in 2021 than in 2016. In 2021, more people reported harassment in the workplace than in 2016 (50.3% versus 41.0%). In 2021, ethnicity, sexual orientation and religion were considered to have little or no impact on professional career opportunities, salary setting or related potential pay gap. However, gender had a significant or major impact on career development (25.5% of respondents), especially in respondents ≤40 years of age and women. As in 2016, highest ranked initiatives to foster workplace equity were promotion of work-life balance, development and leadership training and flexible working. Significantly more 2021 respondents (mainly women) supported the need for culture and gender equity education at work than in 2016., Conclusions: Gender remains a major barrier to career progression in oncology and, although some obstacles may have been reduced since 2016, we are a long way from closing the gender gap. Increased reporting of discrimination and inappropriate behaviour in the workplace is a major, priority concern. The W4O 2021 survey findings provide new evidence and highlight the areas for future ESMO interventions to support equity and diversity in oncology career development., (Copyright © 2023 European Society for Medical Oncology (ESMO). Published by Elsevier Ltd.. All rights reserved.)

The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4-hydroxy-tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6). Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross-ancestry genome-wide association study with well-characterized patients of European, Middle-Eastern, and Asian descent (n = 497) to identify genetic factors impacting active and parent metabolite formation. Genome-wide significant variants were functionally evaluated in an independent liver cohort (n = 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (n = 287, n = 189). Within a single 1-megabase (Mb) region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and metabolic ratio (MR) endoxifen/N-desmethyltamoxifen (minimal P = 5.4E-35 and 2.5E-65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (ρ = 0.35 to -0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (n = 12) plus CYP2D6 activity score (AS) increased the explained variability (~ 9%) compared with AS alone, explaining up to 49% (median R 2 ) and 72% of the variability in endoxifen and MR endoxifen/N-desmethyltamoxifen, respectively. Our findings suggest that the extended CYP2D6 locus at 22q13 is the principal genetic determinant of endoxifen plasma concentration. Long-distance haplotypes connecting CYP2D6 with adjacent regulatory sites and nongenetic factors may account for the unexplained portion of variability., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This article describes the "The Admissions Revolution: Bold Strategies for Diversifying the Healthcare Workforce" conference, which preceded the 2022 Beyond Flexner Alliance Conference and called for health professions institutions to boldly reimagine the admission process to diversify the health care workforce. Proposed strategies encompassed 4 key themes: admission metrics, aligning admission practices with institutional mission, community partnerships to fulfill social mission, and student support and retention. Transformation of the health professions admission process requires broad institutional and individual effort. Careful consideration and implementation of these practices will help institutions achieve greater workforce diversity and catalyze progress toward health equity., Competing Interests: Conflicts of interest: authors report none., (© 2023 Annals of Family Medicine, Inc.)

Contamination of pulse compression gratings during the manufacturing process is known to give rise to reduced laser damage performance and represents an issue that has not yet been adequately resolved. The present work demonstrates that the currently used etching methods introduce carbon contamination inside the etched region extending to a 50- to 80-nm layer below the surface. This study was executed using custom samples prepared in both, a laboratory setting and by established commercial vendors, showing results that are very similar. The laser-induced-damage performance of the etched and unetched regions in the grating-like samples suggest that contaminants introduced by etching process are contributing to the reduction of the laser-induced damage threshold.

Purpose: Roux-en-Y gastric bypass (RYGB) surgery produces significant weight loss. However, a number of patients experience weight regain years after surgery. Factors driving weight regain after surgical interventions are currently being explored. Our objective was to investigate appetite-related measures associated with weight regain after RYGB surgery., Materials and Methods: Using a cross-sectional design, 29 participants (49.6 ± 9.1 years of age; current BMI 32.4 ± 4.7 kg/m 2 , 43.6 ± 8.9 months post-RYGB) were stratified into tertiles according to weight regain per month after nadir (weight maintenance (WM), n = 9; low weight regain (LWR), n = 10; and high weight regain (HWR), n = 10). The average weight regain was, by design, significantly different between the groups (WM = 2.2 ± 2.5 kg; LWR = 10.0 ± 3.4 kg; HWR = 14.9 ± 6.3 kg regained, p < 0.05). Appetite (visual analog scales), olfactory performance ("sniffin sticks"), eating behaviors (Three Factor Eating Questionnaire), food reward (Leeds Food Preference Questionnaire), and appetite-related hormones (ghrelin, PYY, GLP-1 and leptin) were measured fasting and in response to a standardized test meal., Results: Dietary restraint was significantly higher than clinical cutoffs in WM and LWR (p < 0.05). As expected, significant time effects were noted for ghrelin, PYY, and GLP-1, but there were no group differences., Conclusion: The results suggest that appetite-related outcomes are similar across individuals who have maintained weight loss and experienced regain following RYGB., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Obesity derives from an extended period of positive energy imbalance due to a complex interplay of environmental and biological factors. Muscle fiber type and physiology have been hypothesized to affect metabolism and energy expenditure and thus to affect an individual's propensity to gain weight. However, there have been conflicting reports regarding a relationship between muscle fiber type and obesity. Here, we systematically reviewed literature investigating this topic from PubMed, Web of Science, and EMBASE. Of these, 32 articles were included in our final review and analysis. Most studies (22/32) reported a significant relationship between muscle fiber-type proportion and a measure of obesity. Overall, there was a significant negative relationship between the proportion of type I fibers and body mass index (BMI) and a significant positive relationship between the proportion of type IIX fibers and BMI. Moreover, between-group comparisons indicated a greater prevalence of type IIX fibers and a lower prevalence of type I fibers in patients living with obesity relative to lean individuals. These significant relationships were confirmed in a meta-analysis of these data. The causal nature of these associations remains to be evaluated., (© 2022 World Obesity Federation.)

In July 2019, the National Institute for Health and Care Excellence (NICE) initiated a major review of its health technology evaluation methods to update its methods guide. This update has recently concluded with the publication of its health technology evaluation manual in January 2022. This paper reports the methods and findings of the review in relation to the recommended approach to use for the measurement and valuation of health-related quality of life (HRQoL) in submissions to NICE. Issues related to (i) the methods to use when NICE's preferred measure (EQ-5D) is not appropriate or not available; (ii) adjusting health state utility values over time to account for age; (iii) measuring and valuing HRQoL in children and young people; and (iv) including carers' QoL in economic evaluations were included in this review. This commentary summarises the methods used to undertake the review, its findings, and the changes to NICE methods that were proposed based on these findings. It also outlines topics where further research is needed before definitive methods guidance can be issued. The broad proposals described here were subject to a public consultation in 2020 and a further consultation on the updated methods guidance was completed in October 2021 before the publication of the manual in January 2022., (© 2022. The Author(s).)

Background: The hypothesis that breast cancer (BC) susceptibility variants are linked to chemotherapy-induced toxicity has been previously explored. Here, we investigated the association between a validated 313-marker-based BC polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever and febrile neutropenia (FNc) in Asian BC patients., Methods: This observational case-control study of Asian BC patients treated with chemotherapy included 161 FNc patients, 219 neutropenia patients, and 936 patients who did not develop neutropenia. A continuous PRS was calculated by summing weighted risk alleles associated with overall, estrogen receptor- (ER-) positive, and ER-negative BC risk. PRS distributions neutropenia or FNc cases were compared to controls who did not develop neutropenia using two-sample t -tests. Odds ratios (OR) and corresponding 95% confidence intervals were estimated for the associations between PRS (quartiles and per standard deviation (SD) increase) and neutropenia-related outcomes compared to controls., Results: PRS distributions were not significantly different in any of the comparisons. Higher PRS overall quartiles were negatively correlated with neutropenia or FNc. However, the associations were not statistically significant (PRS per SD increase OR neutropenia: 0.91 [0.79-1.06]; FNc: 0.87 [0.73-1.03]). No dose-dependent trend was observed for the ER-positive weighted PRS (PRS ER-pos ) and ER-negative weighted PRS (PRS ER-neg )., Conclusion: BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.

Objectives: Our aim in this study was to compare the change in waist circumference given the same degree of weight loss in patients who meet the criteria for metabolic syndrome or type 2 diabetes and those who do not meet these criteria. Because visceral adiposity is a key feature of both conditions and intra-abdominal adipocytes show higher lipolytic activity, we sought to determine whether changes in waist circumference differed in individuals with and without these conditions., Methods: The Ottawa Hospital Weight Management Clinic offers a course in lifestyle modification and uses 12 weeks of total meal replacement. We compared the decrease in waist circumference between patients with metabolic syndrome or diabetes and those without these conditions who had lost a similar amount of weight using measurements from the first 6 weeks of meal replacement., Results: We evaluated 3,559 patients who attended the program between September 1992 and April 2015. The patient population was largely Caucasian and of European descent and all meetings were face to face. The mean weight loss for men was 15.1±20.2 kg, and the mean weight loss for women was 9.7±2.4 kg. There were no significant differences in decrease in waist circumference between those with and without metabolic syndrome in both men (11.7±3.9 cm vs 11.4±3.8 cm, p=0.48) and women (9.0±3.6 cm vs 9.1±3.7 cm, p=0.26)., Conclusions: Our results show that, given the same degree of weight loss, patients with and without diabetes or metabolic syndrome experience a similar change in waist circumference., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: The addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early triple-negative breast cancer having a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery in an earlier analysis of this phase 3 trial of neoadjuvant and adjuvant therapy. The primary results regarding event-free survival in this trial have not been reported., Methods: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response (the results for which have been reported previously) and event-free survival, defined as the time from randomization to the date of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also assessed., Results: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. The median follow-up at this fourth planned interim analysis (data cutoff, March 23, 2021) was 39.1 months. The estimated event-free survival at 36 months was 84.5% (95% confidence interval [CI], 81.7 to 86.9) in the pembrolizumab-chemotherapy group, as compared with 76.8% (95% CI, 72.2 to 80.7) in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% CI, 0.48 to 0.82; P<0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy., Conclusions: In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.)., (Copyright © 2022 Massachusetts Medical Society.)

Purpose: Given known differences between real-world and clinical trial populations, we characterized demographics, clinical characteristics, and outcomes using real-world (RW) data for patients with heart failure with reduced ejection fraction (HFrEF), including those similar to subjects enrolled in an HFrEF clinical trial to better understand patient populations that could benefit from novel therapies., Patients and Methods: Using Vanderbilt University Medical Center electronic health records (2006-2019), two RW cohorts of HFrEF patients were identified. The "Clinical Cohort" was based on a validated HFrEF algorithm and left ventricular ejection fraction (LVEF) ≤40%. The "GALACTIC-HF-like Cohort" mirrored enrollment requirements of the GALACTIC-HF clinical trial including hospitalizations, medications, laboratory values, and LVEF ≤35%., Results: Median age at index for the Clinical Cohort (N = 3954) and GALACTIC-HF-like Cohort (N = 1541) were 65 and 61 years, respectively; both were 67% male and 80% white. Over half had coronary artery disease (55% Clinical vs 64% GALACTIC-HF-like); hypercholesterolemia was common (69% Clinical vs 74% GALACTIC-HF-like). Chronic kidney disease (31 vs 21%), atrial fibrillation (32 vs 29%), and cardiac resynchronization or implantable cardioverter defibrillator (26 vs 23%) were higher in the GALACTIC-HF-like Cohort. ACE inhibitor use was high in both groups but more common in the GALACTIC-HF-like Cohort (71% and 82%, respectively). Beta-blockers or loop diuretics were used by >90% of both cohorts. HF hospitalization rates were 261 (95% CI 224, 297) per 1000 person-years in Clinical versus 523 (484, 562) in GALACTIC-HF-like Cohort (median follow-up of 2.9 and 4.2 years, respectively)., Conclusion: Approximately 40% of RW HFrEF patients met criteria for the GALACTIC-HF trial. While findings of ongoing clinical trials may be directly generalizable to this sizable proportion of patients, future trials should examine whether the majority of patients with lower prevalence of comorbidities and rate of HF hospitalization could benefit from emerging HF treatments., Competing Interests: Paul Dluzniewski, Ricardo Dent, and John Umeijiego are employees and stockholders of Amgen, Inc. Sarah S Cohen is an employee of EpidStrategies, A D ivision of ToxStrategies, Inc., who received research funds from Amgen, Inc. All other authors have no financial or non-financial interests to declare., (© 2022 Wells et al.)

Background: Evidence to date supports continued human epidermal growth factor receptor 2 (HER2) suppression beyond progression on HER2-directed therapy for advanced HER2-positive breast cancer. Data from several phase II and III trials evaluating HER2-directed therapy following second-line T-DM1 have recently become available., Methods: We performed a systematic search of the published and presented literature to identify phase II and phase III trials assessing novel HER2-targeted agents as third-line therapy or beyond for HER2-positive advanced breast cancer using search terms 'breast cancer' AND 'HER2' AND 'advanced' AND ('phase II' OR 'phase III')., Results: Eight clinical trials reporting efficacy outcomes on third-line or greater HER2-directed therapy for HER2-positive advanced breast cancer were identified. In phase III trials, margetuximab and neratinib combinations demonstrated significant 1.3-month (hazard ratio, HR = 0.71, p  < 0.001) and 0.1-month (HR = 0.76, p  = 0.006) net improvements in median progression-free survival (PFS), respectively, with no significant improvements in overall survival (OS). Tucatinib added to trastuzumab and capecitabine demonstrated a significant 2.7-month improvement in median PFS (HR = 0.57, p  < 0.00001) and a 5.5-month improvement in median OS (HR = 0.73, p  = 0.004) in a randomized phase II trial, including significant clinical benefit for patients with brain metastases. Finally, trastuzumab-deruxtecan, zenocutuzumab, and poziotinib demonstrated benefit in phase II trials with the most robust overall response rate (62.0%) and median duration of response (18.2 months) observed for trastuzumab-deruxtecan among heavily pretreated patients., Conclusion: Tucatinib plus trastuzumab and capecitabine significantly prolongs OS, and promising preliminary response outcomes for trastuzumab-deruxtecan suggest that sequencing of these regimens following second-line therapy is reasonable., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Christine Simmons has served in a consultancy or advisory role and received honorarium from Pfizer, Eli Lilly, Roche, and Mylan, and has received research funding from AstraZeneca Global, Roche, Knight Therapeutics, Viatris, and Pfizer. Daniel Rayson has served in a consultancy or advisory role and received honorarium from AstraZeneca, Pfizer, Eli Lilly, Merck, Gilead, Novartis, and Seagen. Anil Abraham Joy has served in a consultancy or advisory role and received honorarium from AstraZeneca, BMS, Eli Lilly, Knight Therapeutics, Gilead, Roche, Novartis, Pfizer, Mylan, and Teva. Jan-Willem Henning has served in a consultancy or advisory role and received honorarium from AstraZeneca, Pfizer, Novartis, Eli Lilly, Roche, Knight Therapeutics, Seagen, and Mylan. Julie Lemieux has served in a consultancy or advisory role and received honorarium from Novartis, Eli Lilly, Gilead, Pfizer, and AstraZeneca, and has received research funding from Celgene, Genentech, GlaxoSmithKline, Roche, Millennium, Novartis, Merck Gilead, Abbvie, Acerta, Bayer, Pfizer, BMS, Esai, Sanofi, Janssen, Ozmosys, Sierra Astrazeneca, and Takeda. Heather McArthur has served in a consultancy or advisory role and received honorarium from Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Puma Biotechnology, Daiichi-Sankyo, Seattle Genetics, Merck, and Lilly, and has received research funding from Bristol-Myers Squibb, MedImmune, LLC/AstraZenica, BTG, and Merck. Paul B. Card has nothing to declare. Rebecca Dent has served in a consultancy or advisory role and received honorarium from AstraZeneca, Viatris, Pfizer, Eisai, Merck, Eli Lilly, Novartis, and Roche, and has received research funding from AstraZeneca. Christine Brezden-Masley has served in a consultancy or advisory role and received honorarium from AstraZeneca, Eli Lilly, Knight Therapeutics, Mylan, Gilead, Roche, Amgen, Seagen, and Novartis, and has received research funding from Eli Lilly and AstraZeneca., (© The Author(s), 2022.)

Competing Interests: Disclosure FA reports receipt of research funding and has served as speaker/advisor (compensated to the hospital) for Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis and Eli Lilly. CHB reports grants/research support (to the institution) from Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline (GSK), Roche/Genentech, Eli Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, AbbVie, Astellas Pharma, BioMarin, Bristol-Myers Squibb (BMS), Daiichi Sankyo, Abraxis Biosciences, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, Merck KGaA, Shanghai Henlius Biotech, Polyphor and PharmaMar; ownership or stocks in Biomarker, Tummi and MEDSir; and advisory boards and consulting for Boehringer Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, Merck Sharp & Dohme (MSD), AstraZeneca, Zodiac, Eli Lilly and Sanofi. JC has served as a consultant/advisor for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, MSD, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab and Gilead; received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Eli Lilly, MSD and Daiichi Sankyo; received research funding to the institution from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GmbH/Servier Affaires, Bayer Healthcare, Eisai, Roche, Guardanth Health, MSD, Pfizer, Piqur Therapeutics, Puma C and Queen Mary University of London; owns stock, patents and intellectual property for MedSIR; and received travel, accommodation and expenses from Roche, Novartis, Eisai, Pfizer and Daiichi Sankyo. GC has served as consultant or advisor for Roche, Eli Lilly and BMS; served on a speaker’s bureau for Roche, Pfizer and Eli Lilly; received travel funding from Pfizer and Roche; and received honoraria from Roche, Pfizer, Eli Lilly, Novartis, AstraZeneca and SeaGen, all outside the submitted work. EdA reports honoraria and/or advisory boards for Roche/Genentech, Novartis, Seattle Genetics, Zodiacs, Libbs and Pierre Fabre and Eli Lilly; travel grants from Roche/Genentech and GSK/Novartis; and research grants for his institute from Roche/Genentech, AstraZeneca, Novartis and Servier. AD reports research funding to institute from Genentech, Novartis, Pfizer and Calithera. RD reports research funding from AstraZeneca; and honoraria for consultancy/advisory board participation from AstraZeneca, Eisai, Eli Lilly, Novartis, Pfizer and Roche. DF reports honoraria for participation in symposia from Roche. AG reports honoraria for advisory boards from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Pfizer and Roche; honoraria for lectures from Eisai and Eli Lilly; and honoraria for expert testimony from Gentili. JG has served as a consultant/advisor for AstraZeneca, Daiichi Sankyo, Eisai, Exact Science, Eli Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Roche/Genentech and Seattle Genetics; received honoraria from AGM communication, Amgen, AstraZeneca, Daiichi Sankyo, Decision Santé, Edimark, Eisai, Exact Science, Kephren, Eli Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Roche/Genentech and Seattle Genetics; received research funding to the institution from Eisai, Exact Science and Roche/Genentech; is an ABC Global Alliance member; has a leadership role in AROMe and Nice St Paul de Vence Cours; and is involved in educational programmes for ESO. NH reports honoraria for lectures, advisory boards and/or personal fees from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz and SeaGen; and minority ownership interest in the West German Study Group. SAH reports contracted research paid to institution from Ambrx, Amgen, AstraZeneca, Arvinas, Bayer, Cytomx, Daiichi Sankyo, Dignitana, Genentech/Roche, Gilead, GSK, Immunomedics, Eli Eli Lilly, Macrogenics, Novartis, Pfizer, OBI Pharma, Pieris, PUMA Biotechnologies, Radius, Sanofi, Seattle Genetics/SeaGen, Zymeworks, Phoenix Molecular Designs, Ltd. and Samumed; unpaid steering committee member for Novartis, Eli Lilly, Daiichi Sankyo/AstraZeneca, Genentech/Roche and Sanofi; travel expenses from Eli Lilly (2019); and uncompensated consulting/advisory boards for 4DPharma, Ambrx, Amgen, Artios, Arvinas, Daiichi Sankyo, Dantari, Genentech/Roche, Immunomedics, Macrogenics, Eli Eli Lilly, Novartis, NK Max, Pieris, Pyxis, SeaGen, Biotheranostics and Loxo. SAI reports advisory board participation (uncompensated) for Amgen, AstraZeneca, Daiichi Sankyo, Eisai, GSK, Hanmi, Eli Lilly, MSD, Novartis, Pfizer and Roche; and receipt of research funding/clinical trial budget from AstraZeneca, Dae Woong, Daiichi Sankyo, Eisai, Hanmi, Pfizer and Roche. DK reports honoraria from the European School of Oncology and MSD; non-renumerated membership of American Society for Clinical Oncology, American Society for Radiation Oncology, Arbeitsgemeinschaft Gynäkologische Onkologie, Arbeitsgemeinschaft Radiologische Onkologie, Deutsche Gesellschaft für Radioonkologie, Deutsche Gesellschaft für Senologie, European Society for Radiotherapy and Oncology and The Radiosurgery Society. WGK reports institutional research funding by the German Research Foundation and the medical faculty of LMU Munich; and serves as a non-compensated committee member of the European Organisation for Research and Treatment of Cancer and the European Society of Oncologic Imaging. SLoi reports research funding to her institution from Novartis, BMS, Merck, PUMA Biotechnologies, Eli Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech and Seattle Genetics; consultancy (not compensated) to Seattle Genetics, Novartis, BMS, Merck, AstraZeneca and Roche/Genentech; consultancy (paid to institution) to Aduro Biotech, Novartis, GSK, Roche/Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics and BMS; and Scientific Advisory Board Member of Akamara Therapeutics. SLoibl reports honoraria for advisory boards (to institute) from Bayer, BMS, Eirgenix, GSK, Eli Lilly and Merck; honoraria for lecture (to institute) from Samsung; honoraria for advisory boards and lectures (to institute) from Pierre Fabre and Prime/Medscape; grants and honoraria for advisory boards (to institute) from AbbVie and Celgene; grants and honoraria for advisory boards and lectures (to institute) from AstraZeneca; grants, non-financial support and honoraria for advisory boards, lectures and medical writing (to institute) from Daiichi Sankyo, Novartis, Pfizer and Roche; grants, non-financial support and honoraria for advisory boards and medical writing (to institute) from Immunomedics/Gilead, non-financial support and honoraria for advisory boards and medical writing (to institute) from PUMA Biotechnologies and SeaGen; and non-financial support and honoraria for advisory boards (to institute) from Amgen, all outside the submitted work. In addition, SLoibl has patents EP14153692.0, EP21152186.9, EP19808852.8 and Digital Ki67 Evaluator pending and patent EP15702464.7 issued, with royalties paid. SP-S reports honoraria and/or advisory board and/or speaker’s bureau and/or travel funding from Roche, Pfizer, Eli Eli Lilly, Novartis, AstraZeneca, MSD, Exact Sciences and Nanostring. Institutional research funding from Sharing Progress in Cancer Care and Pfizer. FP-L has received honoraria and/or advisory board and/or speaker’s bureau and/or travel funding from Roche, Pfizer, Eli Lilly, Novartis, AstraZeneca, MSD, SeaGen, Illumina, Exact Sciences, Myriad and Nanostring; and institutional research funding from AstraZeneca, Roche, MSD and Illumina. JR reports honoraria or research grants (to the institution) from Terumo, Sirtex Medical, Boston Scientific, Roche and AstraZeneca. MR reports honoraria from Research to Practice, Intellisphere and Physicians’ Education Resource; consultant or advisor for Artios Pharma (uncompensated), AstraZeneca (uncompensated), Change Healthcare, Daiichi Sankyo (uncompensated), Epic Sciences (uncompensated), Merck (uncompensated), Pfizer (uncompensated) and Zenith Pharmaceuticals (uncompensated); research funding to institute from AstraZeneca, Merck and Pfizer; and editorial services for AstraZeneca and Pfizer. HSR reports research support for clinical trials through the University of California from Pfizer, Merck, Novartis, Eli Lilly, Roche, Daiichi Sankyo, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, Ayala and Gilead; and honoraria from PUMA Biotechnologies (grant reviews for the US National Comprehensive Cancer Network 2021, steering committee 2020), Mylan (educational talk 2019), Samsung (educational talk and consultant 2019) and Napo Pharmaceuticals, Inc (consultant). CFS reports institutional research funding from Amgen, AstraZeneca, Daiichi Sanyko and the US Department of Defence; and travel funding and speaker honoraria from Novartis, AstraZeneca, Roche and Amgen. PS reports honoraria for participation in advisory boards and satellite symposia from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, PUMA Biotechnologies, Roche, Eisai and Celgene; research funding to institute from Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche and Medivation. CS has served as consultant, participated in advisory boards or received travel grants from AstraZeneca, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, Roche, MediTech, MSD, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, PUMA Biotechnologies, Sanofi-Aventis, SeaGen and Zymeworks. TS reports receipt of honoraria for advisory board participation for Roche and Pfizer. SMT reports receipt of institutional research funding from AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics/Gilead, Exelixis, BMS, Eisai, Nanostring, Cyclacel, Odonate and Seattle Genetics; and has served as an advisor/consultant (compensated) for AstraZeneca, Eli Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics/Gilead, BMS, Eisai, Nanostring, PUMA Biotechnologies, Sanofi, Silverback Therapeutics, G1 Therapeutics, Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Daiichi Sankyo, Ellipsis, Infinity, 4D Pharma, Samsung Bioepsis Inc., Chugai Pharmaceuticals, BeyondSpring Pharmaceuticals, OncXerna, OncoSec Medical Incorporated, Certara, Mersana Therapeutics, CytomX and Seattle Genetics. NCT reports receipt of advisory board honoraria from AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche/Genentech, GSK, Zentalis Pharmaceuticals, Repare Therapeutics and Arvinas; and research funding from AstraZeneca, BioRad, Pfizer, Roche/Genentech, MSD, Guardant Health, Invitae, Inivata, Personalis and Natera.

Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states.

Purpose: In LOTUS (NCT02162719), adding the oral AKT inhibitor ipatasertib to first-line paclitaxel for locally advanced/metastatic triple-negative breast cancer (aTNBC) improved progression-free survival (PFS; primary endpoint), with an enhanced effect in patients with PIK3CA/AKT1/PTEN-altered tumors (FoundationOne next-generation sequencing [NGS] assay). We report final overall survival (OS) results., Methods: Eligible patients had measurable previously untreated aTNBC. Patients were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status, and were randomized 1:1 to paclitaxel 80 mg/m 2 (days 1, 8, 15) plus ipatasertib 400 mg or placebo (days 1-21) every 28 days until disease progression or unacceptable toxicity. OS (intent-to-treat [ITT], immunohistochemistry PTEN-low, and PI3K/AKT pathway-activated [NGS PIK3CA/AKT1/PTEN-altered] populations) was a secondary endpoint., Results: Median follow-up was 19.0 versus 16.0 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively. In the ITT population (n = 124), median OS was numerically longer with ipatasertib-paclitaxel than placebo-paclitaxel (hazard ratio 0.80, 95% CI 0.50-1.28; median 25.8 vs 16.9 months, respectively; 1-year OS 83% vs 68%). Likewise, median OS favored ipatasertib-paclitaxel in the PTEN-low (n = 48; 23.1 vs 15.8 months; hazard ratio 0.83) and PIK3CA/AKT1/PTEN-altered (n = 42; 25.8 vs 22.1 months; hazard ratio 1.13) subgroups. The ipatasertib-paclitaxel safety profile was unchanged., Conclusions: Final OS results show a numerical trend favoring ipatasertib-paclitaxel and median OS exceeding 2 years with ipatasertib-paclitaxel. Overall, results are consistent with the reported PFS benefit; interpretation within biomarker-defined subgroups is complicated by small sample sizes and TNBC heterogeneity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The therapeutic landscape of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents and their combinations with endocrine therapies. In this scenario, optimizing treatment selection and sequencing is daunting for clinicians. The purpose of this review is to provide evidence-based answers to key clinical questions on treatment selection and sequencing for the management of HR + HER2 - mBC., Design: A panel of nine key opinion leaders from Argentina, Brazil, Colombia, Mexico, Moscow, Singapore, South Korea, Taiwan, and UAE convened in October 2018. They reviewed the literature and formulated answers to clinical questions on optimizing the management of HR + HER2 - mBC., Results: Evidence-based answers were formulated for: (1) optimal initial treatment choice; (2) ovarian function suppression, optimal endocrine partner, and role of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (in premenopausal women); (3) better first-line standard of care than aromatase inhibitors; (4) preferred second-line treatment; (5) treatment of oligometastatic disease; (6) factors influencing first-line single-agent endocrine therapy choice; (7) influence of endocrine resistance on treatment selection; (8) optimal maintenance regimen in visceral crisis; and (9) need for a breast cancer registry for patients with HR + HER2 - mBC. The panel also proposed a treatment-sequencing algorithm for the management of HR + HER2 - mBC., Conclusion: The current article will serve as a comprehensive guide for optimizing the management of HR + HER2 - mBC. The proposed breast cancer registry will help identify unmet needs and develop strategic regional policies to help improve access to optimized care for HR + HER2 - mBC., (© 2021. The Author(s).)

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3 , whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11 . Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC , ADCY3 and DNAJC27 . In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.

This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers., Competing Interests: The authors have declared that no competing interests exist.

Background: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer., Methods: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657., Findings: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax)., Interpretation: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer., Funding: Merck Sharp & Dohme., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: We conducted a randomized controlled trial evaluating the efficacy and tolerability of cryotherapy in preventing chemotherapy-induced peripheral neuropathy (CIPN) in patients with early breast cancer receiving neo/adjuvant weekly paclitaxel. Methods: Patients were recruited from the National Cancer Centre Singapore and randomized (1:1) to receive either cryotherapy or usual care. Cryotherapy was applied as frozen gloves and socks on all extremities from 15 min before paclitaxel until 15 min post-infusion every cycle. Efficacy was measured by patient-reported outcomes (Patient Neurotoxicity Questionnaire [PNQ] and EORTC QLQ-CIPN20) and electrophysiological assessments. The primary endpoint was PNQ severity at 2 weeks after 12 cycles of weekly paclitaxel. Results: A total of 46 patients were recruited, of which 8 dropped out before paclitaxel treatment, leaving 38 evaluable. There was no significant difference in PNQ severity between cryotherapy and usual care at 2 weeks after paclitaxel treatment (sensory: p = 0.721; motor: p = 1.000). A benefit was observed at 3 months post-paclitaxel based on PNQ (sensory: 14.3 vs. 41.2%, p = 0.078; motor: 0 vs. 29.4%, p = 0.012) and CIPN20 (sensory: β = -3.6, 95%CI = -10.5-3.4, p = 0.308; motor: β = -7.3, 95%CI = -14.6-0, p = 0.051). Additionally, cryotherapy subjects have lower CIPN20 autonomic score (β = -5.84, 95%CI = -11.15 to -0.524, p = 0.031) and higher sympathetic skin response hand amplitudes (β = 0.544, 95%CI = 0.108-0.98, p = 0.014), suggesting possible autonomic benefits from cryotherapy. Temporary interruption with cryotherapy occurred in 80.9% of the subjects due to cold intolerance. Conclusions: There is insufficient evidence that cryotherapy prevents sensory neuropathy which may be due to the high rates of cryotherapy interruption in this study. The autonomic benefits of cryotherapy should be further investigated with appropriate outcome measures. Clinical Trial Registration: ClinicalTrials.gov: NCT03429972., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Ng, Tan, Soh, Tan, Loh, Tan, Ong, Teng, Chan, Chay, Lee, Lai, Beh, Tan, Yap, Lee, Wong, Dent, Lo, Chan and Loh.)

Current obesity treatment strategies include diet, exercise, bariatric surgery, and a limited but growing repertoire of medications. Individual weight loss in response to each of these strategies is highly variable. Here we review research into factors potentially contributing to inter-individual variability in response to treatments for obesity, with a focus on studies in humans. Well-recognized factors associated with weight loss capacity include diet adherence, physical activity, sex, age, and specific medications. However, following control for each of these, differences in weight loss appear to persist in response to behavioral, pharmacological and surgical interventions. Adaptation to energy deficit involves complex feedback mechanisms, and inter-individual differences likely to arise from a host of poorly defined genetic factors, as well as differential responses in neurohormonal mechanisms (including gastrointestinal peptides), metabolic efficiency and capacity of tissues, non-exercise activity thermogenesis, thermogenic response to food, and in gut microbiome. A better understanding of the factors involved in inter-individual variability in response to therapies will guide more personalized approaches to the treatment of obesity., Competing Interests: Declaration of competing interest None of the authors has any financial or personal relationships with people or organizations that could inappropriately influence this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Combining the oral AKT inhibitor ipatasertib with paclitaxel as first-line therapy for metastatic triple-negative breast cancer significantly improved progression-free survival (PFS) in the placebo-controlled, randomized, phase II LOTUS trial, with a more pronounced effect in patients with PIK3CA/AKT1/PTEN -altered tumors. We report findings from the extensive translational research program., Patients and Methods: Pretreatment plasma and tumor samples were evaluated for genetic alterations using FoundationACT and FoundationOne (Foundation Medicine, Cambridge, MA) hybrid capture next-generation sequencing assays, respectively. Prevalences of the most common mutations and PIK3CA/AKT1 mutation status were determined using both assays, and concordance was assessed. In longitudinal analyses, circulating tumor DNA (ctDNA) mutations were quantified in baseline and on-treatment (cycle 3, day 1 [C3D1]) samples. The relationship between outcomes and ctDNA fraction (CTF; highest variant allele frequency) and CTF ratio (C3D1 CTF to baseline CTF) was explored., Results: Among 89 patients evaluable for ctDNA sequencing, 81 patients (91%) had 149 detectable mutations. There was high agreement between plasma- and tissue-based sequencing for known or likely short variant mutations but not amplifications. There was 100% concordance between ctDNA and tissue sequencing in patients with activating PIK3CA or AKT1 mutations. High baseline CTF was associated with shorter PFS in both treatment arms. Longitudinal analyses showed more favorable outcomes with lower absolute CTF at C3D1 and, to a lesser extent, greater CTF decreases., Conclusion: These results suggest that plasma ctDNA sequencing may allow reliable and convenient assessment of prognosis and identification of genetic markers associated with increased benefit from ipatasertib. On-treatment CTF showed a meaningful association with objective response and PFS.

In late 2018, the Food and Drug Administration (FDA) outlined a framework for evaluating the possible use of real-world evidence (RWE) to support regulatory decision-making. This framework was created to facilitate studies that would generate high-quality RWE, including pragmatic clinical trials (PCTs), which are randomized trials designed to inform clinical or policy decisions by assessing the real-world effectiveness of an intervention. There is general agreement among experts that the use of existing healthcare and patient-generated data holds promise for making randomized trials more efficient, less costly, and more generalizable. Yet the benefits of relying on real-world data sources must be weighed against difficulties with ensuring data integrity and completeness. Additionally, appropriately monitoring patient safety in randomized trials of new drugs using healthcare system data that might not be available in real time can be quite difficult. Recognizing that these and other concerns are critical to the development and acceptability of PCTs, a group of stakeholders from academia, industry, professional organizations, regulatory bodies, government agencies, and patient advocates discussed a path forward for PCT growth and sustainability at a think tank meeting entitled "Monitoring and Analyzing Data from Pragmatic Streamlined Randomized Clinical Trials," which took place in January 2019 (Washington, DC). The goals of this meeting were to: (1) evaluate study design and methodological options specific to PCTs that have the potential to yield high-quality evidence; (2) discuss best practices to ensure data quality in PCTs; and (3) identify appropriate methods for study monitoring. Proceedings from the think tank meeting are summarized in this manuscript.

Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.

Purpose: The coronavirus disease 2019 (COVID-19) pandemic has had a global impact, and Singapore has seen 33,000 confirmed cases. Patients with cancer, their caregivers, and health care workers (HCWs) need to balance the challenges associated with COVID-19 while ensuring that cancer care is not compromised. This study aimed to evaluate the psychological effect of COVID-19 on these groups and the prevalence of burnout among HCWs., Methods: A cross-sectional survey of patients, caregivers, and HCWs at the National Cancer Centre Singapore was performed over 17 days during the lockdown. The Generalized Anxiety Disorder-7 and Maslach Burnout Inventory were used to assess for anxiety and burnout, respectively. Self-reported fears related to COVID-19 were collected., Results: A total of 624 patients, 408 caregivers, and 421 HCWs participated in the study, with a response rate of 84%, 88%, and 92% respectively. Sixty-six percent of patients, 72.8% of caregivers, and 41.6% of HCWs reported a high level of fear from COVID-19. The top concern of patients was the wide community spread of COVID-19. Caregivers were primarily worried about patients dying alone. HCWs were most worried about the relatively mild symptoms of COVID-19. The prevalence of anxiety was 19.1%, 22.5%, and 14.0% for patients, caregivers, and HCWs, respectively. Patients who were nongraduates and married, and caregivers who were married were more anxious. The prevalence of burnout in HCWs was 43.5%, with more anxious and fearful HCWs reporting higher burnout rates., Conclusion: Fears and anxiety related to COVID-19 are high. Burnout among HCWs is similar to rates reported prepandemic. An individualized approach to target the specific fears of each group will be crucial to maintain the well-being of these vulnerable groups and prevent burnout of HCWs.