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Background: The heterogeneous biology of ductal carcinoma in situ (DCIS), as well as the variable outcomes, in the setting of numerous treatment options have led to prognostic uncertainty. Consequently, making treatment decisions is challenging and necessitates involved communication between patient and provider about the risks and benefits. We developed and investigated an interactive decision support tool (DST) designed to improve communication of treatment options and related long-term risks for individuals diagnosed with DCIS., Findings: The DST was developed for use by individuals aged > 40 years with DCIS and is based on a disease simulation model that integrates empirical data and clinical characteristics to predict patient-specific impacts of six DCIS treatment choices. Personalized risk predictions for each treatment option were communicated using icon arrays and percentages for each outcome. Users of the DST were asked before and after interacting with the DST about: (1) awareness of DCIS treatment options, (2) willingness to consider these options, (3) knowledge of risks associated with DCIS, and (4) helpfulness of the DST. Data were collected from January 2019 to April 2022. Users' median estimated risk of dying from DCIS in 10 years decreased from 9% pre-tool to 3% post-tool (p < 0.0001). 76% (n = 101/132) found the tool helpful., Conclusions: Information about DCIS treatment options and related risk predictions was effectively communicated, and a large majority participants found the DST to be helpful. Successfully informing patients about their treatment options and how their individual risks affect those options is a critical step in the decision-making process., Clinicaltrials: gov Identifier NCT02926911., (© 2024. The Author(s).)

Lack of patient diversity in clinical trial enrollment remains an obstacle to achieving equitable healthcare outcomes. Under-representation has resulted in non-generalizable clinical knowledge, inequitable access to treatment, and health disparities among minority and disadvantaged groups. A multidisciplinary panel was convened to consider the challenges of diverse patient accrual and provide actionable solutions to improve representation in clinical trials. The panel was comprised of participants with knowledge in gynecologic oncology and included physician, advanced practice nurse, patient navigator, patient advocate, and pharmaceutical industry representation. Focus was given to recruitment barriers for Asian and Hispanic patients. The panel identified several areas of concern, including explicit and implicit biases for the physician and care teams, language and cultural nuances, inadequate inclusion of family in the decision-making process, and under-representation of women in clinical trials. The panel also identified the important role patient navigators, nurses, and advanced practice providers have in patient recruitment from under-represented populations. The role of study sponsors, and global and regional initiatives, to address historic disparities in clinical trial recruitment were also considered critical. The actionable solutions proposed should enable study sponsors and clinical trial sites to achieve greater diversity in enrollment globally., Competing Interests: Competing interests: BP has received grants from Tesaro/GSK, Merck, Astra Zeneca, Karyopharm Therapeutics, Incyte, Toray, VBL Therapeutics, InxMed, Agenus, Clovis Oncology, Roche/Genentech, Mersana, Celsion/Immunon, I-Mab, Takeda, Onconova, Celgene, Sutro Biopharma, Novocure, Seagen, NRG Oncology, Duality Bio, Xencor, Immunogen, Eisai, Acrivon, and Alkermes; consulting fees from Tesaro/GSK, Astra Zeneca, Merck, Immunogen, GOG Foundation, Seagen, Lilly, Eisai, Signatera, Celsion, Sutro Biopharma, Imvax, Incyte, InxMed, Onconova Therapeutics, R-Pharm, Regeneron, and Duality Bio; honoraria from Bioascend, PERS, Vanium, Curio, OncLive, Yale University, and PeerView; support for attending meetings and/or travel from GOG Partners; participated on data safety monitoring boards (DSMBs) or advisory boards for Sutro Biopharma, Astra Zeneca, GOG Foundation, Celsion/Immunon, Toray, InxMed, Onconova, Imvaz, I-Mab, Tesaro/GSK, Merck, Mersana, Nuvation, and BioNTech; and served as SGO Clinical Practice Committee Chair, SGO Board of Directors, SGO COVID-19 Taskforce Co-chair, GOG Partners, and NYOB Society Second Vice President. PT has received grants (paid to the institution) from Merck and GSK; participated on DSMBs or advisory boards for Iovance, Astra Zeneca, Verastem, GSK, Seagen, Immunon, Immunogen, Mersana, Novocure, Zentalis, Caris, and Merck; and holds stock or stock options in Immunon. AM has received honoraria and travel fees from Foundation for Women’s Cancer and served as President of Endometrial Cancer Action Network for African Americans. KM has received consulting fees from Eisai. DC has received honoraria from Antibacterial Resistance Leadership Group (ARLG); grants from Duke University for COMET study (cancer) Patient Leadership Group, UCSF for STORMing Cancer Patient Advocate Team, and MD Anderson for PRECISION Patient Advisory Involvement Panel; consulting fees from SimBioSys, MaxisHealth, Health Literacy Media (HLM; as Patient Advisor), Apellis Pharmaceuticals, and Kinnate Biopharma; honoraria and travel support from HMP Education; support for travel from Agile Falcon Strategic Group, DGE Events, and Informa; participated on DSMBs for American Society for Clinical Oncology and on Patient Partner Council for Evidera; has a role on Executive Group for Metastatic Breast Cancer Alliance and a role as committee member for Alliance for Clinical Trials in Oncology; and received manuscript writing support from IQVIA through Regeneron. KL has received fees for participation on advisory boards for Astra Zeneca, Merck, and Eisai. MCM is an employee and stockholder of Incyte. BS has received consulting fees from Astra Zeneca, Clovis, GSK, Genentech, Lilly, Novartis, Gilead, Seagen, Karyopharm, Addy, Circulogene, GOG Foundation, Merck, Imvax, EQRx, and Nuvation; and honoraria from Seagen., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)., Methods: Through comprehensive examination of data from nearly 4000 participants enrolled in six registrational trials for HABP/VABP submitted to the Food and Drug Administration (FDA) between 2005 and 2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that a participant assigned to the study treatment arm would have a more favorable overall DOOR or component outcome than a participant assigned to comparator., Results: DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 48.3% to 52.9% and were not statistically different. There were no significant differences between treatment arms in the component analyses. Although infectious complications and serious adverse events occurred more frequently in ventilated participants compared to non-ventilated participants, the types of events were similar., Conclusions: Through a data-driven approach, we constructed and applied a potential DOOR endpoint for HABP/VABP trials. The inclusion of syndrome-specific events may help to better delineate and evaluate participant experiences and outcomes in future HABP/VABP trials and could help inform data collection and trial design., Competing Interests: Potential conflicts of interest. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Roche, grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Deep Blue, Basilea, Janssen; Royalties from UpToDate, stock options from Valanbio and ArcBio, Honoraria from Infectious Diseases of America for his service as Associate Editor of Clinical Infectious Diseases, and a patent sepsis diagnostics pending. H. W. B. reports royalties to author from Sanford Guide; editorial consulting fees from Sanford Guide, Antimicrobial Agents and Chemotherapy/ASM, ID Clinics of North America/Elsevier; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Grand Rounds at Temple; IDWeek lecture travel support from Finland Award; role as PACCARB Voting Member (travel reimbursed) and on Board of Trustees, College of the Holy Cross (travel reimbursed). T. H. reports grants or contracts from Aceragen; consulting fees from Astellas Pharma US and Mitsubishi Tanabe Pharma; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Cancer and Chemotherapy KK. S. R. E. reports NCI/NIH grant, NHLBI/NIH grant, CDC grant, and grants or contracts from Degruyter (Editor-in-Chief: Statistical Communications in Infectious Diseases); book royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickenson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, SVB Leerink, Medtronic, Regeneron, Wake Forest University, Recor, Janssen, IDDI; honorarium from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), and payment or honorarium for travel from Liver Forum and Paris NASH Meeting; support for attending meetings and/or travel from FDA (honorarium); paid participation on a Data Safety Monitoring Board or Advisory Board for NIH, BARDA, Breast International Group, University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, Abbvie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, Novartis; unpaid Board member for American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. J. H. A. reports grant funding to institution for work unrelated to this from the Centers for Disease Control and Prevention (CDC); support for speaking at SHEA Spring Conference from SHEA. S. N. reports support for travel to meetings is supported by my employer, Johnson and Johnson; stocks in J&J, author's employer. T. H. reports grant from NIH to Antibacterial Resistance Leadership Group and grants or contracts from Karius for Adjudication committee; royalties or licenses from UpToDate; consulting fees from Aridis, Pfizer, Lysovant, Affinivax, Basilea, Concert Genetics; participation on Data and Safety Monitoring Board (DSMB) for Staphylococcus aureus Network Adaptive Platform (SNAP) trial and Spero and on Advisory Board for Basilea and Paul Scherrer Institut (PSI). S. B. D. reports grants or contracts to University of California San Francisco (UCSF) from Gilead, Pfizer, F2G, Regeneron, Chan Zuckerberg Biohub, and NIAID/NIH; consulting fees to author from Genentech and Janssen/J + J; support for travel to speak at IDWeek from Infectious Diseases Society of America (IDSA); patent US20100143379A1 for Mif agonists and antagonist and therapeutic uses thereof; leadership or fiduciary roles on IDSA Antibacterial Resistance Committee, CADPH HAI Advisory Committee, Antibacterial Resistance Leadership Group Innovations Group, Laboratory Center, Mentorship Committee, Gram Positive Committee, Immunosuppressed Host Group; payment for clinical events committee/adjudication committee participation from Shinogi, Basilea, Duke Clinical Research Institute. H. C. reports stock or stock options from Merck and Moderna; membership of DSMB for COVID antiviral RCT for Merck. D. C. reports grants or contracts from Duke University for COMET study (cancer) Patient Leadership Group, from UCSF for STORMing Cancer Patient Advocate Team, and from MD Anderson for PRECISION Patient Advisory Involvement Panel; consulting fees for ongoing projects from SimBioSys and MaxisHealth, from Health Literacy Media (HLM) for Patient Advisor for ongoing projects, and from Appelis Pharmaceuticals, Inc., for consulting/project ended in 12/2022 and from Kinnate Biopharma for consulting/project ended in 06/2022; honoraria and travel support from HMP Education; support for travel from Agile Falcon Strategic Group, DGE Events, and Informa; participation on DSMB for American Society for Clinical Oncology and on Patient Partner Council for Evidera; a role on Executive Group for Metastatic Breast Cancer Alliance and a role as committee member for Alliance for Clinical Trials in Oncology; receitp of manuscript writing support from IQVIA through Regeneron. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Cancer immunotherapy has flourished over the last 10-15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge. For example, advances in technologies such as single-cell sequencing and spatial transcriptomics have provided deep insights into the immunobiology of the tumor microenvironment. With this rapid clinical and scientific progress, the field of cancer immunotherapy is currently at a critical inflection point, with potential for exponential growth over the next decade. Recognizing this, the Society for Immunotherapy of Cancer convened a diverse group of experts in cancer immunotherapy representing academia, the pharmaceutical and biotechnology industries, patient advocacy, and the regulatory community to identify current opportunities and challenges with the goal of prioritizing areas with the highest potential for clinical impact. The consensus group identified seven high-priority areas of current opportunity for the field: mechanisms of antitumor activity and toxicity; mechanisms of drug resistance; biomarkers and biospecimens; unique aspects of novel therapeutics; host and environmental interactions; premalignant immunity, immune interception, and immunoprevention; and clinical trial design, endpoints, and conduct. Additionally, potential roadblocks to progress were discussed, and several topics were identified as cross-cutting tools for optimization, each with potential to impact multiple scientific priority areas. These cross-cutting tools include preclinical models, data curation and sharing, biopsies and biospecimens, diversification of funding sources, definitions and standards, and patient engagement. Finally, three key guiding principles were identified that will both optimize and maximize progress in the field. These include engaging the patient community; cultivating diversity, equity, inclusion, and accessibility; and leveraging the power of artificial intelligence to accelerate progress. Here, we present the outcomes of these discussions as a strategic vision to galvanize the field for the next decade of exponential progress in cancer immunotherapy., Competing Interests: Competing interests: LAE, employee, Ankyra Therapeutics; researcher, AbbVie, AstraZeneca, Bolt Therapeutics, Bristol Meyers Squibb, Compugen, Corvus, CytomX, EMD Serono, Genentech, F Hoffman La Roche, Immune Onc, Merck, Next Cure, Silverback, Takeda, and Tempest; consultant/advisor/speaker, AstraZeneca, BioLineRx, DNAMx, Genentech, F Hoffman La Roche, GPCR, Gilead, Immune Onc, Immunitas, Immutep, Lilly, Macrogenics, Mersana, and Shionogi; royalty and patent beneficiary, potential for royalties in the future from Molecuvax; publicly traded stocks, potential for stock options in the future from Ankyra Therapeutics; Other, NSABP Foundation, Translational Breast Cancer Research Consortium, Breast Cancer Research Foundation, NCI, Department of Defense, Johns Hopkins University, University of California San Francisco, Cornell University, Dana-Farber Cancer Institute, and Stand Up to Cancer. These are grants from non-industry entities. TCB, advisory board, Kalivir, Tabby; consultant, Galvanize, Attivare, Mestag, and Tallac. CMC, consultant/advisor/speaker, Bayer, Elephas, Novartis, Nektar Therapeutics, and WiCell Research Institute. ACA, member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, Excepgen, and ImmuneOncia, which have interests in cancer immunotherapy. ACA is also a paid consultant for iTeos Therapeutics and Larkspur Biosciences. ACA is an inventor on patents related to the checkpoint receptor Tim-3. DC, executive role, ORIEN Patient Advisory Council. JLG, royalty and patent beneficiary, Bethesda Handbook of Clinical Oncology (royalty) and UpToDate (royalty); JITC interim editor-in-chief. PH, consultant/advisor/speaker, Dragonfly SAB and Immatics SAB. ADP, researcher, Astellas; consultant/advisor/speaker, ImmunoACT, Stromatis Pharma, GO Therapeutics, Astellas, and MaxCyte. PJR, employee, Novigenix and SA; researcher, Roche, pRED, Schilieren, and CH; consultant/advisor/speaker, Enterome, Transgene, and Maxivax. AWS, researcher, Biohaven Pharmaceuticals, Replimune, Morphogenesis, Shattuck Laboratories, Regeneron, and Merck; consultant/advisor/speaker, InStil Bio, Signatera, Merck, and Regeneron; royalty and patent beneficiary, UpToDate; and publicly traded stocks, Illumina. JAW reports compensation for speaker’s bureau and honoraria from PeerView and serves as a consultant and/or advisory board member for Gustave Roussy Cancer Center, EverImmune, OSE Immunotherapeutics, Bayer Therapeutics, James Cancer Center OSU, Daiichi Sanyko. SITC staff: EG, nothing to disclose. JW, nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation., Methods: A multidisciplinary committee created an infectious diseases DOOR endpoint customized for HABP/VABP, incorporating infectious complications, serious adverse events, and mortality. We applied this to 2 previously completed, large randomized controlled trials for HABP/VABP. ZEPHyR compared vancomycin to linezolid and VITAL compared linezolid to tedizolid. For each trial, we evaluated the DOOR distribution and probability, including DOOR component and partial credit analyses. We also applied DOOR in subgroup analyses., Results: In both trials, the HABP/VABP DOOR demonstrated similar overall clinical outcomes between treatment groups. In ZEPHyR, the probability that a participant treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% confidence interval [CI], 45.1%--55.3%). In VITAL, the probability that a participant treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%-52.6%). The DOOR component analysis revealed that participants treated with tedizolid had a less desirable outcome than those treated with linezolid when considering clinical response alone. However, participants with decreased renal function had improved overall outcomes with tedizolid., Conclusions: The HABP/VABP DOOR provided more granular information about clinical outcomes than is typically presented in clinical trials. HABP/VABP trials would benefit from prospectively using DOOR., Competing Interests: Potential conflicts of interest. H. W. B. declares consulting fees from Antimicrobial Agents and Chemotherapy/American Society for Microbiology (ASM), Sanford Guide, and ID Clinics of North America/Elsevier; royalties from Sanford Guide; payment or honoraria from Grand Rounds at Temple; Finland Award for IDWeek Lecture travel; and role with travel reimbursed as Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB) Voting Member and Board of Trustees, College of the Holy Cross. D. C. reports honoraria from ARLG, SimBioSys, AstraZeneca, Apellis Pharmaceutical, Kinnate Biopharma, MaxisIT Clinical Sciences, Pfizer, Parexel, Health Literacy Media, Incyte, American Society of Clinical Oncology, and Aster Insights, all unrelated to this work; and consulting fees from AstraZeneca, Incyte, Apellis Pharmaceuticals, Kinnate Biopharma, Maxis Health, Parexel, Health Literacy Media (nonprofit), and SimBioSys; reimbursement for personal expenses for attending meetings and/or travel from Aster Insights and the American Society of Clinical Oncology (ASCO); participation with honorarium to author on a data and safety monitoring board (DSMB) or advisory board for ASCO; a role as unpaid volunteer for the Metastatic Breast Cancer Alliance; and a role with honorarium to author from ORIEN Patient Advisory Council. H. F. C. reports grant funding from NIH; royalties from Sanford Guide to Antimicrobial Therapy; payment from The George Washington University for ID board review course lectures; participation in a DSMB for Merck; and stock in Merck and Moderna. S. B. D. reports research funding for clinical research studies from Gilead, Regeneron, Pfizer, F2G, Chan Zuckerberg Initiative Biohub, and NIH/NIAID; payments for clinical event adjudication committees from Basilea, Duke Clinical Research Institute, and Shionogi; a patent pending for Mif agonists (patent US20100143379A1); money for travel to conference from the Infectious Diseases Society of America (IDSA); and consulting fees from Genentech and Janssen/Johnson & Johnson (J&J); and leadership or fiduciary roles with IDSA Antibacterial Resistance Committee, California Department of Public Health Healthcare Associated Infections Advisory Committee, and the ARLG Innovations Group, Laboratory Center, Mentorship Committee, Gram Positive Committee, and Immunosuppressed Host Group. S. R. E. reports grant funding from NIH (NIAID, National Cancer Institute, National Heart, Lung, and Blood Institute), Centers for Disease Control and Prevention (CDC), and De Gruyter (Editor-in-Chief of Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genetech, AstraZeneca, Takeda, Microbiotix, J&J, Endologix, ChemoCentryx, Becton Dickenson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute (IDDI), SVB Leerink, Medtronic, Regeneron, Wake Forest University, Recor, Janssen, and IDDI; payments from lectures from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); support for attending meetings from FDA; and participation on DSMBs for NIH, Breast International Group, University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouous, Appelis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Candel, Novartis, and Advantagene; and being an unpaid board member for the American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, The Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, ContraFect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, ContraFect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from IDSA for his service as Associate Editor of Clinical Infectious Diseases; and a patent pending in sepsis diagnostics. H. L.-T. is an employee of Pfizer and holds stock in Pfizer. C. H. receives stock dividends from GlaxoSmithKline. T. L. H. declares grant funding from NIH and Karius; royalties from UpToDate; consulting fees from Basilea Pharmaceutica, Affinivax, Lysovant, Aridis, and Pfizer; and participation on DSMB for platform trial for SNAP Trial and advisory board for Basilea. J. H.-A. reports grant funding from NIH and CDC; and payment from IDSA (reviewing IDSA/Clinical Infectious Diseases supplement), ARLG (for speaking at IDWeek dinner and Texas Medical Center Antimicrobial Resistance and Stewardship Conference conference), and Society for Healthcare Epidemiology of America (SHEA) (for speaking at SHEA Spring Conference). S. N. is an employee of J&J and holds stock in J&J; received support for travel to meetings paid by employer; and participated as unpaid member of a scientific advisory committee of Global Antibiotic Research and Development Partnership. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Master protocols (MPs) are an important addition to the clinical trial repertoire. As defined by the U.S. Food and Drug Administration (FDA), this term means "a protocol designed with multiple sub-studies, which may have different objectives (goals) and involve coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure." This means we now have a unique, scientifically based MP that describes how a clinical trial will be conducted using one or more potential candidate therapies to treat patients in one or more diseases. Patient engagement (PE) is also a critical factor that has been recognized by FDA through its Patient-Focused Drug Development (PFDD) initiative, and by the European Medicines Agency (EMA), which states on its website that it has been actively interacting with patients since the creation of the Agency in 1995. We propose that utilizing these PE principles in MPs can make them more successful for sponsors, providers, and patients. Potential benefits of MPs for patients awaiting treatment can include treatments that better fit a patient's needs; availability of more treatments; and faster access to treatments. These make it possible to develop innovative therapies (especially for rare diseases and/or unique subpopulations, e.g., pediatrics), to minimize untoward side effects through careful dose escalation practices and, by sharing a control arm, to lower the probability of being assigned to a placebo arm for clinical trial participants. This paper is authored by select members of the American Statistical Association (ASA)/DahShu Master Protocol Working Group (MPWG) People and Patient Engagement (PE) Subteam. DahShu is a 501(c)(3) non-profit organization, founded to promote research and education in data science. This manuscript does not include direct feedback from US or non-US regulators, though multiple regulatory-related references are cited to confirm our observation that improving patient engagement is supported by regulators. This manuscript represents the authors' independent perspective on the Master Protocol; it does not represent the official policy or viewpoint of FDA or any other regulatory organization or the views of the authors' employers. The objective of this manuscript is to provide drug developers, contract research organizations (CROs), third party capital investors, patient advocacy groups (PAGs), and biopharmaceutical executives with a better understanding of how including the patient voice throughout MP development and conduct creates more efficient clinical trials. The PE Subteam also plans to publish a Plain Language Summary (PLS) of this publication for clinical trial participants, patients, caregivers, and the public as they seek to understand the risks and benefits of MP clinical trial participation., (© 2023. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Objective: To examine the association between size and margin status of ductal carcinoma in situ (DCIS) and risk of developing ipsilateral invasive breast cancer and ipsilateral DCIS after treatment, and stage and subtype of ipsilateral invasive breast cancer., Design: Multinational, pooled cohort study., Setting: Four large international cohorts., Participants: Patient level data on 47 695 women with a diagnosis of pure, primary DCIS between 1999 and 2017 in the Netherlands, UK, and US who underwent surgery, either breast conserving or mastectomy, often followed by radiotherapy or endocrine treatment, or both., Main Outcome Measures: The main outcomes were 10 year cumulative incidence of ipsilateral invasive breast cancer and ipsilateral DCIS estimated in relation to DCIS size and margin status, and adjusted hazard ratios and 95% confidence intervals, estimated using multivariable Cox proportional hazards analyses with multiple imputed data RESULTS: The 10 year cumulative incidence of ipsilateral invasive breast cancer was 3.2%. In women who underwent breast conserving surgery with or without radiotherapy, only adjusted risks for ipsilateral DCIS were significantly increased for larger DCIS (20-49 mm) compared with DCIS <20 mm (hazard ratio 1.38, 95% confidence interval 1.11 to 1.72). Risks for both ipsilateral invasive breast cancer and ipsilateral DCIS were significantly higher with involved compared with clear margins (invasive breast cancer 1.40, 1.07 to 1.83; DCIS 1.39, 1.04 to 1.87). Use of adjuvant endocrine treatment was not significantly associated with a lower risk of ipsilateral invasive breast cancer compared to treatment with breast conserving surgery only (0.86, 0.62 to 1.21). In women who received breast conserving treatment with or without radiotherapy, higher DCIS grade was not significantly associated with ipsilateral invasive breast cancer, only with a higher risk of ipsilateral DCIS (grade 1: 1.42, 1.08 to 1.87; grade 3: 2.17, 1.66 to 2.83). Higher age at diagnosis was associated with lower risk (per year) of ipsilateral DCIS (0.98, 0.97 to 0.99) but not ipsilateral invasive breast cancer (1.00, 0.99 to 1.00). Women with large DCIS (≥50 mm) more often developed stage III and IV ipsilateral invasive breast cancer compared to women with DCIS <20 mm. No such association was found between involved margins and higher stage of ipsilateral invasive breast cancer. Associations between larger DCIS and hormone receptor negative and human epidermal growth factor receptor 2 positive ipsilateral invasive breast cancer and involved margins and hormone receptor negative ipsilateral invasive breast cancer were found., Conclusions: The association of DCIS size and margin status with ipsilateral invasive breast cancer and ipsilateral DCIS was small. When these two factors were added to other known risk factors in multivariable models, clinicopathological risk factors alone were found to be limited in discriminating between low and high risk DCIS., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Cancer Research UK and by KWF Kankerbestrijding and Patient-Centered Outcomes Research Institute; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Clinical research networks conduct important studies that would not otherwise be performed by other entities. In the case of the Antibacterial Resistance Leadership Group (ARLG), such studies include diagnostic studies using master protocols, controlled phage intervention trials, and studies that evaluate treatment strategies or dynamic interventions, such as sequences of empiric and definitive therapies. However, the value of a clinical research network lies not only in the results from these important studies but in the creation of new approaches derived from collaborative thinking, carefully examining and defining the most important research questions for clinical practice, recognizing and addressing common but suboptimal approaches, and anticipating that the standard approaches of today may be insufficient for tomorrow. This results in the development and implementation of new methodologies and tools for the design, conduct, analyses, and reporting of research studies. These new methodologies directly impact the studies conducted within the network and have a broad and long-lasting impact on the field, enhancing the scientific value and efficiency of generations of research studies. This article describes innovations from the ARLG in diagnostic studies, observational studies, and clinical trials evaluating interventions for the prevention and treatment of antibiotic-resistant bacterial infections., Competing Interests: Potential conflicts of interest. All authors report funding support from the Antibacterial Resistance Leadership Group (ARLG) of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID) (grant number UM1AI104681). S. R. E. reports grants from the NIAID and the NIH and Degruter (Editor-in-Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, Medtronic, Regeneron, Wake Forest University, Recor, Janssen, IDDI, and SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); meeting support from the US Food and Drug Administration, Deming Conference on Applied Statistics, Clinical Trial Transformation Initiative, Council for International Organizations of Medical Sciences, International Chinese Statistical Association Applied Statistics Symposium, and Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, Breast International Group, Washington University, University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, Abbvie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, Novartis, American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. R. P. reports grants or contracts from ContraFect, TenNor Therapeutics Limited, BIOFIRE, and Adaptive Phage Therapeutics; a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics through the Mayo Clinic; consulting fees from PhAST, Torus Biosystems, Day Zero Diagnostics, Mammoth Biosciences, HealthTrackRx, Netflix, Abbott Laboratories, Trellis Bioscience, Inc, Oxford Nanopore Technologies, and CARB-X; honoraria from the National Board of Medical Examiners, Up-to-Date, and the Infectious Diseases Board Review Course; a patent on Bordetella pertussis/parapertussis polymerase chain reaction (PCR) issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued; and a financial relationship with Pathogenomix through the Mayo Clinic. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma and honoraria from Duke University and Cancer and Chemo Therapy. J. H.-A. reports funding from the Centers for Disease Control and Prevention unrelated to the report reported in this manuscript, honoraria from the Infectious Diseases Society of America, and travel and meeting support from the Society for Healthcare Epidemiology of America (SHEA) and the ARLG. D. C. reports personal consulting fees from AstraZeneca, Incyte, Apellis Pharmaceuticals, Inc, Kinnate Biopharma, Maxis Health, Parexel, and Health Literacy Media (nonprofit); travel and meeting support from M2GEN and the American Society of Clinical Oncology; participation on a Data and Safety Monitoring Board (DSMB) for the American Society of Clinical Oncology; and leadership in the Metastatic Breast Cancer Alliance. H. C. reports salary support from the ARLG via Duke University. H. F. C. reports royalties from the Sanford Guide to Antimicrobial Therapy, payment for expert testimony from Nexus Pharmaceuticals, participation on a Merck DSMB for molnupiravir, and stock ownership in Moderna and Merck. V. G. F. reports personal consulting fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer (paid to the author); grants from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases Society of America for his service as Associate Editor of Clinical Infectious Diseases; travel support from Contrafect to the 2019 European Society of Clinical Microbiology and Infectious Diseases (ECCMID); and a sepsis diagnostics patent pending. H. B. reports royalties from the Sanford Guide; consulting fees from the Sanford Guide, Antimicrobial Agents and Chemotherapy/ASM, and ID Clinics of North America/Elsevier; honoraria for Grand Rounds at Temple University; travel and meeting support for an IDWeek Lecture; and membership as a voting member on the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB) and membership on the Board of Trustees at the College of the Holy Cross. H. K. reports funding awarded to her institution(s) from the Durham Center of Innovation to Accelerate Discovery and PracticeTransformation (CIN 13-410) at the Durham Veterans Affairs Health Care System, NIH, and Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA. They also report serving on the editorial board for the Journal of Antimicrobial Chemotherapy- Antimicrobial Resistance (JAC-AMR). T. K. reports no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Desirability of outcome ranking (DOOR) is a novel approach to clinical trial design that incorporates safety and efficacy assessments into an ordinal ranking system to evaluate overall outcomes of clinical trial participants. Here, we derived and applied a disease-specific DOOR endpoint to registrational trials for complicated intra-abdominal infection (cIAI)., Methods: Initially, we applied an a priori DOOR prototype to electronic patient-level data from 9 phase 3 noninferiority trials for cIAI submitted to the US Food and Drug Administration between 2005 and 2019. We derived a cIAI-specific DOOR endpoint based on clinically meaningful events that trial participants experienced. Next, we applied the cIAI-specific DOOR endpoint to the same datasets and, for each trial, estimated the probability that a participant assigned to the study treatment would have a more desirable DOOR or component outcome than if assigned to the comparator., Results: Three key findings informed the cIAI-specific DOOR endpoint: (1) a significant proportion of participants underwent additional surgical procedures related to their baseline infection; (2) infectious complications of cIAI were diverse; and (3) participants with worse outcomes experienced more infectious complications, more serious adverse events, and underwent more procedures. DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 47.4% to 50.3% and were not significantly different. Component analyses depicted risk-benefit assessments of study treatment versus comparator., Conclusions: We designed and evaluated a potential DOOR endpoint for cIAI trials to further characterize overall clinical experiences of participants. Similar data-driven approaches can be utilized to create other infectious disease-specific DOOR endpoints., Competing Interests: Potential conflicts of interest. H. W. B. declares consulting fees from Antimicrobial Agents and Chemotherapy, Sanford Guide, and ID Clinics of North America. H. C. reports grant funding from the NIH; participation in a data and safety monitoring board (DSMB) for Merck; and stock in Merck and Moderna. D. C. reports grant funding from Apellis Pharmaceuticals, CRUK Cancer Grand Challenges, Kinnate Biopharma, and Incyte; consulting fees from Health Literacy Media and MaxisIT Clinical Science; payment for expert panel session from Pfizer; participation on a patient advisory council and travel support for meetings from M2GEN; and participation in the American Society of Clinical Oncology TAPUR Study DSMB and Parexel patient advisory council. S. B. D. reports grant funding from NIH; grant funding for COVID-19–related clinical trials from Gilead and Regeneron; payments for clinical event adjudication committees from Basilea and Shinogi; and consulting fees from Genentech. S. E. reports grant funding from NIH, Degruyter, and Aceragen; royalties from Taylor & Francis; consulting fees from Genetech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, and SVB Leerink; payments for lectures from the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); support for attending meetings from FDA, Deming Conference on Applied Statistics, Clinical Trial Transformation Initiative, Council for International Organization of Medical Sciences, International Chinese Statistical Association Applied Statistics Symposium, and Antimicrobial Resistance and Stewardship Conference; participation on DSMB for NIH, Breast International Group, University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouous, Appelis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, and Candel; and board membership for the American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. V. G. F. reports grant funding or contracts from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genetech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; consulting fees from Novartis, Debiopharm, Genetech, Achaogen, Affinium, The Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer; support from Contrafect to present phase 2 data at 2019 European Congress of Clinical Microbiology and Infectious Diseases; a patent for sepsis diagnostics; serving as Associate Editor of Clinical Infectious Diseases in 2017–2022; and stock options from ArcBio and Valanbio. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma K.K; a contract from Aceragen; payment for lectures from Duke University and Johnson & Johnson K.K.; and payment for manuscript preparation from Cancer and Chemotherapy K.K. (Japanese Journal of Cancer and Chemotherapy). T. L. H. reports grant funding from NIH; royalties from UpToDate; consulting fees from Lysovant and Affinivax; and participation on DSMB for SNAP Trial Platform. J. H.-A. reports grant funding from NIH. S. N. is an employee of Johnson & Johnson. U. W. reports support from the American Society for Microbiology to attend ASM Microbe 2022 as a speaker. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience., Methods: Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTIs). ZEUS compared fosfomycin to piperacillin/tazobactam, APEKS-cUTI compared cefiderocol to imipenem, and DORI-05 compared doripenem to levofloxacin. Using DOOR, we estimated the probability of a more desirable outcome with each investigational antibacterial drug., Results: In each RCT, the DOOR distribution was similar and the probability that a patient in the investigational arm would have a more desirable outcome than a patient in the control arm had a 95% confidence interval containing 50%, indicating no significant difference between treatment arms. DOOR facilitated improved understanding of potential trade-offs between clinical efficacy and safety. Partial credit and subgroup analyses also highlight unique attributes of DOOR., Conclusions: DOOR can effectively be used in registrational cUTI trials. The DOOR end point presented here can be adapted for other infectious disease syndromes and prospectively incorporated into future clinical trials., Competing Interests: Potential conflicts of interest. H. W. B. declares consulting fees from Antimicrobial Agents and Chemotherapy, Sanford Guide, and ID Clinics of North America. T. B. is an employee of and holds stock in Shionogi & Co and reports a nondisclosure agreement between Duke University and Shionogi (to share the analysis conducted by Shionogi with the Antibacterial Resistance Leadership Group [ARLG]). H. F. C. reports grant funding from NIH; consulting fees from Johnson & Johnson; participation on a data and safety monitoring board (DSMB) for Merck; and stock in Merck and Moderna. S. B. D. reports research funding from Gilead, Regeneron, and NIH; payments for clinical event adjudication committees from Basilea and Shionogi (pending); and consulting fees from Genentech. S. R. E. reports grant funding from NIH and Degruyter; royalties from Taylor & Francis; consulting fees from Genetech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Bickenson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, and SVB Leerink; payments for lectures from the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks; support for attending meetings from FDA, Clinical Trial Transformation Initiative, Council for International Organization of Medical Sciences, International Chinese Statistical Association, participation on DSMBs for NIH, Breast International Group, University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouous, Appelis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, and Advantagene; and being a board member for the American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche; grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases of America for service as associate editor of Clinical Infectious Diseases; and a patent for sepsis diagnostics is pending. S. P. G. is an employee of Nabriva Therapeutics and holds stock in Nabriva Therapeutics. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma and payment for lectures from Johnson & Johnson and Duke University. T. L. H. declares royalties from UpToDate and consulting fees from Basilea Pharmaceutica, MotifBio, Genentech, and Lysovant. D. M. is an employee of Nabriva Therapeutics and holds stock in Nabriva Therapeutics. S. N. is an employee of Johnson & Johnson and holds stock in Johnson & Johnson. J. H.-A. report grants from NIH (funding to ARLG, payments made to institution). S. B. D. reports grants or contracts from NIH funding to the ARLG; research funding from Gilead, Regeneron, and NIH; payments for clinical event adjudication committees from Basilea and Shionogi (pending); and consulting fees from Genentech. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ductal carcinoma in situ (DCIS) is a non-invasive breast neoplasia that accounts for 25% of all screen-detected breast cancers diagnosed annually. Neoplastic cells in DCIS are confined to the ductal system of the breast, although they can escape and progress to invasive breast cancer in a subset of patients. A key concern of DCIS is overtreatment, as most patients screened for DCIS and in whom DCIS is diagnosed will not go on to exhibit symptoms or die of breast cancer, even if left untreated. However, differentiating low-risk, indolent DCIS from potentially progressive DCIS remains challenging. In this Review, we summarize our current knowledge of DCIS and explore open questions about the basic biology of DCIS, including those regarding how genomic events in neoplastic cells and the surrounding microenvironment contribute to the progression of DCIS to invasive breast cancer. Further, we discuss what information will be needed to prevent overtreatment of indolent DCIS lesions without compromising adequate treatment for high-risk patients., (© 2022. Springer Nature Limited.)

Introduction: Regulatory agencies encourage the incorporation of the patient voices throughout clinical drug development. Patient-Reported Outcomes (PROs) offer one way of doing this and their use has markedly increased in many therapeutic areas, particularly oncology, in recent years. However, few oncology drug labels include PRO data and those which do, offer little consistency. Objective: To provide multidisciplinary perspectives (patient, pharmaceutical industry, PRO researcher, regulatory expert) on PRO data in oncology drug labels. Methods: PRO data in the labels of drugs approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for oncology indications between 2010 and 2020 were critically reviewed by authors who provided their insights on the advantages and disadvantages/gaps. Results: Forty-six oncology drugs included PRO data in their labels. Differences were observed between FDA and EMA PRO labeling (e.g., PRO concept, use of tables and graphs to display PROs or reference to clinical meaningfulness). In providing their perspectives on the number and nature of PROs in labels, authors noted limitations including: the low proportion of oncology drugs with PRO labeling, limited PRO information in labels, lack of patient-friendly language, and potential bias towards positive outcomes. Lack of consistency within- and between-agencies was noted. Conclusion: Despite regulatory agencies' commitment to incorporate patient voices in regulatory decisions, availability of PRO information is limited in oncology drug labels. While several PRO guidance documents are available from regulatory and Health Technology Assessment agencies, harmonization of PRO guidance for labeling inclusion around the world is needed to better inform prescribers and consequently their patients in the process of shared medical decisions., Competing Interests: DaC reported being Copyright holder or overseer for FACT/FACIT, PROMIS, and Neuro-QoL. C-IC, RQ, and VM are all employees of Regeneron Pharmaceuticals, Inc. and are shareholders of the company. In addition, RQ owns stocks of Pfizer Inc. and Amgen Inc. AU and MR are employees of IQVIA, which received professional service fees from Regeneron Pharmaceuticals, Inc. for conducting the study. The remaining 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 © 2022 Cella, Chen, Quek, Uribarren, Reaney, Mastey, Collyar and Chassany.)

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers., (© 2022. The Author(s).)

Purpose: CALGB 40603 (NCT00861705), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points., Patients and Methods: The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing., Results: Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS., Conclusion: Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival., Competing Interests: Karla BallmanConsulting or Advisory Role: Medtronic, Takeda, AgenusPatents, Royalties, Other Intellectual Property: Prostate cancer signature patent (Inst)Expert Testimony: Janssen Oncology, Lilly, Sanofi Sara SelitskyEmployment: QuantBio, Sash BiosciencesConsulting or Advisory Role: GeneCentric, C4 Therapeutics, Select ImmunoGenomics, FORMA Therapeutics, Atlas Venture, CytomX Therapeutics (Inst), Actym Therapeutics (Inst), Capulus Therapeutics (Inst), Codagenix (Inst) Joel S. ParkerStock and Other Ownership Interests: GeneCentric, Reveal GenomicsConsulting or Advisory Role: Bristol Myers Squibb/CelgenePatents, Royalties, Other Intellectual Property: J.S.P. has authored patents related to the PAM50 algorithm, which are licensed to NanoString Technologies Patricia A. SpearsConsulting or Advisory Role: Pfizer Sara M. TolaneyThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech, Eisai, Sanofi, Celldex, Bristol Myers Squibb, Paxman, Seattle Genetics, Odonate Therapeutics, AbbVie, Silverback Therapeutics, G1 Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Immunomedics/Gilead, Mersana, Certara, 4D Pharma, Ellipses Pharma, OncoSec, Chugai Pharma, BeyondSpring Pharmaceuticals, OncXerna TherapeuticsResearch Funding: Genentech/Roche (Inst), Merck (Inst), Exelixis (Inst), Pfizer (Inst), Lilly (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Eisai (Inst), AstraZeneca (Inst), NanoString Technologies (Inst), Cyclacel (Inst), Nektar (Inst), Immunomedics (Inst), Odonate Therapeutics (Inst), Sanofi (Inst), Seattle Genetics (Inst)Travel, Accommodations, Expenses: AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Eisai, NanoString Technologies, Puma Biotechnology, Celldex Cynthia MaConsulting or Advisory Role: Novartis, Seattle Genetics, Agendia, AstraZeneca, Athenex, Bayer HealthCare Pharmaceuticals, Biovica Inc, Eisai, Olaris, Philips Electronics, Puma Biotechnology, Sanofi Genzyme, Jacobio, Natera, InivataResearch Funding: Pfizer (Inst), Puma Biotechnology (Inst) Eleftherios MamounasHonoraria: Genentech/Roche, Genomic Health, PreciscaConsulting or Advisory Role: Genomic Health, BioTheranostics, Roche/Genentech, Merck, Puma Biotechnology, Precisca, AgendiaSpeakers' Bureau: Genomic Health, Genentech/Roche Mehra GolshanConsulting or Advisory Role: AbbVie, BertisResearch Funding: Breast Cancer Research Foundation Jennifer R. BellonThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Leadership: International Journal of Radiation Oncology Biology PhysicsHonoraria: UpToDate, Accuray, Leidos Biomedical Research, Grupo OncoclinicasResearch Funding: NanoString Technologies (Inst)Patents, Royalties, Other Intellectual Property: Coeditor of breast cancer textbook (Radiation Therapy Techniques and Treatment Planning for Breast Cancer). Honorarium, SpringerOther Relationship: Varian Medical Systems Deborah CollyarHonoraria: PfizerConsulting or Advisory Role: Parexel, MaxisIT, Kinnate BiopharmaTravel, Accommodations, Expenses: Parexel Olwen M. HahnLeadership: Via OncologyStock and Other Ownership Interests: Teleflex MedicalHonoraria: Cardinal Health (I)Consulting or Advisory Role: Pfizer, hmpglobal.comTravel, Accommodations, Expenses: Cardinal Health (I) Clifford A. HudisUncompensated Relationships: Alliance Foundation Trials, Columbia University, Memorial Sloan-Kettering Cancer CenterOpen Payments Link: https://openpaymentsdata.cms.gov/physician/471974/summary Eric P. WinerHonoraria: Genentech/Roche, Genomic HealthConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, Zymeworks, AthenexResearch Funding: Genentech (Inst)Other Relationship: InfiniteMD Ann PartridgePatents, Royalties, Other Intellectual Property: I receive small royalty payments for coauthoring the breast cancer survivorship section of UpToDateOpen Payments Link: https://openpaymentsdata.cms.gov/physician/835197 Terry HyslopConsulting or Advisory Role: AbbVieTravel, Accommodations, Expenses: AbbVie Lisa A. CareyResearch Funding: Syndax (Inst), Novartis (Inst), NanoString Technologies (Inst), AbbVie (Inst), Seattle Genetics (Inst), Veracyte (Inst)Patents, Royalties, Other Intellectual Property: Royalty-sharing agreement, investorship interest in licensed IP to startup company, Falcon Therapeutics, that is designing neural stem-cell–based therapy for glioblastoma multiforme (I)Uncompensated Relationships: Sanofi (Inst), Novartis (Inst), G1 Therapeutics (Inst), Genentech/Roche (Inst), GlaxoSmithKline (Inst), AstraZeneca/Daiichi Sankyo (Inst), Aptitude Health (Inst), Exact Sciences (Inst), EisaiOpen Payments Link: https://openpaymentsdata.cms.gov/physician/179671 Charles M. PerouLeadership: GeneCentricStock and Other Ownership Interests: Bioclassifier, GeneCentric, Reveal GenomicsConsulting or Advisory Role: Bioclassifier, GeneCentric, NanoString Technologies, Veracyte, Reveal GenomicsPatents, Royalties, Other Intellectual Property: Royalties from PAM50 breast cancer gene patent application and from lung gene signature patentTravel, Accommodations, Expenses: Takeda, Chugai Pharma William M. SikovHonoraria: UpToDateSpeakers' Bureau: Lilly, Daiichi Sankyo, Seattle GeneticsNo other potential conflicts of interest were reported.

Health technology assessment (HTA) is intended to determine the value of health technologies and, once a technology is recommended for funding, bridge clinical research and practice. Understanding the values and beliefs expressed by patients and health professionals can help guide this knowledge transfer and work toward managing the expectations of end users. We gathered patient and patient group leader experiences to gain insights into the roles that patients and patient advocacy groups are playing. We argue that through partnerships and co-creation between HTA professionals, researchers and patient advocates we can strengthen the HTA process and better align with service delivery where person-centered care and shared decision making are key elements. Patient experiences and knowledge are important to the democratization of evidence and the legitimacy of HTAs. Patient preference studies are used to balance benefits with potential harms of technologies, and patient-reported outcomes (PROs) can measure what matters to patients over time. A change in culture in HTA bodies is occurring and with further transformative thinking patients can be involved in every step of the HTA process. Patients have a right to be involved in HTAs, with patients' values central to HTA deliberations on a technology and where patients can provide valuable insights to inform HTA decision-making; and in ensuring that HTA methodologies evolve. By evaluating the implementation of HTA recommendations we can determine how HTA benefits patients and their communities. Our shared commitment can positively effect the common good and provide benefits to individual patients and their communities., 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 © 2022 Wale, Chandler, Collyar, Hamerlijnck, Saldana and Pemberton-Whitely.)

Health literacy research and interventions have provided multiple tools to improve communication between professionals and patients in clinical contexts for many years. Despite the reality that many patients participate in clinical trials in conjunction with standard medical care, only recently have efforts extended to address and improve the health literacy of both clinical trial researchers and participants. To date, the primary focus of health literacy activities in clinical trials has centered on communicating trial results to trial participants. This report describes the opportunities and strategies necessary to layer health literacy activities across the clinical trial process from consent to conclusion.

Importance: Information to be included in advance informed consent forms for health care-associated pneumonia treatment trials remains to be determined., Objective: To identify and determine how to describe information to be included in an advance informed consent form for an early-enrollment noninferiority hospital-acquired and/or ventilator-associated bacterial pneumonia (HABP/VABP) clinical trial., Design, Setting, and Participants: A Delphi consensus process with stakeholders in HABP/VABP clinical trials was conducted using qualitative semistructured telephone interviews from June to August 2016, followed by 2 online surveys, the first from April to May 2017, and the second from September to October 2017. All stakeholders who participated in the interview were invited to participate in the first survey. Stakeholders who participated in the first survey were invited to participate in the second survey. Stakeholders were patients at risk of pneumonia, caregivers, representatives of institutional review boards, investigators, and study coordinators., Main Outcomes and Measures: Description and consensus of information to be included in advance informed consent forms for early enrollment in noninferiority HABP/VABP clinical trials., Results: Suggestions from 52 stakeholders about what key informed consent concepts to include and how to explain them were used to create 3 categories to be included in an advance consent form: (1) reassurances on patient health and treatment, (2) rationale for advance consent and early enrollment, and (3) an explanation of noninferiority. At the end of the Delphi process, at least 80% consensus was reached among the 40 stakeholders who participated in the second online survey on each of the statements to include in the proposed consent text. Throughout the process, however, describing and reaching consensus on statements about noninferiority was more problematic than the other categories., Conclusions and Relevance: The stakeholders endorsed consent language to be used in combination with a strategy for enrolling patients at highest risk for pneumonia before infection onset. Data-driven consent language may help potential participants make informed decisions about their involvement in clinical research and improve enrollment rates, which are necessary to evaluate new treatments and improve patient care. The proposed consent language may be adapted for other trials using an early enrollment strategy and for noninferiority trials.

Objective: The majority of 'low-risk' (grade I/II) Ductal Carcinoma In Situ (DCIS) may not progress to invasive breast cancer during a women's lifetime. Therefore, the safety of active surveillance versus standard surgical treatment for DCIS is prospectively being evaluated in clinical trials. If proven safe and selectively implemented in clinical practice, a significant group of women with low-risk DCIS may forego surgery and radiotherapy in the future. Identification of modifiable and non-modifiable risk factors associated with prognosis after a primary DCIS would also enhance our care of women with low-risk DCIS., Methods: To identify modifiable and non-modifiable risk factors for subsequent breast events after DCIS, we performed a systematic literature search in PUBMED, EMBASE and Scopus., Results: Six out of the 3870 articles retrieved were included for final data extraction. These six studies included a total of 4950 patients with primary DCIS and 640 recorded subsequent breast events. There was moderate evidence for an association of a family history of breast cancer, premenopausal status, high BMI, and high breast density with a subsequent breast cancer or further DCIS., Conclusion: There is a limited number of recent studies published on the impact of modifiable and non-modifiable risk factors on subsequent events after DCIS. The available evidence is insufficient to identify potential targets for risk reduction strategies, reflecting the relatively small numbers and the lack of long-term follow-up in DCIS, a low-event condition., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Oncology research increasingly involves biospecimen collection and data sharing. Ethical challenges emerge when researchers seek to use archived biospecimens for purposes that were not well defined in the original informed consent document (ICD). We sought to inform ongoing policy debates by assessing patient views on these issues., Materials and Methods: We administered a cross-sectional self-administered survey to patients with cancer at an academic medical center. Survey questions addressed attitudes toward cancer research, willingness to donate biospecimens, expectations regarding use of biospecimens, and preferences regarding specific ethical dilemmas., Results: Among 240 participants (response rate 69%), virtually all (94%) indicated willingness to donate tissue for research. Most participants (86%) expected that donated tissue would be used for any research deemed scientifically important, and virtually all (94%) expected that the privacy of their health information would be protected. Broad use of stored biospecimens and data sharing with other researchers increased willingness to donate tissue. For three scenarios in which specific consent for proposed biobank research was unclear within the ICD, a majority of patient's favored allowing the research to proceed: 76% to study a different cancer, 88% to study both inherited (germline) and tumor specific (somatic) mutations, and 70% to permit data sharing. A substantial minority believed that research using stored biospecimens should only proceed with specific consent., Conclusion: When debates arise over appropriate use of archived biospecimens, the interests of the research participants in seeing productive use of their blood or tissue should be considered, in addition to addressing concerns about potential risks and lack of specific consent., Implications for Practice: This survey evaluated views of patients with cancer regarding the permissible use of stored biospecimens from cancer trials when modern scientific methods are not well described in the original informed consent document. The vast majority of patients support translational research and expect that any biospecimens they donate will be used to advance knowledge. When researchers, policy makers, and those charged with research oversight debate use of stored biospecimens, it is important to recognize that research participants have an interest in productive use of their blood, tissue, or data, in addition to considerations of risks and the adequacy of documented consent., (© AlphaMed Press 2019.)

Background: As scientific techniques evolve, historical informed consent forms may inadequately address modern research proposals, leading to ethical questions regarding research with archived biospecimens., Subjects, Materials, and Methods: We conducted focus groups among patients with cancer recruited from Massachusetts General Hospital to explore views on medical research, biobanking, and scenarios based on real biospecimen research dilemmas. Our multidisciplinary team developed a structured focus group guide, and all groups were recorded and transcribed. Transcripts were coded for themes by two independent investigators using NVivo software., Results: Across five focus groups with 21 participants, we found that most participants were supportive of biobanks and use of their own tissue to advance scientific knowledge. Many favor allowing research beyond the scope of the original consent to proceed if recontact is impossible. However, participants were not comfortable speaking for other patients who may oppose research beyond the original consent. This was viewed as a potential violation of participants' rights or interests. Participants were also concerned with a "slippery slope" and potential scientific abuse if research were permitted without adherence to original consent. There was strong support for recontact and reconsent when possible and for the concept of broad consent at the time of tissue collection., Conclusion: Our participants support use of their tissue to advance research and generally support any productive scientific approach. However, in the absence of broad initial consent, when recontact is impossible, a case-by-case decision must be made regarding a proposal's potential benefits and harms. Many participants support broad use of their tissue, but a substantial minority object to use beyond the original consent., Implications for Practice: For prospective studies collecting tissue for future research, investigators should consider seeking broad consent, to allow for evolution of research questions and methods. For studies using previously collected tissues, researchers should attempt recontact and reconsent for research aims or methods beyond the scope of the original consent. When reconsent is not possible, a case-by-case decision must be made, weighing the scientific value of the biobank, potential benefits of the proposed research, and the likelihood and nature of risks to participants and their welfare interests. This study's data suggest that many participants support broad use of their tissue and prefer science to move forward., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Introduction: Ductal carcinoma in situ (DCIS) is a non-invasive non-obligate precursor of invasive breast cancer. With guideline concordant care (GCC), DCIS outcomes are at least as favourable as some other early stage cancer types such as prostate cancer, for which active surveillance (AS) is a standard of care option. However, AS has not yet been tested in relation to DCIS. The goal of the COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial for low-risk DCIS is to gather evidence to help future patients consider the range of treatment choices for low-risk DCIS, from standard therapies to AS. The trial will determine whether there may be some women who do not substantially benefit from current GCC and who could thus be safely managed with AS. This protocol is version 5 (11 July 2018). Any future protocol amendments will be submitted to Quorum Centralised Institutional Review Board/local institutional review boards for approval via the sponsor of the study (Alliance Foundation Trials)., Methods and Analysis: COMET is a phase III, randomised controlled clinical trial for patients with low-risk DCIS. The primary outcome is ipsilateral invasive breast cancer rate in women undergoing GCC compared with AS. Secondary objectives will be to compare surgical, oncological and patient-reported outcomes. Patients randomised to the GCC group will undergo surgery as well as radiotherapy when appropriate; those in the AS group will be monitored closely with surgery only on identification of invasive breast cancer. Patients in both the GCC and AS groups will have the option of endocrine therapy. The total planned accrual goal is 1200 patients., Ethics and Dissemination: The COMET trial will be subject to biannual formal review at the Alliance Foundation Data Safety Monitoring Board meetings. Interim analyses for futility/safety will be completed annually, with reporting following Consolidated Standards of Reporting Trials (CONSORT) guidelines for non-inferiority trials., Trial Registration Number: NCT02926911; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Better treatment options are needed in life-threatening infections, including health care-associated pneumonia. Enrolling patients in antibacterial clinical trials before diagnosis may circumvent existing time-to-enrollment constraints. However, the acceptability of an early enrollment strategy using advance consent is unknown., Objective: To assess the perceived acceptability of an early enrollment strategy for enrolling patients in an antibacterial clinical trial before a pneumonia diagnosis., Design, Setting, and Participants: This qualitative, descriptive study used semistructured telephone interviews. Framed within a planned noninferiority pneumonia antibiotic trial, an early enrollment strategy was described and perceptions were assessed. Using this strategy, patients give consent to enroll before developing pneumonia, to be monitored by study staff, and to be randomly assigned a study antibiotic if pneumonia develops. All interviews were audiorecorded, transcribed verbatim, and analyzed using applied thematic analysis. Fifty-two key stakeholders from across the United States, including 18 patients at risk of pneumonia, 12 caregivers, 10 representatives of institutional review boards, 7 investigators, and 5 study coordinators, were interviewed from June 20 to August 19, 2016., Main Outcomes and Measures: Perceived acceptability of the early enrollment strategy., Results: Among the 52 stakeholders interviewed (ages 29-75 years; 14 women), patients and caregivers expressed no concerns about patients being approached about participation before developing pneumonia; however, some patients may experience anxiety on learning about their risk for pneumonia. No concerns with study staff accessing patients' medical records were expressed. The clarity of consent information was important for understanding the study rather than having the condition under investigation. Among patients, caregivers, and institutional review board representatives, preferences varied regarding opt-out and precedent autonomy procedures. Nearly all patients would be willing to join a trial using the early enrollment strategy and caregivers would be willing to provide proxy consent. Institutional review board representatives were supportive of the strategy and made recommendations for the study protocol, primarily around informed consent. Investigators and study coordinators believed the strategy would not be burdensome and offered suggestions to ensure its feasibility., Conclusion and Relevance: Results of the study suggest that the early enrollment strategy is acceptable. Future research should evaluate whether the strategy improves enrollment rates in registrational pneumonia trials and in trials of other acute infection syndromes with narrow enrollment windows and/or patients with transient decisional incapacity.

The Center for Medical Technology Policy and the Molecular Evidence Development Consortium gathered a diverse group of more than 50 stakeholders to develop consensus on a core set of data elements and values essential to understanding the clinical utility of molecularly targeted therapies in oncology., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Approximately 70% of all breast cancers express the estrogen receptor, and are regulated by estrogen. While the ovaries are the primary source of estrogen in premenopausal women, most breast cancer is diagnosed following menopause, when systemic levels of this hormone decline. Estrogen production from androgen precursors is catalyzed by the aromatase enzyme. Although aromatase expression and local estrogen production in breast adipose tissue have been implicated in the development of primary breast cancer, the source of estrogen involved in the regulation of estrogen receptor-positive (ER+) metastatic breast cancer progression is less clear., Methods: Bone is the most common distant site of breast cancer metastasis, particularly for ER+ breast cancers. We employed a co-culture model using trabecular  bone tissues obtained from total hip replacement (THR) surgery specimens to study ER+ and estrogen receptor-negative (ER-) breast cancer cells within the human bone microenvironment. Luciferase-expressing ER+ (MCF-7, T-47D, ZR-75) and ER- (SK-BR-3, MDA-MB-231, MCF-10A) breast cancer cells were cultured directly on bone tissue fragments or in bone tissue-conditioned media, and monitored over time with bioluminescence imaging (BLI). Bone tissue-conditioned media were generated in the presence vs. absence of aromatase inhibitors, and testosterone. Bone tissue fragments were analyzed for aromatase expression by immunohistochemistry., Results: ER+ breast cancer cells were preferentially sustained in co-cultures with bone tissues and bone tissue-conditioned media relative to ER- cells. Bone fragments analyzed by immunohistochemistry revealed expression of the aromatase enzyme. Bone tissue-conditioned media generated in the presence of testosterone had increased estrogen levels and heightened capacity to stimulate ER+ breast cancer cell proliferation. Pretreatment of cultured bone tissues with aromatase inhibitors, which inhibited estrogen production, reduced the capacity of conditioned media to stimulate ER+ cell proliferation., Conclusions: These results suggest that a local estrogen signaling axis regulates ER+ breast cancer cell viability and proliferation within the bone metastatic niche, and that aromatase inhibitors modulate this axis. Although endocrine therapies are highly effective in the treatment of ER+ breast cancer, resistance to these treatments reduces their efficacy. Characterization of estrogen signaling networks within the bone microenvironment will identify new strategies for combating metastatic progression and endocrine resistance.

Objectives: To explore patient, caregiver and physician perceptions and attitudes regarding the balance of benefit and risk in using antibacterial drugs developed through streamlined development processes., Design: Semistructured focus groups and in-depth interviews were conducted to elicit perceptions and attitudes about the use of antibacterial drugs to treat multidrug-resistant infections. Participants were given background information about antibiotic resistance, streamlined drug development programmes and FDA drug approval processes. Audio recordings of focus groups/interviews were reviewed and quotes excerpted and categorised to identify key themes., Participants: Two primary stakeholder groups were engaged: one comprising caregivers, healthy persons and patients who had recovered from or were at risk of resistant infection (N=67; 11 focus groups); and one comprising physicians who treat resistant infections (N=23)., Results: Responses from focus groups/interviews indicated widespread awareness among patients/caregivers and physicians of the seriousness of the problem of antibacterial resistance. Both groups were willing to accept a degree of uncertainty regarding the balance of risk and benefit in a new therapy where a serious unmet need exists, but also expressed a desire for rigorous monitoring and rapid, transparent reporting of safety/effectiveness data. Both groups wanted to ensure that >1 physician had input on whether to treat patients with antibiotics developed through a streamlined process. Some patients/caregivers unfamiliar with exigencies of critical care suggested a relatively large multidisciplinary team, while physicians believed individual expert consultations would be preferable. Both groups agreed that careful oversight and stewardship of antibacterial drugs are needed to ensure patient safety, preserve efficacy and prevent abuse., Conclusions: Groups comprising patients/caregivers and physicians were aware of serious issues posed by resistant infections and the lack of effective antibacterial drug therapies and shared a consensus that streamlined development programmes represent a necessary response to the resistance crisis, but one that requires enhanced safeguards and risk communication., Competing Interests: Three authors (JS, RT, JT.) are employees of the US Food and Drug Administration, a funder of the Clinical Trials Transformation Initiative and the present study. The FDA is responsible for the review and approval of antibacterial drugs, including those developed using streamlined approaches., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Contralateral prophylactic mastectomy (CPM) is commonly performed for the treatment of breast cancer, despite its limited oncologic benefit. Little is known about surgeons' perceptions of performing CPM. We hypothesized that a proportion of surgeons would report discomfort with performing CPM, particularly when there is discordance between patients' perceived benefit from CPM and the expected oncologic benefit., Methods: A survey was sent to members of the American Society of Breast Surgeons seeking self-reports of surgeons' practice patterns, perceptions, and comfort levels with CPM., Results: Of the 2436 members surveyed, 601 responded (response rate = 24.7 %). The median age of respondents was 52 years, and 59 % of responders were women. The majority (58 %) reported that 80 % of their practice was devoted to the treatment of breast disease. Fifty-seven percent (n = 326) of respondents reported discomfort with performing CPM at some point in their practice. While most surgeons (95 %) were comfortable with CPM on a patient with a deleterious BRCA mutation, only 34 % were comfortable performing CPM on an average-risk patient. The most common reasons reported for surgeon discomfort with CPM were a concern for overtreatment, an unfavorable risk/benefit ratio, and inadequate patient understanding of the anticipated risks and benefits of CPM., Conclusions: Despite the increasing use of CPM for the treatment of breast cancer, many surgeons report discomfort with CPM. Concerns with performing CPM predominantly focus on ambiguities surrounding the oncologic benefit and relative risk of this procedure. Further research is needed to define optimal shared decision-making practices in this area.

Purpose: One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab., Patients and Methods: Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m(2) once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed., Results: Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated., Conclusion: In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent., (© 2014 by American Society of Clinical Oncology.)

Cancer is not one disease. Outcomes and endpoints in trials should incorporate the therapeutic modality and cancer type because these factors affect clinician and patient expectations. In this Review, we discuss how to: define the importance of endpoints; make endpoints understandable to patients; improve the use of patient-reported outcomes; advance endpoints to parallel changes in trial design and therapeutic interventions; and integrate these improvements into trials and practice. Endpoints need to reflect benefit to patients, and show that changes in tumour size either in absolute terms (response and progression) or relative to control (progression) are clinically relevant. Improvements in trial design should be accompanied by improvements in available endpoints. Stakeholders need to come together to determine the best approach for research that ensures accountability and optimises the use of available resources., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase I clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker)., (©2014 American Association for Cancer Research.)

As the need for patient participation in biospecimen and correlative research increases, challenging ethical and potentially legal questions are emerging.