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Background: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM., Patients and Methods: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed., Results: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months., Conclusions: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients with early-stage triple-negative breast cancer (TNBC) with residual invasive disease after neoadjuvant therapy have a high risk of recurrence even with neoadjuvant and adjuvant treatment with pembrolizumab. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload, improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with pre-treated metastatic TNBC. Moreover, preclinical data suggest that topoisomerase I inhibitors may enhance the effects of immune checkpoint inhibitors through activation of the cGAS-STING pathway. Here we describe the international randomized phase III AFT-65/ASCENT-05/OptimICE-RD trial, which evaluates the efficacy and safety of sacituzumab govitecan plus pembrolizumab versus treatment of physician's choice (pembrolizumab ± capecitabine) among patients with early-stage TNBC with residual invasive disease after neoadjuvant therapy. Clinical Trial Registration: NCT05633654 (ClinicalTrials.gov) Other Study ID Number(s): Gilead Study ID: GS-US-595-6184 Registration date: 1 December 2022 Study start date: 12 December 2022 Recruitment status: Recruiting.

The purpose of this study was to describe the health status and barriers of people who sought care on a free mobile health clinic for women without insurance in California. Participants were 221 women who attended the Salud para Mujeres (Women's Health) mobile medical clinic between 2019 and 2021. Medical chart abstractions provided data on sociodemographic factors, medical history, barriers to care, depressive symptoms, and dietary factors. Anthropometric measure, blood pressure, and biomarkers of cardiometabolic disease risk were also abstracted. Participants were young adult (29.1 [SD 9.3] years), Hispanic (97.6%), farm-working (62.2%) women from Mexico (87.0%). Prevalent barriers to accessing (non-mobile) medical care included high cost (74.5%), language (47.6%), hours of operation (36.2%), and transportation (31.4%). The majority (89.5%) of patients had overweight (34.0%) or obesity (55.5%), and 27% had hypertension. Among those (n = 127) receiving a lipid panel, 60.3% had higher than recommended levels of low-density lipoprotein and 89% had lower than recommended levels of high-density lipoprotein. Point-of-care HbA1c tests (n = 133) indicated that 9.0% had diabetes and 24.8% had prediabetes. Over half (53.1%) of patients reported prevalent occupational exposure to pesticides and 19% had moderate to severe depressive symptoms. Weekly or more frequent consumption of sugar sweetened beverages (70.9%) and fast food (43.5%) were also prevalent. Mobile health units have potential for reaching women who face several barriers to care and experience major risk factors for cardometabolic disease. Findings suggest a compelling need to assure that Hispanic and Indigenous women and farmworkers have access to healthcare., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1., Significance: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials., Significance: Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti-PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance. This article is featured in Selected Articles from This Issue, p. 201., (©2023 The Authors; Published by the American Association for Cancer Research.)

Importance: Agents targeting programmed death ligand 1 (PD-L1) have demonstrated efficacy in triple-negative breast cancer (TNBC) when combined with chemotherapy and are now the standard of care in patients with PD-L1-positive metastatic disease. In contrast to microtubule-targeting agents, the effect of combining platinum compounds with programmed cell death 1 (PD-1)/PD-L1 immunotherapy has not been extensively determined., Objective: To evaluate the efficacy of atezolizumab with carboplatin in patients with metastatic TNBC., Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted in 6 centers from August 2017 to June 2021., Interventions: Patients with metastatic TNBC were randomized to receive carboplatin area under the curve (AUC) 6 alone or with atezolizumab, 1200 mg, every 3 weeks until disease progression or unacceptable toxic effects with a 3-year duration of follow-up., Main Outcome and Measures: The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). Other objectives included correlation of response with tumor PD-L1 levels, tumor-infiltrating lymphocytes (TILs), tumor DNA- and RNA-sequenced biomarkers, TNBC subtyping, and multiplex analyses of immune markers., Results: All 106 patients with metastatic TNBC who were enrolled were female with a mean (range) age of 55 (27-79) years, of which 12 (19%) identified as African American/Black, 1 (1%) as Asian, 73 (69%) as White, and 11 (10%) as unknown. Patients were randomized and received either carboplatin (n = 50) or carboplatin and atezolizumab (n = 56). The combination improved PFS (hazard ratio [HR], 0.66; 95% CI, 0.44-1.01; P = .05) from a median of 2.2 to 4.1 months, increased ORR from 8.0% (95% CI, 3.2%-18.8%) to 30.4% (95% CI, 19.9%-43.3%), increased CBR at 6 months from 18.0% (95% CI, 9.8%-30.1%) to 37.5% (95% CI, 26.0%-50.6%), and improved OS (HR, 0.60; 95% CI, 0.37-0.96; P = .03) from a median of 8.6 to 12.6 months. Subgroup analysis showed PD-L1-positive tumors did not benefit more from adding atezolizumab (HR, 0.62; 95% CI, 0.23-1.65; P = .35). Patients with high TILs (HR, 0.12; 95% CI, 0.30-0.50), high mutation burden (HR, 0.50; 95% CI, 0.23-1.06), and prior chemotherapy (HR, 0.59; 95% CI, 0.36-0.95) received greater benefit on the combination. Patients with obesity and patients with more than 125 mg/dL on-treatment blood glucose levels were associated with better PFS (HR, 0.35; 95% CI, 0.10-1.80) on the combination. TNBC subtypes benefited from adding atezolizumab, except the luminal androgen receptor subtype., Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to carboplatin significantly improved survival of patients with metastatic TNBC regardless of PD-L1 status. Further, lower risk of disease progression was associated with increased TILs, higher mutation burden, obesity, and uncontrolled blood glucose levels., Trial Registration: ClinicalTrials.gov Identifier: NCT03206203.

FloPy is a Python package for creating, running, and post-processing MODFLOW-based groundwater flow and transport models. FloPy functionality has expanded to support the latest version of MODFLOW (MODFLOW 6) including support for unstructured grids. FloPy can simplify the process required to download MODFLOW-based and other executables for Linux, MacOS, and Windows operating systems. Expanded FloPy capabilities include (1) full support for structured and unstructured spatial discretizations; (2) geoprocessing of spatial features and raster data to develop model input for supported discretization types; (3) the addition of functionality to provide direct access to simulated output data; (4) extension of plotting capabilities to unstructured MODFLOW 6 discretization types; and (5) the ability to export model data to shapefiles, NetCDF, and VTK formats for processing, analysis, and visualization by other software products. Examples of using expanded FloPy capabilities are presented for a hypothetical watershed. An unstructured groundwater flow and transport model, with several advanced stress packages, is presented to demonstrate how FloPy can be used to develop complicated unstructured model datasets from original source data (shapefiles and rasters), post-process model results, and plot simulated results., (© 2023 The Authors. Groundwater published by Wiley Periodicals LLC on behalf of National Ground Water Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Tebotelimab, a bispecific PD-1×LAG-3 DART molecule that blocks both PD-1 and LAG-3, was investigated for clinical safety and activity in a phase 1 dose-escalation and cohort-expansion clinical trial in patients with solid tumors or hematologic malignancies and disease progression on previous treatment. Primary endpoints were safety and maximum tolerated dose of tebotelimab when administered as a single agent (n = 269) or in combination with the anti-HER2 antibody margetuximab (n = 84). Secondary endpoints included anti-tumor activity. In patients with advanced cancer treated with tebotelimab monotherapy, 68% (184/269) experienced treatment-related adverse events (TRAEs; 22% were grade ≥3). No maximum tolerated dose was defined; the recommended phase 2 dose (RP2D) was 600 mg once every 2 weeks. There were tumor decreases in 34% (59/172) of response-evaluable patients in the dose-escalation cohorts, with objective responses in multiple solid tumor types, including PD-1-refractory disease, and in LAG-3 + non-Hodgkin lymphomas, including CAR-T refractory disease. To enhance potential anti-tumor responses, we tested margetuximab plus tebotelimab. In patients with HER2 + tumors treated with tebotelimab plus margetuximab, 74% (62/84) had TRAEs (17% were grade ≥3). The RP2D was 600 mg once every 3 weeks. The confirmed objective response rate in these patients was 19% (14/72), including responses in patients typically not responsive to anti-HER2/anti-PD-1 combination therapy. ClinicalTrials.gov identifier: NCT03219268 ., (© 2023. The Author(s).)

Purpose: Treatment-associated symptoms drive early discontinuation of adjuvant endocrine therapy (ET) for breast cancer. We hypothesized that symptom monitoring with electronic patient-reported outcomes (ePROs) during adjuvant ET will enhance symptom detection, symptom management, and persistence., Methods: Eligible patients were initiating ET for stage 0-III breast cancer. Participants completed ePRO surveys via smartphone at baseline and 1, 3, 6, and 12 months. Measures included Patient-Reported Outcomes Measurement Information System Anxiety, Depression, Fatigue, and Vaginal Discomfort; plus Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items assessing joint pain, hot flashes, vaginal dryness, concentration problems, and memory problems. Scores surpassing prespecified thresholds triggered alerts, and recommended symptom management pathways were provided to clinicians. The primary objective was to evaluate feasibility, assessed by survey completion rates, with targets of >65% for the baseline survey and ≥1 follow-up survey during the first 6 months. Secondary objectives included 12-month ET discontinuation rate (target: ≤15%), describing symptoms and evaluating pathway implementation., Results: Among 250 participants, 73.2% completed the baseline survey and 69.6% completed ≥1 follow-up survey during the first 6 months. Thirty-one percent of participants had ≥1 symptom alert at baseline and 74% had ≥1 symptom alert during follow-up. The proportions of participants for whom pathway-concordant symptom management was documented at each time point ranged from 12.8% to 36.6%. Twenty-eight participants (11.2%) discontinued ET by 12 months., Conclusion: Symptom monitoring with ePROs during adjuvant ET is feasible. Despite infrequent documentation of pathway-concordant symptom management after symptom alerts, ePROs were associated with favorable short-term ET persistence.

Background: Preconception lifestyle intervention holds potential for reducing gestational diabetes mellitus, but clinical trial data are lacking., Objective: This study aimed to determine the effects of a prepregnancy weight loss intervention on gestational diabetes mellitus recurrence in women with overweight/obesity and previous gestational diabetes mellitus., Study Design: A 2-site, randomized controlled trial comparing a prepregnancy lifestyle intervention with educational control was conducted between December 2017 and February 2022. A total of 199 English- and Spanish-speaking adults with overweight/obesity and previous gestational diabetes mellitus were randomized to a 16-week prepregnancy lifestyle intervention with ongoing treatment until conception or educational control. The primary outcome was gestational diabetes mellitus recurrence. Analyses excluded 6 participants who conceived but did not have gestational diabetes mellitus ascertained by standard methods., Results: In the 63 (33%) women who conceived and had gestational diabetes mellitus ascertained (Ns=38/102 [37%] intervention vs 25/91 [28.0%] control; P=.17), those in the intervention group had significantly greater weight loss at 16 weeks compared with controls (4.8 [3.4-6.0] vs 0.7 [-0.9 to 2.3] kg; P=.001) and a greater proportion lost ≥5% of body weight (50.0% [17/34] vs 13.6% [3/22]; P=.005). There was no significant difference in the incidence of gestational diabetes mellitus recurrence between the intervention (57.9% [ns=23/38]) and the control group (44.0% [ns=11/25]; odds ratio, 1.8 [0.59-5.8]). Independent of group, greater prepregnancy weight loss predicted 21% lower odds of gestational diabetes mellitus recurrence (odds ratio, 0.79 [0.66-0.94]; P=.008). A ≥5% weight loss before conception reduced the odds of gestational diabetes mellitus recurrence by 82% (odds ratio, 0.18 [0.04-0.88]; P=.03)., Conclusion: Lifestyle intervention produced considerable prepregnancy weight loss but did not affect gestational diabetes mellitus rates. Given that the conception rate was 50% lower than expected, this study was underpowered., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care., Competing Interests: Declaration of interests TSA, DKS, PSS, JAH, MGE, JSB-S, PGP, CNC, and MMA are employees of the US National Institutes of Health. BME received consulting fees from Medicenna, MedQIA, Servier, Chimerix, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Ellipses Pharma, Alpheus Medical, Curtana Pharma, Sagimet Biosciences, and Sapience Therapeutics; and other support from Siemens. SCF received grants from Siemens and Neosoma; consulting fees from Medicenna, MedQIA, Servier, Chimerix, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Ellipses Pharma, Alpheus Medical, Curtana Pharma, Sagimet Biosciences, and Sapience Therapeutics; and other services from Siemens. AAA received grants from Varian and NH TheraAguix, and consulting fees from Novartis and Seagen. DMT received grants from Varian Medical Systems, Blue Earth Diagnostics, and NovoCure, and consulting fees from Boston Scientific. RK received grants from Medtronic, Blue Earth Diagnostics, NovoCure, GT Medical Technologies, AstraZeneca, Exelixis, Viewray, Brainlab, and Cantex Pharmaceuticals; consulting fees from Kazia Therapeutics, Elekta, Viewray, Castle Biosciences, and NovoCure; travel support from Elekta, Accuray, NovoCure, and Peerview Institute for Medical Education; other support from Elekta, Accuray, Novocure, and the Peerview Institute for Medical Education; and is on the Viewray Medical Advisory Board. CKA received grants from PUMA, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1-Therapeutics, ZION, Novartis, Pfizer, AstraZeneca, Elucida, and Caris; licences from UpToDate and Jones and Bartlett; other support from Genentech, Eisai, IPSEN, Seattle Genetics, AstraZeneca, Novartis, Immunomedics, Elucida, and Athenex; and is on the Genentech board. PWS received consulting fees from Varian. JH-G has funding from the National Institutes of Health (NIH)/National Cancer Institute (NCI) and received payment for a lecture from Aptitude Health. DNY has a Robert Wood Johnson Foundation Medical Grant and Brockman Foundation Medical Grant. ICGO received grants from Bristol Myers Squibb, Merck, and Pfizer; and consulting fees from Bristol Myers Squibb, Array, Novartis, Sintetica, and Leal Therapeutics. AM received grants from Eisai/H3B Pharmaceutical, Takeda Millenium Pharm, Lilly, Pfizer, MTEM, Merck, Roche, Zion, Norvatis, Dantari, and Genentech; payment from Taiho; research support from Tempus and PUMA; and was on the boards for Seagen and Eli Lilly. EG received grants from Celgene, Denovo Biopharma, MedImmune, and Servier Pharmaceuticals; and is on the boards for Karyopharm Therapeutics, Kiyatec, and Boston Scientific. VG received grants from ImmunoChem Therapeutics. PKB received grants from Mirati, Eli Lilly, Kinnate, Merck, NIH, the Breast Cancer Research Foundation, Damon Runyon, AACR, the Terry and Jean de Gunzburg MGH Research Scholar Fund, and the Demetra fund; consulting fees from Axiom Healthcare, Pfizer, Dantari, Advice Connect inspire, ElevateBio, Sintetica, SK Life Sciences, Voyager Therapeutics, Kazia, MPM Capital, Medscape, Eli Lilly, and Tesaro; other payments from Medscape and Pfizer; other support from GSK, Genentech-Roche, Eli Lilly, AstraZeneca, Kazia, Merck, Mirati, and Pfizer; and was the Chair of Society of Annual Neuro-Oncology Meetings. LC has grants from CDC/Johns Hopkins, DSI, Hological, and Myriad; US patent US7734496B1; stock from UNH; and a leadership role at Touch4Life and MD HBEB. MPM received consulting fees from Kazia, Novocure, Zap, Xoft, Karyopharm, and Sapience; has stocks at Oncoceutics and Chimerix; and is on the boards for Mevion, Oncoceutics, and Xcision. MK received grants from AbbVie, Bristol Myers Squibb, Daiichi Sankyo, BioNTech, CNS pharmaceuticals, Immorna Therapeutics, Celldex Therapeutics, and Astellas; consulting fees from Novocure and George Clinical; miscellaneous payment from Jax Lab, GSK, Voyager Therapeutics, and Johnson and Johnson; and is on the board for Berg Pharmaceuticals. MSA received grants from Seagen, AstraZeneca, Bristol Myers Squibb, Bayer, Incyte, Pharmacyclics, Novocure, Mimivax, and Merck; consulting fees from Bayer, Novocure, Kiyatec, Insightec, GSK, Xoft, Nuvation, Cellulartity, SDP Oncology, Apollomics, Prelude, Janssen, Tocagen, Voyager Therapeutics, Viewray, Caris Lifesciences, Pyramid Biosciences, Anheart Therapeutics, Varian Medical Systems, Theraguix, and Menarini Ricerche; has stocks from Mimivax, Cytodyn, and Medlnnovate Advisors; and is on the boards for Cairn Therapeutics, Pyramid Biosciences, Modifi Biosciences, and Bugworks. MHG has grant number U54CA261717 from the NIH/NCI and received consulting fees from Midatech. JL has research funding from Bristol Myers Squibb. MMK has a grant (number R50CA276015) from the NIH/NCI and Blue Earth Diagnostics; and is on the boards for the NCCN CNS Cancers Guidelines Committee, International Journal of Radiation Oncology*Biology*Physics, Neuro-Oncology, and the External Advisory Board for Stanford U54 MetNet. JR received grants from Black Diamond Therapeutics, Blueprint Medicines, Hummingbird, Merck Sharp & Dohme, Vall d’Hebron Institute of Oncology/Cancer Core Europe, Yingli, AadiBioscience, Amgen, Bayer, Bicycle Therapeutics, BioAtla, BioMed Valley Discoveries, Cellestia, Curis, CytomX, Deciphera, ForeBio, GenMab, GlaxoSmithKline, Hummingbird, Hucthinson MediPharma, Ideaya, Kelun-Biotech, Linnaeus Therapeutics, Loxo Oncology, Merus, Mirati, Novartis, Nuvation, Pfizer, Roche Pharmaceuticals, Spectrum Pharmaceuticals, Symphogen, Taiho, Takeda-Millennium, and Tango Therapeutics; consulting fees from Alnylam Pharmaceuticals, Avoro Capital Advisors, Boxer Capital, the Chinese University of Hong Kong, Clarion Healthcare, Columbus Venture Partners, Cullgen, Debiopharm, Incyte, Macrogenics, Merus, Monte Rosa Therapeutics, Oncology One, Pfizer, Sardona Therapeutics, Tang Advisors, and the Vall d’Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social; travel support from European Society for Medical Oncology; is on boards for AadiBioscience, Ellipses Pharma, Envision Pharma Limited, Incyte, IONCTURA, Merus, and Monte Rosa Therapeutics; and is on the steering committee for the Vall d’Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social. AB received support from NIH grant number P30 CA008748, has four US patents, and is on the Evren Technologies Scientific Advisory Board. HT has grants from BMS Bristol Myers Squibb, Novartis, Merck, Genentech, Eisai, GSK, RAPT, and Dragonfly; and received consulting fees from BMS Bristol Myers Squibb, Novartis, Merck, Genentech, Eisai, Iovance, Pfizer, Karyopharm, Boxer Capital, Jazz Pharma, and Medicenna. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Triple-negative breast cancer (TNBC), a highly metastatic breast cancer subtype, has limited treatment options. While a small number of patients attain clinical benefit with single-agent checkpoint inhibitors, identifying these patients before the therapy remains challenging. Here, we developed a transcriptome-informed quantitative systems pharmacology model of metastatic TNBC by integrating heterogenous metastatic tumors. In silico clinical trial with an anti-PD-1 drug, pembrolizumab, predicted that several features, such as the density of antigen-presenting cells, the fraction of cytotoxic T cells in lymph nodes, and the richness of cancer clones in tumors, could serve individually as biomarkers but had a higher predictive power as combinations of two biomarkers. We showed that PD-1 inhibition neither consistently enhanced all antitumorigenic factors nor suppressed all protumorigenic factors but ultimately reduced the tumor carrying capacity. Collectively, our predictions suggest several candidate biomarkers that might effectively predict the response to pembrolizumab monotherapy and potential therapeutic targets to develop treatment strategies for metastatic TNBC.

Purpose: Cancers deficient in homologous recombination DNA repair, such as those with BRCA1 or BRCA2 (BRCA1/2) mutations rely on a pathway mediated by the enzyme poly(adenosine diphosphate-ribose) polymerase (PARP). PARP inhibitors (PARPi's) have demonstrated efficacy in treating patients with germline (g)BRCA1/2, somatic (s)BRCA1/2, and gPALB2 mutations in clinical trials. However, patients with a poor performance status (PS) and those with severe organ impairment are often excluded from clinical trials and cancer-directed treatment., Methods: We report the cases of two patients with metastatic breast cancer who had poor PS, significant visceral disease, and gPALB2 and sBRCA mutations, who derived significant clinical benefit from treatment with PARP inhibition., Results: Patient A had germline testing demonstrating a heterozygous PALB2 pathogenic mutation (c.3323delA) and a BRCA2 variant of unknown significance (c.9353T>C), and tumor sequencing revealed PALB2 (c.228_229del and c.3323del) and ESR1 (c.1610A>C) mutations. Patient B was negative for pathologic BRCA mutations upon germline testing, but tumor sequencing demonstrated somatic BRCA2 copy number loss and a PIK3CA mutation (c.1633G>A). Treatment with PARPi's in these two patients with an initial PS of 3-4 and significant visceral disease resulted in prolonged clinical benefit., Conclusion: Patients with a poor PS, such as those described here, may still have meaningful clinical responses to cancer treatments targeting oncogenic drivers. More studies evaluating PARPi's beyond gBRCA1/2 mutations and in sub-optimal PS would help identify patients who may benefit from these therapies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Palbociclib is highly efficacious and well tolerated in hormone-receptor positive (HR+) metastatic breast cancer (BC) but its activity for HER2+ BC with brain metastases (BM) is unknown., Methods: In a single-arm phase II study we evaluated palbociclib with trastuzumab for patients with HER2+ MBC and BM. The primary endpoint was BM response rate. Circulating tumor DNA (ctDNA) was evaluated at baseline, and in a subset of patients at cycle 3 and progression. We also retrospectively identified additional patients with metastatic BC, active BM, and a ctDNA assessment prior to therapy for BM., Results: Twelve patients with HER2+ MBC were enrolled, 4 with HR+ and 8 with HR- disease. No responses were seen. Best response was stable disease for 6 patients and progressive disease for 6 patients. The median PFS was 2.2 months, interquartile range (IQR) was 1.56 to 3.63 months. The median OS was 13.1 months and IQR was 9.4 to 23.8 months The CNS was the primary site of progression for all patients. The median variant allele fraction (VAF) of the dominant variant in each patient was 0.18% (interquartile range [IQR] 0.12%-0.47%) with a median number of somatic alterations of 1. We additionally evaluated ctDNA results from 26 patients with BC and active BM, among whom the median VAF was 11.8% (IQR 3.9%-27.3%) with a median number of alterations was 6 (IQR 4-9). Notably, progressive systemic disease was significantly less frequent in the trial cohort compared with additional retrospectively identified patients (8% vs. 81%)., Conclusion: Palbociclib did not demonstrate activity in HER2+ MBC with BM. Patients with progressive BM but stable, responding, or absent systemic disease have low VAF and number of alterations detected by ctDNA analysis from blood., (Copyright © 2022. Published by Elsevier Inc.)

Type 1 diabetes mellitus (DM) occurs when insulin-producing beta cells are destroyed. Destruction of these cells and subsequent loss of insulin signaling can cause diabetic keto acidosis (DKA). This case describes a type 1 DM patient who presented to the emergency department (ED) with nausea and vomiting after glucose like peptide-1 (GLP-1) agonist administration. The patient was noted to have elevated anion gap and elevated beta-hydroxybutyrate with euglycemic blood glucose levels. The patient was confirmed to have a functioning insulin pump and then was sent home with nausea control. The patient was not able to consume food without vomiting and therefore did not administer any postprandial insulin. These symptoms were attributed to the GLP-1 agonist. It contributed to suppression of the patient's appetite while also inhibiting gluconeogenesis, and glycogenolysis resulting in small amounts of blood glucose entering the blood stream, negating the need for a bolus of insulin. The patient was admitted and given dextrose with an insulin drip until the anion gap was returned to normal. As GLP-1 agonists become more popular, this presentation may become more common. If not easily recognized this can lead to patient endangerment and unnecessary medical costs., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Atezolizumab with chemotherapy has shown improved progression-free and overall survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Atezolizumab with anthracycline- and taxane-based neoadjuvant chemotherapy has also shown increased pathological complete response (pCR) rates in early TNBC. This trial evaluated neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with clinical stages II-III TNBC. The co-primary objectives were to evaluate if chemotherapy and atezolizumab increase pCR rate and tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in the mITT population. Sixty-seven patients (ages 25-78 years; median, 52 years) were randomly assigned - 22 patients to Arm A, and 45 to Arm B. Median follow up was 6.6 months. In the modified intent to treat population (all patients evaluable for the primary endpoints who received at least one dose of combination therapy), the pCR rate was 18.8% (95% CI 4.0-45.6%) in Arm A, and 55.6% (95% CI 40.0-70.4%) in Arm B (estimated treatment difference: 36.8%, 95% CI 8.5-56.6%; p = 0.018). Grade 3 or higher treatment-related adverse events occurred in 62.5% of patients in Arm A, and 57.8% of patients in Arm B. One patient in Arm B died from recurrent disease during the follow-up period. TIL percentage increased slightly from baseline to cycle 1 in both Arm A (mean ± SD: 0.6% ± 21.0%) and Arm B (5.7% ± 15.8%) (p = 0.36). Patients with pCR had higher median TIL percentages (24.8%) than those with non-pCR (14.2%) (p = 0.02). Although subgroup analyses were limited by the small sample size, PD-L1-positive patients treated with chemotherapy and atezolizumab had a pCR rate of 75% (12/16). The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in a statistically significant and clinically relevant increased pCR rate in patients with clinical stages II and III TNBC. (Funded by National Cancer Institute)., (© 2022. The Author(s).)

Introduction: In contrast to other breast cancer subtypes, there are currently limited options of targeted therapies for triple-negative breast cancer (TNBC). Immense research has demonstrated that not only cancer cells but also stromal cells and immune cells in the tumor microenvironment (TME) play significant roles in the progression of TNBC. It is thus critical to understand the components of the TME of TNBC and the interactions between the various cell populations., Areas Covered: The components of the TME of TNBC identified by single-cell technologies are reviewed. Furthermore, the molecular interactions between the cells and the potential therapeutic targets contributing to the progression of TNBC are discussed., Expert Opinion: Single-cell omics studies have contributed to the classification of cells in the TME and the identification of important cell types involved in the progression and the treatment of the tumor. The interactions between cancer cells and stromal cells/immune cells in the TME have led to the discovery of potential therapeutic targets. Experimental data with spatial and temporal resolution will further boost the understanding of the TME of TNBC.

Background: CompactDry™ Yeast/Mold Rapid (YMR) is a ready-to-use dry media sheet using a chromogenic medium with selective agents for the enumeration of yeasts and molds in a variety of food products after incubation at 25 ± 1°C for 3 days. The method is certified as AOAC Performance Tested MethodSM 092002., Objective: The CompactDry YMR method was validated for a matrix extension to cannabis flower through the AOAC Emergency Response Validation process., Methods: The performance of the CompactDry YMR was compared to Dichloran Rose Bengal Chloramphenicol (DRBC) agar for the enumeration of yeasts and molds in cannabis flower. Matrix data were normalized by log10 transformation, and performance indicators included repeatability, difference of means (DOM), and inclusivity/exclusivity., Results: The results demonstrated that the CompactDry YMR method is equivalent to the DRBC agar method at 72 h of incubation. In the independent laboratory validation study, there was no significant difference in detection, enumeration, or repeatability between the CompactDry YMR method and DRBC agar at 72 h. Eighteen inclusivity and 16 exclusivity strains specific to cannabis plant materials that were not evaluated in the original CompactDry YMR method validation were tested in this study. All inclusivity organisms produced typical colonies on the CompactDry YMR. The two exclusivity bacterial strains that showed growth on CompactDry YMR at 72 h were inoculated at a high concentration., Conclusions: CompactDry YMR is equivalent in performance to traditional culture media detection methods of yeasts and molds., Highlights: CompactDry YMR will streamline dried cannabis flower testing., (© The Author(s) 2022. Published by Oxford University Press on behalf of AOAC INTERNATIONAL. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: DSD reports institutional support from Bristol Myers Squibb and Pfizer; and consults for AstraZeneca, Clovis, Regeneron, and Pfizer. BHP receives consulting and advisory board fees from Jackson Labs, EQRx, Sermonix, Hologics, Guardant Health, and Celcuity; has research contracts with GE Healthcare and Eli Lilly; and is entitled to royalties on sales of products licensed by Horizon Discovery and Johns Hopkins University. JP reports funding from the Color Foundation unrelated to this work. CAS-M reports funding from AstraZeneca, Pfizer, Bristol Myers Squibb, and Tesaro/GSK; and is on the advisory board of Seattle Genetics. AT reports royalties for breast cancer chapters written for an online UpToDate book; payment for expert testimony; plans to patent a device to be used in lymphoedema patients; non-paid advisory board service for Puretech; and received Sozo bioimpedance equipment for an investigator-led study on lymphoedema. AN-R reports honoraria and support for attending meetings and travel from Roche, MSD, Astra Zeneca, and Eisai; and leadership roles with the Brazilian Group of Gynecology Oncology and Brazilian Society of Medical Oncology. All other authors declare no competing interests.

Purpose: Understanding real-time relationships between physical activity (PA) and symptoms during chemotherapy (CT) could have important implications for intervention. This study used ecological momentary assessment to examine the relationship between objective PA and symptoms during CT., Methods: Breast cancers patients (n = 67; M age  = 48.6 (SD = 10.3)) participated in data collection at three time points during CT: beginning, middle, and end. At each time point, participants answered four prompts assessing symptoms and wore an accelerometer for 10 days (3 days pre-CT, day of CT, and 6 days post-CT). Multilevel linear regression models examined the between- and within-person associations between moderate to vigorous (MVPA) and light-intensity physical activity (LPA) and same and next-day symptom ratings controlling for covariates., Results: On days when individuals engaged in more LPA or MVPA, separately, they reported improved affect, anxiety, fatigue, physical functioning (walking and activities of daily living), pain, and cognition that day (p < 0.001 for all). Findings were consistent for next-day symptom ratings with the exception that only previous day LPA was related to next-day fatigue and neither LPA nor MVPA were related to next-day cognition (p < 0.001 for all). No between-person effects were found., Conclusions: Within person higher than usual PA on a given day, regardless of intensity, is associated with improved symptoms ratings on the current and next day., Implications for Cancer Survivors: Encouraging breast cancer patients undergoing CT to engage in daily PA could help manage CT-associated symptoms., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This single-arm pilot study (NCT03329937) evaluated neoadjuvant niraparib antitumor activity and safety in patients with localized HER2-negative, BRCA-mutated breast cancer. Twenty-one patients received niraparib 200 mg once daily in 28-day cycles. After 2 cycles, tumor response (≥30% reduction from baseline) by MRI was 90.5% and 40.0% (6 of 15) of patients who received only niraparib (2-6 cycles) had pathological complete response; no new safety signals were identified. High niraparib intratumoral concentration was observed., (© 2022. The Author(s).)

The KEYNOTE-522 study is a practice-changing phase III randomized study that demonstrated that the addition of pembrolizumab to polychemotherapy improves outcomes in patients with high-risk early-stage triple-negative breast cancer (TNBC). This regimen is highly efficacious with unprecedented pathologic complete response (pCR) rates, and clinically meaningful improvements in event-free survival (EFS). However, the combination is also associated with significant high-grade treatment-related toxicity. The backbone regimen deviated from common practice, including the addition of carboplatin, lack of dose dense anthracyclines, and adjuvant capecitabine for residual disease, thus brining important questions regarding real-world translation of these results. This brief report practically addresses some of the most relevant questions physicians and patients face in optimizing care using the best available evidence.

Immune checkpoint inhibitors (ICI) can have significant anticancer activity, and are approved for many different cancer types, including breast cancer. In breast cancer, programmed cell death 1 (PD-1) inhibitors in combination with chemotherapy have demonstrated significant clinical benefit in early-stage and metastatic settings; however, these combinations can have significant side effects, and there are still many breast cancer patients who do not respond to these approaches. Novel combinations with immunotherapy are needed to improve responses. Given the effects of radiation therapy (RT) on the tumor micro-environment, combinations of RT with immune checkpoint blockade are active areas of investigation. In this review, we discuss experience ICI in breast cancer, including current clinical indications, emerging data in combination with RT, and ongoing studies exploring optimal dosing of RT, and novel combinations with other therapeutics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Quantitative systems pharmacology (QSP) modeling is an emerging mechanistic computational approach that couples drug pharmacokinetics/pharmacodynamics and the course of disease progression. It has begun to play important roles in drug development for complex diseases such as cancer, including triple-negative breast cancer (TNBC). The combination of the anti-PD-L1 antibody atezolizumab and nab-paclitaxel has shown clinical activity in advanced TNBC with PD-L1-positive tumor-infiltrating immune cells. As tumor-associated macrophages (TAMs) serve as major contributors to the immuno-suppressive tumor microenvironment, we incorporated the dynamics of TAMs into our previously published QSP model to investigate their impact on cancer treatment. We show that through proper calibration, the model captures the macrophage heterogeneity in the tumor microenvironment while maintaining its predictive power of the trial results at the population level. Despite its high mechanistic complexity, the modularized QSP platform can be readily reproduced, expanded for new species of interest, and applied in clinical trial simulation., Competing Interests: Dr. Emens has had research funding from Genentech, F Hoffman La Roche, EMD Serono, Merck, AstraZeneca, Tempest, Bolt, Silverback, Takeda, CytomX, Compugen, Abbvie, BMS, Next Cure, Immune Onc. She has served as a paid consultant for, F Hoffman La Roche, Genentech, Macrogenics, Lilly, Chug, Silverback, Shionogi, CytomX, GPCR, Immunitas, DNAMx, Gilead, and Mersana. Dr. Emens also has an executive role at the Society for Immunotherapy of Cancer and has ownership interest in Molecuvax. Dr. Popel is a consultant to AsclepiX Therapeutics and CytomX Therapeutics. He receives research funding from AstraZeneca, Boehringer Ingelheim, CytomX Therapeutics. Dr Cesar Santa-Maria has research funding from Pfizer, AstraZeneca, Novartis, Bristol Meyers Squibb and has served on advisory boards for Bristol Meyers Squibb, Genomic Health, Seattle Genetics, Athenex, Halozyme and Polyphor. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies. 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. Dr. Santa-Maria has research funding from Pfizer, Astrazeneca, Novartis, Bristol Meyers Squibb and has served on advisory boards for Bristol Meyers Squibb, Genomic Health, Seattle Genetics, Athenex, Halozyme and Polyphor., (© 2022 The Author(s).)

Purpose: In pre-planned observational analysis of the POWER-remote trial, we examined the impact of weight loss on patient-reported outcomes (PROs). We hypothesized a priori that survivors with ≥ 5% weight loss would have improved physical function (PF) at 6 months vs. those who did not., Methods: Patients with stage 0-III breast cancer who completed local therapy and chemotherapy with BMI ≥ 25 kg/m 2 were randomized to POWER-remote (telephone coaching; diet/activity tracking) or self-directed weight loss (booklet). Participants completed PROs at baseline, 6, and 12 months: PROMIS PF, pain, fatigue, anxiety, depression, sleep; FACT-endocrine symptoms; MOS-sexual function. Changes in PROs among those with ≥ 5% weight loss vs. those with < 5% were tested with multivariable mixed effect models, across randomized groups., Results: Of 94 women who completed PROs, 84 and 69 participants were evaluable at 6 and 12 months, respectively. Regardless of intervention, PF improved in those with ≥ 5% weight loss vs. those with < 5% at 6 months (4.4 vs. 0.3 points; p = 0.02) and 12 months (3.6 vs. 0 points; p = 0.04). While endocrine symptoms, fatigue, and anxiety improved at 6 months in those who lost ≥ 5%, differences were not significant vs. those who lost < 5%. There was no significant change within or between groups in sexual function, depression, or sleep. Findings at 12 months were similar, except pain improved in those losing ≥ 5%., Conclusions: These results support the benefits of weight loss in overweight/obese breast cancer survivors., Implications for Cancer Survivors: Weight management in breast cancer survivors may improve PF., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Young people in the United States know little about contraceptive options available to them, although method use is sensitive to individual preferences, and method switching is common. For young people to gain reproductive autonomy, a first step is to be aware of different contraceptives, including hormonal and nonhormonal methods. We tested whether an educational intervention delivered on community college campuses was effective in increasing contraceptive awareness. Materials and Methods: We developed a low-cost educational intervention featuring youth-friendly visual tools and tested its impact on method awareness and knowledge among 1,051 students of all genders, aged 18-25 years, at five community colleges. We used generalized estimating equations to test changes in awareness of a range of methods, including male and female (internal) condoms, the pill, patch, vaginal ring, shot, intrauterine devices, implant, and emergency contraception. Results: Over 90% of participants were aware of male condoms and the pill at baseline, but fewer had heard of other options (ranging from 31% to 76% for different methods). Across all methods, awareness increased to a mean of 88% among female participants and 82% among male participants postintervention. Awareness of the full range of methods increased from 31% to 55% (adjusted odds ratio [aOR]: 4.4, 95% confidence interval [CI]: 3.1-6.2]) among female participants and 11% to 36% (aOR: 10.8, 95% CI: 5.3-21.8) among male participants postintervention. The intervention was similarly effective by sexual orientation, race/ethnicity, nativity, or insurance coverage. Conclusion: This educational intervention significantly improved all students' awareness of a range of contraceptives, supporting one important aspect of reproductive health for young people in community settings.

Background: The benefit of immune checkpoint inhibitors (ICIs) in patients with leptomeningeal metastases (LMM) is unknown., Methods: We undertook a phase II trial of pembrolizumab in patients with LMM from solid tumors. Eligible patients had radiologic/cytologic LMM and Eastern Cooperative Oncology Group performance status 0-1. Pembrolizumab was administered intravenously at 200 mg q3W until disease progression/unacceptable toxicity. The primary endpoint was central nervous system (CNS) response after four cycles, defined radiologically/cytologically/clinically. Serial cerebrospinal fluid (CSF) was assessed for tumor-derived DNA (t-DNA) aneuploidy and cytokines., Results: Thirteen of a planned 16 patients were treated between April 2017 and December 2019. The study closed early for poor accrual. Median age was 57 years (range: 22-79). Sixty-two percent of patients had tumors not traditionally ICI-responsive (hormone-receptor (HR)-positive breast carcinoma=39%; high-grade glioma=23%), while 38% had ICI-responsive tumors (non-small cell lung cancer (NSCLC)=23%, head and neck carcinoma=8%, cutaneous squamous carcinoma (CSC)=8%). CNS response was observed in 38% of patients at 12 weeks (95% CI 13.9% to 68.4%) by pre-defined criteria and LM-RANO, and 2 achieved durable complete responses (CSC=1, overall survival (OS) 3+ years; NSCLC=1, OS 9 months). Median CNS progression-free survival and OS was 2.9 months (95% CI 1.3 to NR) and 4.9 months (95% CI 3.7 to NR), respectively. Grade 3+ treatment-related adverse events occurred in 15% of patients. Sensitivity for LMM detection by t-DNA and cytopathology was 84.6% (95% CI 54.6% to 98.1%) and 53.9% (95% CI 25.1% to 80.8%), respectively. Pre-therapy and on-therapy CSF cytokine analysis demonstrated complete responders clustered together., Conclusions: Pembrolizumab conferred a 38% CNS response rate in patients with LMM, a tolerable safety profile, and deep responses in selected patients with ICI-responsive tumors. CSF t-DNA may be sensitive for LMM detection, and immunologic subsets of CNS response warrant further study., Trial Registration Number: NCT03091478., Competing Interests: Competing interests: JN: research funding: Merck, AstraZeneca; consulting: AstraZeneca, Bristol-Myers Squibb; Takeda, Daiichi Sankyo, Roche/Genentech; Honoraria: Merck, AstraZeneca, Bristol-Myers Squibb, Roche/Genentech. CD: consultant: Depuy-Synthes, Bionaut Labs; royalties: Thrive (through Johns Hopkins University). CH: research funding: NCI/NIH; consultant: Merck & Co. CAS-M: research funding: NCI/NIH, Pfizer, AstraZeneca, Novartis, BMS, Tesaro/GSK; consultant: BMS, Seattle Genetics, Genomic Health, Athenex, Polyphor, Halozyme. MH: consultant: BTG International, NewLink Genetics, Celgene, AbbVie. PMF: consultant: AstraZeneca, Abbvie, Amgen, BMS, Janssen; research funding: AstraZeneca, BMS. CD, KWK, NP, CB, and BP are founders of, hold equity in, and are consultants to Thrive and Personal Genome Diagnostics. KWK and NP are on the Board of Directors of Thrive. KWK is a consultant to Sysmex, Eisai, and CAGE Pharma. KWK and NP are consultants to Neophore. CB is a consultant to Depuy-Synthes and Bionaut Labs. CD is a consultant to Thrive and is compensated with income and equity. The companies named above as well as other companies have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. CD, CB, KWK, and NP are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. The terms of all of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. KJR: research funding: Accuray, Elekta AB; travel expenses: Brainlab, Accuray, Elekta AB; honoraria: Elekta AB; data safety monitoring board: BioMimetixRC; research funding to institution from Novartis, Genentech, Merck, Macrogenics, Puma Biotechnology. Unrestricted educational grant from Pfizer., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)