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BackgroundObservational and experimental data support a potential breast cancer chemopreventive effect of green tea.MethodsWe conducted an ancillary study using archived blood/urine from a phase IB randomised, placebo-controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in breast cancer patients. Using an adaptive trial design, women with stage I-III breast cancer who completed adjuvant treatment were randomised to Poly E 400 mg (n = 16), 600 mg (n = 11) and 800 mg (n = 3) twice daily or matching placebo (n = 10) for 6 months. Blood and urine collection occurred at baseline, and at 2, 4 and 6 months. Biological endpoints included growth factor [serum hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], lipid (serum cholesterol, triglycerides), oxidative damage and inflammatory biomarkers.ResultsFrom July 2007-August 2009, 40 women were enrolled and 34 (26 Poly E, eight placebo) were evaluable for biomarker endpoints. At 2 months, the Poly E group (all dose levels combined) compared to placebo had a significant decrease in mean serum HGF levels (-12.7% versus +6.3%, P = 0.04). This trend persisted at 4 and 6 months but was no longer statistically significant. For the Poly E group, serum VEGF decreased by 11.5% at 2 months (P = 0.02) and 13.9% at 4 months (P = 0.05) but did not differ compared to placebo. At 2 months, there was a trend toward a decrease in serum cholesterol with Poly E (P = 0.08). No significant differences were observed for other biomarkers.ConclusionsOur findings suggest potential mechanistic actions of tea polyphenols in growth factor signalling, angiogenesis and lipid metabolism.

Purpose: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need., Methods: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia., Results: After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively., Conclusion: Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

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.)

Importance: The conditions required for health record data sources to accurately assess treatment effectiveness remain unclear. Emulation of randomized clinical trials (RCTs) with health record data and subsequent calibration of the results can help elucidate this., Objective: To pilot an emulation of the KEYNOTE-189 RCT using a commercially available electronic health record (EHR) data source., Design, Setting, and Participants: This retrospective cohort study used an EHR database spanning from April 2007 to February 2023. Follow-up began on treatment initiation and proceeded until an outcome event, loss to follow-up, end of data, or end of study period (640 days). The population-based cohort was ascertained from EHRs provided by 52 health systems across the US. Eligibility criteria were defined as closely as possible to the benchmark RCT. Patients with non-small cell lung cancer initiating first-line treatment for metastatic disease were included. Patients with evidence of squamous non-small cell lung cancer, primary nonlung malignant neoplasms, or identified EGFR/ALK variations were excluded. Data were analyzed from June to October 2023., Exposures: Initiation of first-line pembrolizumab and chemotherapy and chemotherapy alone. Chemotherapy in both groups was defined as a combination of pemetrexed and platinum-based (carboplatin or cisplatin) therapy., Main Outcomes and Measures: Outcomes of interest were 12-month survival probability and mortality hazard ratio (HR)., Results: A total of 1854 patients (mean [SD] age, 63.7 [9.6] years; 971 [52.4%] men) were eligible, including 589 patients who initiated pembrolizumab and chemotherapy and 1265 patients who initiated chemotherapy only. The cohort included 364 Black patients (19.6%) and 1445 White patients (77.9%). The 12-month survival probabilities were 0.60 (95% CI, 0.54-0.65) in the pembrolizumab group and 0.58 (95% CI, 0.55-0.62) in the chemotherapy-only group, compared with 0.69 (95% CI, 0.64-0.74) in the KEYNOTE-189 pembrolizumab group and 0.49 (95% CI, 0.42-0.56) in the KEYNOTE-189 chemotherapy-only group. The mortality HR was 0.95 (95% CI, 0.78-1.16), compared with 0.49 (95% CI, 0.38-0.64) in the KEYNOTE-189 RCT., Conclusions and Relevance: In this cohort study piloting an RCT emulation, results were incongruous with the benchmark trial. Differences in patient treatment and data capture between the RCT and EHR populations, confounding by indication, treatment crossover, and accuracy of captured diagnoses may explain these findings. Future feasibility assessments will require data sources to have important oncology-specific measures curated.

Intrinsic breast cancer molecular subtyping (IBCMS) provides significant prognostic information for patients with breast cancer and helps determine treatment. This study compared IBCMS methods on various gene-expression platforms in PALOMA-2 and PALLET trials. PALOMA-2 tumor samples were profiled using EdgeSeq and nanostring and subtyped with AIMS, PAM50, and research-use-only (ruo)Prosigna. PALLET tumor biopsies were profiled using mRNA sequencing and subtyped with AIMS and PAM50. In PALOMA-2 (n = 222), a 54% agreement was observed between results from AIMS and gold-standard ruoProsigna, with AIMS assigning 67% basal-like to HER2-enriched. In PALLET (n = 224), a 69% agreement was observed between results from PAM50 and AIMS. Different IBCMS methods may lead to different results and could misguide treatment selection; hence, a standardized clinical PAM50 assay and computational approach should be used.Trial number: NCT01740427., (© 2024. The Author(s).)

Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies., Competing Interests: The authors declare no conflict of interest.

Predictive biomarkers of response to human epidermal growth factor receptor 2 (HER2)-directed therapy are essential to inform treatment decisions. The TBCRC026 trial reported that early declines in tumor SUVs corrected for lean body mass (SUL max ) on 18 F-FDG PET/CT predicted a pathologic complete response (pCR) to HER2 therapy with neoadjuvant trastuzumab and pertuzumab (HP) without chemotherapy in estrogen receptor (ER)-negative, HER2-positive breast cancer. We hypothesized that 18 F-FDG PET/CT SUL max parameters would predict recurrence-free survival (RFS) and overall survival (OS). Methods: Patients with stage II/III ER-negative, HER2-positive breast cancer received neoadjuvant HP ( n = 88). pCR after HP alone was 22% (18/83), additional nonstudy neoadjuvant therapy was administered in 28% (25/88), and the majority received adjuvant therapy per physician discretion. 18 F-FDG PET/CT was performed at baseline and at cycle 1, day 15 (C1D15). RFS and OS were summarized using the Kaplan-Meier method and compared between subgroups using logrank tests. Associations between 18 F-FDG PET/CT (≥40% decline in SUL max between baseline and C1D15, or C1D15 SUL max ≤ 3) and pCR were evaluated using Cox regressions, where likelihood ratio CIs were reported because of the small numbers of events. Results: Median follow-up was 53.7 mo (83/88 evaluable), with 6 deaths and 14 RFS events. Estimated RFS and OS at 3 y was 84% (95% CI, 76%-92%) and 92% (95% CI, 87%-98%), respectively. A C1D15 SUL max of 3 or less was associated with improved RFS (hazard ratio [HR], 0.36; 95% CI, 0.11-1.05; P = 0.06) and OS (HR, 0.14; 95% CI, 0.01-0.85; P = 0.03), the latter statistically significant. The association of an SUL max decline of at least 40% (achieved in 59%) with RFS and OS did not reach statistical significance. pCR was associated with improved RFS (HR, 0.25; 95% CI, 0.01-1.24; P = 0.10) but did not reach statistical significance. Conclusion: For the first time, we report a potential association between a C1D15 SUL max of 3 or less on 18 F-FDG PET/CT and RFS and OS outcomes in patients with ER-negative, HER2-positive breast cancer receiving neoadjuvant HP alone. If confirmed in future studies, this imaging-based biomarker may facilitate early individualization of therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy., Patients and Methods: We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence., Results: Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10 -4 (range 7.9 × 10 -7 -4.9 × 10 -1 ). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12., Conclusions: Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is the leading form of dementia worldwide, but its early detection and diagnosis remain a challenge. MicroRNAs (miRNAs) are a group of small endogenous RNA molecules that regulate mRNA expression. Recent evidence suggests miRNAs play an important role in the five major hallmarks of AD pathophysiology: amyloidogenesis, tauopathy, neuroinflammation, synaptic dysfunction, and neuronal death. Compared to traditional biomarkers of AD, miRNAs display a greater degree of stability in cerebrospinal fluid. Moreover, aberrant changes in miRNA expression can be measured over time to monitor and guide patient treatment. Specific miRNA profiles and combinations may also be used to distinguish AD subjects from normal controls and other causes of dementia. Because of these properties, miRNAs are now being considered as promising and potential biomarkers of AD. This review comprehensively summarizes the diagnostic potential and regulatory roles miRNAs play in AD., 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 © 2023 Noor Eddin, Hamsho, Adi, Al-Rimawi, Alfuwais, Abdul Rab, Alkattan and Yaqinuddin.)

Legislative and technological advancements over the past decade have given rise to the proliferation of healthcare data generated from routine clinical practice, often referred to as real-world data (RWD). These data have piqued the interest of healthcare stakeholders due to their potential utility in generating evidence to support clinical and regulatory decision making. In the oncology setting, studies leveraging RWD offer distinct advantages that are complementary to randomized controlled trials (RCTs). They also permit the conduct of investigations that may not be possible through prospective designs due to ethics or feasibility. Despite its promise, the use of RWD for the generation of clinical evidence remains controversial due to concerns of unmeasured confounding and other sources of bias that must be carefully addressed in the study design and analysis. To facilitate a better understanding of when RWD can provide reliable conclusions on drug effectiveness, we seek to conduct 10 RWD-based studies that emulate RCTs in oncology using a systematic, protocol-driven approach described herein. Results of this investigation will help inform clinical, scientific, and regulatory stakeholders on the applications of RWD in the context of product labeling expansion, drug safety, and comparative effectiveness in oncology., (© 2022 Aetion, Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Co-clinical trials are the concurrent or sequential evaluation of therapeutics in both patients clinically and patient-derived xenografts (PDX) pre-clinically, in a manner designed to match the pharmacokinetics and pharmacodynamics of the agent(s) used. The primary goal is to determine the degree to which PDX cohort responses recapitulate patient cohort responses at the phenotypic and molecular levels, such that pre-clinical and clinical trials can inform one another. A major issue is how to manage, integrate, and analyze the abundance of data generated across both spatial and temporal scales, as well as across species. To address this issue, we are developing MIRACCL (molecular and imaging response analysis of co-clinical trials), a web-based analytical tool. For prototyping, we simulated data for a co-clinical trial in "triple-negative" breast cancer (TNBC) by pairing pre- (T0) and on-treatment (T1) magnetic resonance imaging (MRI) from the I-SPY2 trial, as well as PDX-based T0 and T1 MRI. Baseline (T0) and on-treatment (T1) RNA expression data were also simulated for TNBC and PDX. Image features derived from both datasets were cross-referenced to omic data to evaluate MIRACCL functionality for correlating and displaying MRI-based changes in tumor size, vascularity, and cellularity with changes in mRNA expression as a function of treatment.

Neutrophils are the first cells to be recruited to sites of acute inflammation and contribute to host defense through phagocytosis, degranulation and neutrophil extracellular traps (NETs). Neutrophils are rarely found in the brain because of the highly selective blood-brain barrier (BBB). However, several diseases disrupt the BBB and cause neuroinflammation. In this regard, neutrophils and NETs have been visualized in the brain after various insults, including traumatic (traumatic brain injury and spinal cord injury), infectious (bacterial meningitis), vascular (ischemic stroke), autoimmune (systemic lupus erythematosus), neurodegenerative (multiple sclerosis and Alzheimer's disease), and neoplastic (glioma) causes. Significantly, preventing neutrophil trafficking into the central nervous system or NET production in these diseases alleviates brain pathology and improves neurocognitive outcomes. This review summarizes the major studies on the contribution of NETs to central nervous system (CNS) disorders., 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 © 2023 Shafqat, Noor Eddin, Adi, Al-Rimawi, Abdul Rab, Abu-Shaar, Adi, Alkattan and Yaqinuddin.)

Purpose: Adoptively transferred, ex vivo expanded multi-antigen-targeted T cells (multiTAA-T) represent a new, potentially effective, and nontoxic therapeutic approach for patients with breast cancer (BC). In this first-in-human trial, we investigated the safety and clinical effects of administering multiTAA T cells targeting the tumor-expressed antigens, Survivin, NY-ESO-1, MAGE-A4, SSX2, and PRAME, to patients with relapsed/refractory/metastatic BC., Materials and Methods: MultiTAA T-cell products were generated from the peripheral blood of heavily pre-treated patients with metastatic or locally recurrent unresectable BC of all subtypes and infused at a fixed dose level of 2 × 10 7 /m 2 . Patients received two infusions of cells 4 weeks apart and safety and clinical activity were determined. Cells were administered in an outpatient setting and without prior lymphodepleting chemotherapy., Results: All patients had estrogen receptor/progesterone receptor positive BC, with one patient also having human epidermal growth factor receptor 2-positive. There were no treatment-related toxicities and the infusions were well tolerated. Of the 10 heavily pre-treated patients enrolled and infused with multiTAA T cells, nine had disease progression while one patient with 10 lines of prior therapies experienced prolonged (5 months) disease stabilization that was associated with the in vivo expansion and persistence of T cells directed against the targeted antigens. Furthermore, antigen spreading and the endogenous activation of T cells directed against a spectrum of non-targeted tumor antigens were observed in 7/10 patients post-multiTAA infusion., Conclusion: MultiTAA T cells were well tolerated and induced disease stabilization in a patient with refractory BC. This was associated with in vivo T-cell expansion, persistence, and antigen spreading. Future directions of this approach may include additional strategies to enhance the therapeutic benefit of multiTAA T cells in patients with BC., Competing Interests: Competing Interests: S.V., M.K., and Y.V. are consultants to AlloVir. V.H. holds Marker Therapeutics and AlloVir stock. N.L. is a consultant to Tessa Therapeutics. J.F.V. is a cofounder and equity holder in AlloVir and Marker Therapeutics and an employee of Marker Therapeutics, which aspires to commercialize the described approach. B.J.G. owns QBRegulatory Consulting which has consulting agreements with Tessa Therapeutics, Marker Therapeutics, LOKON, and AlloVir. H.E.H. is a co-founder with equity in Allovir and Marker Therapeutics, has served on advisory boards for Tessa Therapeutics, Kiadis, Novartis, Gilead Biosciences, Fresh Wind Biotechnologies and GSK, and received research support from Kuur Therapeutics and Tessa Therapeutics. C.M.R. has Stock and Other Ownership Interests with Coya, Bluebird Bio, Tessa Therapeutics, Marker Therapeutics, AlloVir, Walking Fish, Allogene Therapeutics, Memgen, Kuur Therapeutics, Bellicum Pharmaceuticals, TScan Therapeutics, Abintus Bio; Consulting or Advisory Role with Abintus Bio, Adaptimmune, Brooklyn Immunotherapeutic, Onk Therapeutics, Tessa Therapeutics, Memgen, Torque, Walking Fish Therapeutics, TScan Therapeutics, Marker Therapeutics, Turnstone Bio; and receives research funding from Kuur Therapeutics. A.M.L is a co-founder and equity holder for AlloVir and Marker Therapeutics and a consultant to AlloVir. P.L. is a member of the advisory board for Karyopharm. J.N. receives research support from Paxman Coolers Ltd. M.R. is a consultant to AstraZeneca, Macrogenics, Seagen and Novartis and receives research support from Pfizer. The remaining authors have no competing financial interests to disclose., (© The Author(s), 2022.)

The excellent outcomes seen in patients treated with adjuvant trastuzumab emtansine (T-DM1) in the ATEMPT trial and the favorable toxicity profile associated with this agent make T-DM1 a potential therapeutic option for select patients with stage I HER2-positive breast cancer. Moreover, T-DM1 is an established adjuvant treatment for patients with HER2-positive breast cancer with the residual invasive disease after neoadjuvant therapy. Given that cardiotoxicity is the most significant adverse event of trastuzumab, which is a main molecular component of T-DM1, we conducted a sub-analysis of the ATEMPT trial to determine the cardiac safety of adjuvant T-DM1. In this analysis, the incidence of grade 3-4 left ventricular systolic dysfunction (LVSD) in T-DM1 or trastuzumab plus paclitaxel arms were respectively 0.8 and 1.8%. In addition, three (0.8%) patients in the T-DM1 arm and six (5.3%) patients in the adjuvant paclitaxel with trastuzumab (TH) arm experienced a significant asymptomatic left ventricular ejection fraction (LVEF) decline that per-protocol required holding T-DM1 or trastuzumab. All patients with available follow-up data experienced full resolution of cardiac symptoms and LVEF normalization. Furthermore, we performed an exploratory analysis to assess the relationship between age, baseline LVEF, and body mass index with cardiac outcomes. No significant association between these baseline characteristics and the incidence of significant asymptomatic LVEF decline or symptomatic LVSD was identified. The low incidence of significant cardiac adverse events in this population during therapy with adjuvant T-DM1 suggests that studies on the cost-effectiveness of cardiac monitoring during adjuvant therapy using anthracycline-free regimens are needed.Clinical Trial Registration: ClinicalTrials.gov, NCT01853748., (© 2022. The Author(s).)

Purpose: Chemotherapy-related amenorrhea (CRA) is a surrogate for ovarian toxicity and associated risk of infertility and premature menopause. Here, we compare CRA rate with paclitaxel (T)-trastuzumab (H) to that with ado-trastuzumab emtansine (T-DM1)., Methods: Patients with T1N0 HER2 + early-stage breast cancer (eBC) enrolled on the ATEMPT trial and were randomized 3:1 to T-DM1 3.6 mg/kg IV every (q) 3 weeks (w) × 17 vs. T 80 mg/m 2 with H IV qw × 12 (4 mg/kg load → 2 mg/kg), followed by H (6 mg/kg IV q3w × 13). Enrollees who self-reported as premenopausal were asked to complete menstrual surveys at baseline and every 6-12 months for 60 months. 18-month CRA (no periods reported during prior 6 months on 18-month survey) was the primary endpoint of this analysis., Results: Of 512 ATEMPT enrollees, 123 who began protocol therapy and answered baseline and at least one follow-up menstrual survey were premenopausal at enrollment. 76 had menstrual data available at 18 months without having received a gonadotropin-releasing hormone agonist or undergone hysterectomy and/or oophorectomy. Median age was 45 (range 23-53) among 18 who had received TH and 46 (range 34-54) among 58 who had received T-DM1. The 18-month rate of CRA was 50% after TH and 24% after T-DM1 (p = 0.045)., Conclusion: Amenorrhea at 18 months was less likely in recipients of adjuvant T-DM1 than TH. Future studies are needed to understand how T-DM1 impacts risk of infertility and permanent menopause, and to assess amenorrhea rates when T-DM1 is administered after standard HER2-directed chemotherapy regimens., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC)., Methods: Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m 2 IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1., Results: The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH ( P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis ( P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH., Conclusion: Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH., Competing Interests: Sara TolaneyConsulting 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, CertaraResearch Funding: Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Immunomedics, Odonate Therapeutics, Sanofi, Seattle GeneticsTravel, Accommodations, Expenses: AstraZeneca, Lilly, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Immunomedics, Eisai, NanoString Technologies, Puma Biotechnology, Celldex Chau DangHonoraria: Puma Biotechnology, eviCore healthcareConsulting or Advisory Role: Puma Biotechnology, eviCore healthcareResearch Funding: Genentech/Roche, Puma Biotechnology Denise YardleyConsulting or Advisory Role: Novartis, Biotheranostics, Bristol Myers Squibb, G1 Therapeutics, Athenex, Immunomedics, Sanofi/Aventis, R-Pharm, LillySpeakers' Bureau: Novartis, Genentech/Roche, Genentech/RocheResearch Funding: Genentech/Roche, Novartis, MedImmune, Lilly, Medivation, Pfizer, Tesaro, Macrogenics, AbbVie, Merck, Clovis Oncology, Amgen, Biomarin, Biothera, Dana Farber Cancer Hospital, Incyte, Innocrin Pharma, Nektar, NSABP Foundation, Odonate Therapeutics, PolyphorTravel, Accommodations, Expenses: Novartis, Genentech/Roche Steven IsakoffConsulting or Advisory Role: AbbVie, OncoPep, Puma Biotechnology, Seattle Genetics, NovartisResearch Funding: Genentech, PharmaMar, AbbVie, OncoPep, Merck, AstraZeneca/MedImmune, Outcomes4Me Vicente ValeroHonoraria: Genentech/Roche, Merck, NovartisConsulting or Advisory Role: Genentech/Roche, Novartis, MerckTravel, Accommodations, Expenses: Genentech/Roche Therese MulveyConsulting or Advisory Role: Outcomes4Me Ron BoseConsulting or Advisory Role: GenentechResearch Funding: Puma Biotechnology Antonio WolffConsulting or Advisory Role: Ionis PharmaceuticalsResearch Funding: Biomarin, CelldexPatents, Royalties, Other Intellectual Property: Antonio Wolff has been named as inventor on one or more issued patents or pending patent applications related to methylation in breast cancer and has assigned his rights to JHU and participates in a royalty sharing agreement with JHUOpen Payments Link: https://openpaymentsdata.cms.gov/physician/357301/summary Katherine Reeder-HayesResearch Funding: Pfizer Hope RugoHonoraria: Puma Biotechnology, MylanConsulting or Advisory Role: SamsungResearch Funding: Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Lilly, Genentech, Merck, Immunomedics, Odonate Therapeutics, Daiichi Sankyo, Seattle Genetics, Sermonix Pharmaceuticals, AstraZenecaTravel, Accommodations, Expenses: Pfizer, Novartis, Macrogenics, Mylan, Daiichi Sankyo, AstraZeneca Spain, MerckOpen Payments Link: https://openpaymentsdata.cms.gov/summary Bhuvaneswari RamaswamyConsulting or Advisory Role: Eisai Lowell HartHonoraria: Novartis, Daiichi Sankyo, AstraZeneca, Seattle Genetics, G1 Therapeutics, Veracyte, Karyopharm TherapeuticsConsulting or Advisory Role: Genentech/Roche, Amgen, G1 Therapeutics, Merck, Seattle GeneticsSpeakers' Bureau: Bristol Myers Squibb, Lilly, Pfizer, Genentech, AstraZeneca, NovartisResearch Funding: Novartis, Genentech/Roche, Bristol Myers Squibb, G1 Therapeutics, Seattle Genetics Vijayakrishna GadiLeadership: SEngine Precision MedicineStock and Other Ownership Interests: Sengine precision medicine, Novilla, 3rdEyeBio, New Equilibrium BiosciencesConsulting or Advisory Role: Seattle Genetics, Puma Biotechnology, Novartis, SanofiSpeakers' Bureau: Seagen, bioTheranosticsResearch Funding: Genentech/Roche, SignalOne Bio, AgendiaTravel, Accommodations, Expenses: NovartisOpen Payments Link: https://openpaymentsdata.cms.gov/physician/2511 Bryan SchneiderHonoraria: Lilly, Research to Practice Paul MarcomConsulting or Advisory Role: Genentech/Roche, ImmunomedicsResearch Funding: Novartis, Genentech/Roche, AstraZeneca, Verily, Glycomimetics, MillenniumOpen Payments Link: https://openpaymentsdata.cms.gov/physician/237508/summary Kathy AlbainConsulting or Advisory Role: Novartis, Pfizer, Myriad Genetics, Genomic Health, Agendia, Genentech/RocheResearch Funding: Seattle GeneticsOther Relationship: Puma Biotechnology Nadine TungResearch Funding: AstraZeneca Rita NandaConsulting or Advisory Role: Merck, Genentech/Roche, Pfizer, Macrogenics, Daiichi Sankyo, Athenex, Aduro Biotech, ION Pharma, Seattle Genetics, ImmunomedicsResearch Funding: Corcept Therapeutics, Celgene, Merck, Seattle Genetics, Genentech/Roche, Odonate Therapeutics, Pfizer, AstraZeneca, AbbVie, ImmunomedicsOther Relationship: G1 Therapeutics Rachel JankowitzHonoraria: EisaiConsulting or Advisory Role: Merck Mothaffar RimawiConsulting or Advisory Role: Macrogenics, Daiichi Sankyo, Seattle Genetics, GenentechResearch Funding: Pfizer Vandana AbramsonEmployment: HCA HealthcareConsulting or Advisory Role: Eisai, Daiichi Sankyo, AbbvieResearch Funding: Genentech/Roche, Lilly Paula PohlmannLeadership: Immunonet BioSciencesStock and Other Ownership Interests: Immunonet BioSciencesHonoraria: Dava Oncology, OncLive/MJH Life Sciences, Frontiers—PublisherConsulting or Advisory Role: Personalized Cancer Therapy, OncoPlex Diagnostics, Immunonet BioSciences, Pfizer, HERON, Puma Biotechnology, Sirtex Medical, Caris Life Sciences, Juniper Pharmaceuticals, Bolt BiotherapeuticsSpeakers' Bureau: Genentech/RocheResearch Funding: Genentech/Roche, Fabre-Kramer, Advanced Cancer Therapeutics, Caris Centers of Excellence, Pfizer, Pieris Pharmaceuticals, Cascadian Therapeutics, Bolt Biotherapeutics, Byondis, SeagenPatents, Royalties, Other Intellectual Property: United States Patent no. 8486413, United States Patent no. 8501417, United States Patent no. 9023362, United States Patent no. 9745377, Patent application Catherine Van PoznakResearch Funding: BayerPatents, Royalties, Other Intellectual Property: UpToDate Andres Forero-TorresEmployment: Seattle GeneticsStock and Other Ownership Interests: Seattle Genetics Minetta LiuResearch Funding: Eisai, Seattle Genetics, Novartis, Roche/Genentech, GRAIL, Merck, Tesaro, Menarini Silicon Biosystems, Genomic HealthTravel, Accommodations, Expenses: GRAIL, Merck, Menarini Silicon Biosystems, Pfizer, Genomic Health, AstraZeneca, Ionis Pharmaceuticals Kathryn RuddyPatents, Royalties, Other Intellectual Property: My husband is a co-inventor of technology licensed by Mayo Clinic to AliveCor (MountainView, CA), which makes a smartphone-enabled remote ECG monitoring system Richard GelberResearch Funding: AstraZeneca, Novartis, Roche, Merck, PfizerTravel, Accommodations, Expenses: Roche, AstraZeneca, Novartis Bill BarryEmployment: Rho Ann PartridgePatents, Royalties, Other Intellectual Property: I receive small royalty payments for co-authoring the breast cancer survivorship section of UpToDateTravel, Accommodations, Expenses: Novartis Eric 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: GenentechOther Relationship: InfiniteMD Ian KropEmployment: AMAG Pharmaceuticals, Freeline TherapeuticsLeadership: AMAG Pharmaceuticals, Freeline TherapeuticsStock and Other Ownership Interests: AMAG Pharmaceuticals, Freeline Therapeutics, VertexHonoraria: Genentech/Roche, AstraZeneca, CelltrionConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Daiichi Sankyo, Macrogenics, Taiho Pharmaceutical, Context Therapeutics, Novartis, Merck, Ionis Pharmaceuticals, Bristol Myers Squibb, AstraZenecaResearch Funding: Genentech, PfizerNo other potential conflicts of interest were reported.