About

Amy S. Clark, MD, MSCE, is the Jill and Alan Miller Associate Professor in Breast Cancer Excellence at the University of Pennsylvania's Perelman School of Medicine. She specializes as a medical oncologist focusing on breast cancer, treating patients with all types of cancers in the hospital setting and exclusively managing breast cancer patients in outpatient care. Her research concentrates on clinical trials and drug development for early stage and metastatic breast cancer, with a particular interest in developing novel predictive biomarkers using molecular imaging as companions to early phase trials. Dr. Clark has contributed to advancing understanding in breast cancer treatment and biomarker development through her clinical and research activities.

Research topics

• Medicine
• Oncology
• Internal medicine
• Biology
• Cardiology

Selected publications

• The ADAPT learning cancer treatment system: ARPA-H’s initiative to revolutionize cancer therapy

  Cancer Cell · 2026-01-08

  articleOpen access
  PublisherOA PDFDOI

• Air Pollution and Cardiac Remodeling and Function in Patients With Breast Cancer

  JAMA Network Open · 2026-01-15

  articleOpen access

  Importance: The relationship between air pollution and cardiac remodeling in patients with cancer treated with cardiotoxic therapy is undefined. Objective: To assess the associations between air pollutants and changes in cardiac function, structure, and remodeling in patients with breast cancer treated with anthracyclines and/or trastuzumab therapy. Design, Setting, and Participants: This longitudinal prospective cohort study included patients with breast cancer enrolled at multiple sites of a quaternary health care system from July 1, 2010, to November 1, 2018. All participants were initiating anthracyclines and/or trastuzumab. Data were analyzed from December 1, 2024, to April 30, 2025. Exposures: Three-year average census tract-level concentrations of fine particulate matter with diameter of 2.5 µm or less (PM2.5), particulate matter with diameter of 10 µm or less (PM10), nitrogen dioxide (NO2), and ozone (O3). Main Outcomes and Measures: Core laboratory-quantified, echocardiography-derived measures of cardiac remodeling and function and incidence of cardiac dysfunction, defined as a left ventricular ejection fraction (LVEF) decline of 10% or more from baseline to less than 50%. Multivariable linear regression and generalized estimating equations defined the cross-sectional and longitudinal associations between air pollution and measures of cardiac remodeling and function. Cause-specific hazard models defined the adjusted associations between air pollution and cardiac dysfunction. Results: Across 580 female patients (median age, 50 years [IQR, 42-58 years]), 3642 echocardiograms were obtained at standardized time intervals over a median of 3.1 years (IQR, 2.3-3.6 years) and centrally quantified. Cardiac dysfunction was observed in 98 of 574 participants (17.1%). Concentrations of PM2.5 (median, 9.26 μg/m3 [IQR, 8.49-10.17 μg/m3]) and O3 (median, 47.00 parts per billion [ppb] [IQR, 45.50-48.19 ppb]) were each associated with cardiac dysfunction and adverse remodeling, cross-sectionally and longitudinally. Over time, each IQR-increment increase in PM2.5 (1.68 μg/m3) and O3 (2.69 ppb) was associated with a mean LVEF change of -1.3% (95% CI, -1.8% to -0.8%) and -1.4% (95% CI, -1.8% to -1.0%), respectively; worse longitudinal strain (-1.0% [95% CI, -1.3% to -0.7%] and -1.1% [95% CI, -1.3% to -0.8%], respectively); and left ventricular mass increase of 4.8 g/m2 (95% CI, 3.1-6.5 g/m2) and 3.2 g/m2 (95% CI, 2.1-4.3 g/m2), respectively. Patients in the highest tertiles of PM2.5 (adjusted hazard ratio [AHR], 2.03; 95% CI, 1.17-3.52) and O3 (AHR, 2.15; 95% CI, 1.23-3.78) exposure were at a significantly higher risk of cardiac dysfunction compared with those in the lowest tertile. Neither PM10 (AHR, 0.84; 95% CI, 0.49-1.44) nor NO2 (AHR, 0.92; 95% CI, 0.50-1.70) showed significant associations with cardiac dysfunction. Conclusions and Relevance: In this cohort study, PM2.5 and O3 exposure was independently associated with worse cardiac remodeling and function in patients with breast cancer treated with cardiotoxic therapy. These findings highlight the importance of modifying environmental exposures to mitigate cardiovascular disease risk.

  PublisherOA PDFDOI

• Missingness in Eligibility Criteria for Target Trial Emulation in EHR With Survival Outcomes

  Statistics in Medicine · 2026-04-01

  articleOpen access

  In certain settings, when conducting a randomized trial would be infeasible, electronic health records (EHR) can be used to emulate a target trial and estimate causal effects of an intervention. This process involves specifying the elements of a hypothetical trial protocol and applying these to the design of an observational study conducted with EHR data (or other observational data source). One element of target trial specification includes defining eligibility criteria. However, defining the eligible population with EHR can be complicated by missingness in eligibility-defining variables. Multiple imputation (MI) is one common approach to missingness in EHR data, but it is unclear whether imputation of eligibility criteria should occur before or after excluding ineligible individuals. Motivated by a target trial emulation of two treatments for advanced breast cancer, we explore this question when estimating the average causal effect under a target trial framework with survival outcomes. We illustrate how alternative MI strategies perform using simulated data and in a real-world analysis of oncology EHR data. We found that in most settings with high proportions of missingness in eligibility-defining variables, imputing missing data using a flexible imputation model, such as a random forest, prior to excluding ineligible individuals resulted in lower bias than complete case analysis or imputation after excluding ineligible individuals. Choices about how to handle practical challenges such as this in the application of target trial emulation to messy, real-world data sources can have substantial effects on causal parameter estimation and should be carefully considered to ensure that the results of observational studies are as rigorous as possible.

  PublisherDOI

• CLO26-104: TBCRC 050: A Phase 1b/2 Trial of Niraparib and Trastuzumab in HER2+ Metastatic Breast Cancer (MBC): Safety and Efficacy

  Journal of the National Comprehensive Cancer Network · 2026-03-27

  article
  PublisherDOI

• Abstract 2994: Integrative pathway analysis of I-SPY2 HER2+ breast cancers reveals drug-repurposing opportunities

  Cancer Research · 2026-04-03

  article

  Abstract Background: HER2-positive breast cancer (HER2+) accounts for approximately 20% of all breast cancers. Major advances in HER2-targeted therapy have improved outcomes; however, substantial room for response improvement remains. Molecular subtyping by BluePrint (BP) stratifies HER2+ disease into HER2 and Luminal types. While BP-HER2 tumors achieve up to 78% pathologic complete response (pCR) with standard therapy, BP-Luminal tumors exhibit persistently low pCR rates (<15%). To address this unmet need, we profiled pretreatment molecular features distinguishing responders from non-responders across all HER2+ tumors and within BP subtypes to identify druggable pathways for rational combination or repurposing strategies. Methods: Baseline microarray profiles from 305 pretreatment HER2+ tumors (87 BP-Luminal, 218 BP-HER2) enrolled across five investigational agents or standard of care in the I-SPY2 trial were analyzed using Gene Set Variation Analysis (GSVA) across 2,265 canonical pathway gene sets. Differential pathway enrichment was assessed using linear models adjusting for treatment arm and false-discovery rate. Two comparisons were performed: (1) pCR vs. no pCR overall and within subtypes, and (2) BP-HER2 vs. BP-Luminal. Shared response- and subtype-specific pathways were grouped by functional similarity and cross-referenced with drug-target databases to identify FDA-approved or investigational compounds. Results: Across HER2+ tumors and within BP-HER2, we identified 42 pathways enriched in non-responders that were also elevated in BP-Luminal relative to BP-HER2, suggesting a luminal-linked resistance program even in non-luminal tumors. These pathways converged into eight metabolic and signaling themes. Growth-factor/RTK bypass (PI3K/AKT) and DNA repair & oxidative stress defense were strongly upregulated in non-responders within BP-HER2, revealing actionable nodes involving PI3K/AKT (alpelisib, capivasertib), IGF1R (linsitinib), MET (crizotinib, capmatinib), and DNA repair (PARP inhibitors). Notably, metabolic rewiring and lipid homeostasis—targetable by vismodegib and sonidegib—were upregulated in non-responders across both BP subtypes, reflecting a shared metabolic vulnerability. Conclusions: Luminal biology-linked transcriptional programs may persist within the HER2+ BP-HER2 subtype and contribute to resistance. BP-HER2 non-responders exhibit coordinated activation of RTK-bypass and DNA repair pathways, exposing therapeutic vulnerabilities targetable by existing agents. Furthermore, targeting lipid metabolic reprogramming alongside anti-HER2 therapy may enhance efficacy and overcome resistance across both BP subtypes. Our future directions include testing these drug combinations in patient-derived HER2+ organoid models. Citation Format: Kingsley V. Chow, Tam Binh Bui, Denise M. Wolf, Annuska Glas, Zheyun Xu, Gillian L. Hirst, I-SPY2 investigators, Amy Clark, Julia Wulfkhule, Angie DeMichele, Emanuel Frank Petricoin, Laura J. Esserman, Jennifer Rosenbluth, Laura van 't Veer, Rosalyn W. Sayaman. Integrative pathway analysis of I-SPY2 HER2+ breast cancers reveals drug-repurposing opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2994.

  PublisherDOI

• 195 Discordant HER2 Results Highlight the Need for Compulsory Biomarker Slide Review in Breast Cancer Referrals

  Laboratory Investigation · 2026-03-01

  article
  PublisherDOI

• Supplementary Table 1 from A Phase II Randomized Study of Paclitaxel Alone or Combined with Pelareorep with or without Avelumab in Metastatic Hormone Receptor–Positive Breast Cancer: The BRACELET-01/PrE0113 Study

  2025-07-01

  supplementary-materialsOpen access1st authorCorresponding

  <p>Supplementary Table 1. CONSORT Checklist.</p>

  PublisherDOI

• Supplementary Table 2 from A Phase II Randomized Study of Paclitaxel Alone or Combined with Pelareorep with or without Avelumab in Metastatic Hormone Receptor–Positive Breast Cancer: The BRACELET-01/PrE0113 Study

  2025-07-01

  supplementary-materialsOpen access1st authorCorresponding

  <p>Supplementary Table 2. Representativeness of Study Participants.</p>

  PublisherDOI

• A Phase II Randomized Study of Paclitaxel Alone or Combined with Pelareorep with or without Avelumab in Metastatic Hormone Receptor–Positive Breast Cancer: The BRACELET-01/PrE0113 Study

  Clinical Cancer Research · 2025-04-29 · 11 citations

  articleOpen access1st authorCorresponding

  PURPOSE: Pelareorep (Pel) is a type 3 oncolytic reovirus that upregulates PD-L1 expression. We determined the objective response rate (ORR) with paclitaxel (Pac), Pac + Pel, or Pac + Pel + avelumab (Ave). PATIENTS AND METHODS: Patients with hormone receptor-positive, HER2-negative metastatic breast cancer who had progressed on at least one line of endocrine therapy with a cyclin-dependent kinase 4/6 inhibitor and had not received chemotherapy for metastatic breast cancer were eligible. Patients were randomized 1:1:1 to Pac, Pac/Pel, or Pac/Pel/Ave after a three-patient run-in confirmed safety of the triplet regimen. Response was assessed every 8 weeks until week 16 and then every 12 weeks using RECIST v1.1. The primary endpoint was 16-week ORR. Statistical comparison across arms was not planned. RESULTS: Forty-eight patients were enrolled, with 45 randomized. The 16-week ORR was 20%, 31%, and 14% in the Pac, Pac/Pel, and Pac/Pel/Ave arms, respectively. The median progression-free survival was 6.4, 12.1, and 5.8 months in the Pac, Pac/Pel, and Pac/Pel/Ave arms, respectively. There were more adverse events, particularly infusion reactions, in the combination arms than the Pac arm. Expansion of peripheral T-cell clones was observed by cycle 4 in Pac/Pel but not the Pac or Pac/Pel/Ave arms. CONCLUSIONS: The addition of Pel to Pac was associated with increased toxicity, expanded peripheral T-cell clones, and numerically increased the ORR and progression-free survival compared with Pac; Pac/Pel/Ave further increased toxicity and blunted T-cell responses without obvious increase in efficacy. Investigation of the Pac/Pel combination warrants consideration with careful attention to acute toxicity.

  PublisherOA PDFDOI

• Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial

  Nature Medicine · 2025-09-02 · 22 citations

  article
  PublisherDOI

Recent grants

• Radiobiology and Imaging Program

  NIH · $93.0M · 1997–2027

Frequent coauthors

• Angela DeMichele

  University of Pennsylvania

  194 shared

• Claudine Isaacs

  59 shared

• Kevin R. Fox

  56 shared

• Hope S. Rugo

  UCSF Helen Diller Family Comprehensive Cancer Center

  53 shared

• Laura J. Esserman

  52 shared

• Susan M. Domchek

  University of Pennsylvania

  50 shared

• Christina Yau

  University of California, San Francisco

  48 shared

• Meghan Karuturi

  The University of Texas MD Anderson Cancer Center

  48 shared

Education

• MSCE

  University of Pennsylvania

  2012

• MD

  Penn State Milton S Hershey Medical Center

  2006

• BS

  Haverford College

  1999

Awards & honors

• Jill and Alan Miller Associate Professor in Breast Cancer Ex…