About

Kara N Maxwell, MD, PhD, is an Assistant Professor of Medicine in Hematology-Oncology at the University of Pennsylvania's Perelman School of Medicine. She is an attending physician at the Hospital of the University of Pennsylvania and a member of the Abramson Cancer Center. Dr. Maxwell's clinical expertise includes cancer risk evaluation, breast cancer risk, hereditary breast ovarian cancer, Li Fraumeni Syndrome, and Fanconi Anemia. Her research interests focus on the genetics of human disease, particularly familial breast and prostate cancers, and determinants of disease penetrance. She leads a translational human genetics and genomics research laboratory dedicated to studying mechanisms of tumor formation in inherited cancer syndromes, with a focus on breast and prostate cancer. Her work involves multi-omics analyses of human samples, in vitro and in vivo modeling systems, and collaborations leveraging resources such as the Basser Center for BRCA, the Penn Medicine Biobank, and the Veterans' Affairs and Prostate Cancer Foundation Partnership. Dr. Maxwell is the Director of the Basser Center’s Men and BRCA program and actively participates in research related to Li Fraumeni Syndrome caused by germline TP53 variants. Her research is funded by multiple organizations including the National Cancer Institute, the Veterans’ Affairs Office of Research and Development, and the Prostate Cancer Foundation.

Research topics

• Internal medicine
• Medicine
• Oncology
• Immunology

Selected publications

• Tumor suppressor genes, treatments, and survival in US veterans with prostate cancer

  The Oncologist · 2026-02-03

  articleOpen access

  BACKGROUND: Tumor suppressor gene (TSG) alterations prognosticate inferior survival in metastatic hormone-sensitive prostate cancer (mHSPC) and may affect response to therapy. We evaluated the association of TSG alterations with overall survival (OS) in mHSPC, stratified by initial treatment. METHODS: We identified veterans with de novo mHSPC diagnosed from 2017 to 2023 within the Veterans Health Administration. TSG alterations included loss-of-function alterations in RB1, TP53, and PTEN identified by somatic sequencing through the National Precision Oncology Program. Treatments within 4 months of diagnosis included androgen deprivation therapy (ADT), docetaxel, and androgen receptor pathway inhibitors (ARPIs). Kaplan-Meier and Cox models evaluated relationships between TSG alterations, clinical factors, and OS. RESULTS: Among 1842 veterans who met criteria, 865 had sequencing within 6 months. TSG alterations were found in 935 veterans, with the most common alterations being TP53 (36.7%), PTEN (23.4%), and RB1 (4.5%). In veterans sequenced within 6 months, RB1, TP53, and PTEN alterations were associated with mortality with a hazard ratio (95% CI) of 2.86 (1.94-4.21) (P < .001), 1.64 (1.30-2.05) (P < .001), and 1.52 (1.20-1.91) (P < .001), respectively. In the same cohort, median OS (95% CI) was 40.7 months (37.5-NR) with no alterations, 34.1 months (30.3-37.3) with 1, and 19.7 months (16.5-25.5) with ≥2 TSG alterations. In veterans with ≥1 alteration and sequencing within 6 months, combination therapy with ARPIs was associated with decreased mortality, aHR (95% CI) of 0.65 (0.48-0.88, P = .005). CONCLUSION: TSG alterations were associated with inferior OS in veterans with mHSPC. In this real-world observational study, ARPI-based combination therapy in veterans with TSG alterations was associated with the longest survival.

  PublisherDOI

• Germline polygenic score for prostate cancer aggressiveness

  medRxiv · 2026-05-10

  articleOpen access

  Background Risk stratification for prostate cancer (PCa) progression or aggressiveness is often based on clinicopathologic features, some of which may be influenced by genetic factors. We developed a novel, germline polygenic risk score (PRSagg) to predict likelihood of developing aggressive PCa. Methods PRSagg was developed using data from 38,688 patients with PCa (case-only analysis) from the Million Veteran Program (MVP) through a genome-wide search for variants associated with PCa grade group at diagnosis. We tested associations of PRSagg with grade group using the entire MVP dataset using the .632 bootstrap method. In an MVP cohort with localized PCa that was initially monitored without treatment, we tested PRSagg for association with unfavorable outcomes (subsequent development of grade group 4-5, metastasis, and/or biochemical recurrence after definitive treatment). We performed external validation in data from patients in the PRACTICAL Consortium (n=45,214) and from participants in the ProtecT randomized trial who underwent active monitoring (n=316). Odds ratios (ORs) were calculated per standard deviation (SD) increase with 95% confidence intervals, while adjusting for age, genetic ancestry, a previously developed polygenic score for risk of PCa (PHS601), and a polygenic score for benign elevated prostate-specific antigen (PRSPSA). For the outcome of metastasis, we additionally adjusted for PSA at diagnosis. Results In the MVP training dataset, PRSagg (172 variants) was associated with higher grade group at diagnosis (OR = 1.53 [1.51-1.56]) and with increased risk of unfavorable outcomes during monitoring (OR = 1.13 [1.09-1.18]). These findings were confirmed in the external datasets. PRSagg was associated with greater odds of higher grade group at diagnosis (OR = 1.09 [1.06-1.11]). Among ProtecT participants undergoing active monitoring, PRSagg was associated with higher risk of metastasis (OR = 2.15 [1.02-3.88]). Among MVP participants with high polygenic risk of developing any PCa, the risk of aggressive disease was highest in men with high PRSagg and low genetic risk of PSA elevation. Conclusions Among men who develop PCa, a weighted sum of common germline variants (PRSagg) is independently associated with PCa aggressiveness. These findings may inform future study of germline influence on tumor evolution and risk-stratified intensity of active surveillance.

  PublisherOA PDFDOI

• Liquid Biopsy for Cancer Screening in Li-Fraumeni Syndrome: Interest in Clinical Trial and Reported Barriers to Standard-of-Care Screening

  Cancer Prevention Research · 2026-04-15

  article

  Abstract Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with significant lifelong risk of cancer, and individuals with LFS undergo recommended screening protocols that are heavily dependent upon radiologic imaging. Recently, liquid biopsy has emerged as a potential new screening technique for LFS. In this study, we conducted a survey of adults with LFS and caregivers of children with LFS to determine interest in a clinical trial evaluating liquid biopsy as an addition to standard-of-care cancer screening. We also assessed barriers to receiving recommended screening and consequent financial toxicity. A total of 81 adults with LFS and 28 parents/guardians (“caregivers”) of children with LFS responded to the survey. Of these, the majority (93%) were interested in the addition of liquid biopsy and were willing to have additional screening as frequently as every 3 months. Although most respondents were able to complete standard-of-care cancer screening as planned, more than a third reported financial barriers to completion of screening. Other reported barriers included scheduling, transportation, and stress around screening results. Additionally, approximately one fifths of adults and one fourths of parents/caregivers reported financial toxicity, with the most prevalent being food insecurity. These results provide data for feasibility and high participant interest in a clinical trial of liquid biopsy for cancer screening in LFS. Additionally, any clinical trial will require planning around barriers to existing screening protocols. Prevention Relevance: Liquid biopsy testing for circulating tumor DNA is a promising strategy for cancer screening. Prior to a clinical trial of liquid biopsy cancer screening in LFS, this prospective survey of individuals with LFS and their caregivers assessed trial interest and barriers to current standard-of-care screening practices.

  PublisherDOI

• Colorectal Neoplasia Rates in Li-Fraumeni Syndrome

  The American Journal of Gastroenterology · 2026-02-25

  articleSenior author

  INTRODUCTION: Individuals with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome caused by TP53 pathogenic germline variants (PGV), have an increased risk of colorectal cancer (CRC). However, limited data exist on colonoscopy metrics, including total neoplasia detection rates, in patients with LFS. METHODS: We conducted a retrospective cohort study of colorectal neoplasia incidence and characteristics in 663 individuals with LFS. We determined total neoplasia detection rate, adenoma detection rate (ADR), advanced ADR, serrated lesion detection rate (SDR), and CRC detection rate, stratified by age, sex, and PGV subtype, in 311 surveillance colonoscopies from 206 adults performed January 2019 to August 2024. RESULTS: CRC was reported in 4.5% of 663 adults and 0.8% of 124 pediatric patients with LFS. Among 206 adults undergoing colonoscopy, total neoplasia detection rate, ADR, SDR, advanced precancerous polyp detection rate, and CRC detection rate were 37%, 27%, 9.3%, 4.5%, and 0.64%, respectively. Detection rates were similar between loss of function and hypomorphic PGVs. Adults aged 45-75 had higher total neoplasia detection rate, ADR, advanced ADR, SDR, and CRC detection rate than those aged 25-45. Male sex was associated with increased total neoplasia detection rate (53.7% vs 30.7%, P = 0.0004), ADR (41.2% vs 22.1%, P = 0.0013), and advanced ADR (7.5% vs 1.3%, P = 0.0105). DISCUSSION: Patients with LFS have comparable ADR and higher SDR with average-risk adults despite earlier, more frequent surveillance, irrespective of TP53 PGV subtype. Our data support current recommendations for earlier and more frequent colonoscopy surveillance than average-risk guidelines, across LFS phenotypes.

  PublisherDOI

• Abstract 4695: Distinct genomic remodeling in Li Fraumeni Syndrome breast cancer

  Cancer Research · 2026-04-03

  articleSenior author

  Abstract Background: Pathogenic germline variants (PGVs) in TP53 cause Li-Fraumeni Syndrome (LFS), a hereditary multicancer predisposition syndrome. Among females with LFS, breast cancer (BC) is the most prevalent malignancy, affecting 80-90% of carriers, typically at a much earlier age than sporadic cases and frequently exhibiting HER2 positivity. Interestingly, LFS-BC displays a high burden of short- amplified segments of aneuploidy (SAAS), suggesting that germline TP53 loss may drive tumorigenesis through distinct genomic mechanisms that remain poorly understood. Methods: To elucidate genotype-phenotype correlations underlying these unique genomic features, we performed whole-genome sequencing (WGS) and targeted sequencing on invasive ductal carcinoma (IDC), ductal carcinoma in situ (DCIS), and matched adjacent and contralateral normal breast tissues from individuals with LFS. Data were compared to early-onset nonLFS-BC and to The Cancer Genome Atlas (TCGA) tumors harboring either wild-type or somatic TP53 mutations. Results: Across hormone receptor (HR) subtypes, expected increases in genomic instability were observed in triple-negative versus ER+ nonLFS-BC. However, overall instability measures were similar or lower in LFS-BC. Specifically, in ER+ tumors, microsatellite instability (MSI) and aneuploidy scores were significantly lower in LFS-BC compared to nonLFS-BC. In contrast, LFS-BC exhibited a notable increase in segmental allelic imbalance (AI) with high-level amplifications-particularly within HER2+ subtypes. These amplified regions were significantly shorter than those in nonLFS-BC and often encompassed oncogenes such as ERBB2, defining a distinct SAAS phenotype. Unlike sporadic TP53-mutant breast cancers in TCGA, which showed globally elevated aneuploidy and HRD, LFS-BC uniquely accumulated focal, short amplifications. WGS of LFS DCIS and invasive tumors revealed predominant chromosomal instability (CN9) and chromothripsis (CN5) copy number signatures, with minimal whole-genome doubling. Amplicon Architect analysis identified ecDNA structures in 14 of 19 tumors, including ERBB2-containing ecDNA in 3/6 DCIS and 5/9 HER2+ IDCs with 4 and 8 number of ecDNA structure in each category respevtively. Our work is consistent with prior reports of ecDNA in ∼23% of breast cancers and up to 46% of HER2+ cases. Conclusion: LFS-associated breast cancers are defined by a unique genomic remodeling pattern characterized by focal, high-level amplifications within short aneuploid amplified segments (SAAS) and frequent ecDNA formation. These features distinguish LFS-BC from sporadic TP53-mutant tumors and highlight a germline TP53-driven mechanism of oncogene amplification and structural genome evolution. Citation Format: Nabamita Boruah, Renyta Moses, Ryan Hausler, Heena Desai, Maliha Tayab, Ahn Le, Gregory Kelly, Anupama Nayak, Kara Maxwell. Distinct genomic remodeling in Li Fraumeni Syndrome breast cancer [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 4695.

  PublisherDOI

• NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate, Version 2.2026

  Journal of the National Comprehensive Cancer Network · 2026-02-01 · 4 citations

  article

  The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate are intended to serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; help guide decisions related to genetic testing; and facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary breast, ovarian, pancreatic, and prostate cancer. The current guidelines focus primarily on assessment of pathogenic and likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants associated with increased risk of these cancers. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding screening for prostate cancer and pancreas cancer, as well as testing criteria for nonepithelial ovarian cancer.

  PublisherDOI

• Immune gene diversity and STING1 variants in shaping cancer immunity across different genetic ancestry populations

  Cell Reports · 2026-01-21

  articleOpen access

  As human populations migrated to diverse geographical regions, they encountered varying pathogens, leading to pronounced natural selection pressures on the immune system. Analysis of non-synonymous single-nucleotide polymorphisms (nsSNPs) across major geographically structured populations showed greater variation in immune-related genes than in non-immune genes, consistent with pathogen-driven selection, whereas cancer-related genes exhibited lower variation, reflecting the evolutionary conservation of critical cellular functions. We prioritized nsSNPs in pattern recognition receptor genes based on population diversity and their association with type I interferon (IFN) activity. Among the top-ranked variants were rs11554776, rs78233829, and rs7380824 in STING1, which demonstrated functional impacts on intrinsic cGAS-STING1-IFN signaling in cancer cells and potential influences on tumor immunity. We further conducted a genome-wide characterization of nsSNPs in immune-related genes across genetic ancestry populations and established a publicly accessible database. Our study suggests that genetic ancestry-related germline variations may influence cancer immunity and treatment, supporting their consideration in personalized medicine.

  PublisherDOI

• Abstract 603: Variation at the R181 residue of p53 confers loss of p53 DNA binding cooperativity with the retention of mitochondrial-associated apoptosis.

  Cancer Research · 2026-04-03

  articleSenior author

  Abstract TP53 is the most frequently mutated gene in cancer, and its encoded protein p53 has many tumor-suppressive functions. p53 primarily acts as a transcription factor and binds to target sites on DNA cooperatively as a tetramer. This cooperative binding is mediated by salt-bridge interactions between p53 residues E180 and R181 from two different p53 monomers. Variants at the R181 residue are one of the most identified TP53 pathogenic variants by germline genetic testing, however the mechanism by which these variants disrupt p53 tumor suppression is not understood. We show that families with TP53 p.R181H and p.R181C variants have an attenuated cancer risk phenotype compared to patients with hotspot loss of function TP53 variants. Despite this clinical phenotype, we find that p53 R181H and R181C variants have significantly diminished ability to transactivate a set of ∼300 known p53 target genes in CRISPR knock-in colorectal and breast cancer cell lines. This loss of transactivation ability does not occur through defects in p53 structure or oligomerization, but through reduced cooperative binding to p53 target sites on DNA as determined using fluorescence polarization assays on purified p53 proteins and using chromatin immunoprecipitation sequencing in R181-mutant cancer cells. Despite the complete loss of p53’s transcriptional function, R181 mutants retain some tumor suppressive function. Colony formation assays show efficient colony suppression by R181H and R181C, and injecting R181 knock-in cancer cells into the subcutaneous tissue of mice results in comparable tumor progression levels between R181H, R181C, and wild-type p53. Interestingly, we observe residual apoptotic activity in R181H and R181C mutant cells when treated with DNA-damaging agent 5-fluorouracil, despite the poor transactivation of p53’s proapoptotic targets. This suggests that the R181 mutants retain the p53 transcription-independent mechanism of apoptosis, where p53 goes to the mitochondria to induce apoptosis. Indeed, proximity ligation assays between p53 and mitochondrial BAK show that R181 mutants traffic to the mitochondria upon genotoxic stress. Our study elucidates p53 tumor suppressive activities that are lost versus retained by R181 variants, which is estimated to account for 0.5% of all p53 missense mutations. Citation Format: Renyta Moses, Alexandra Indeglia, Alison Schwartz-Levine, Ryan Hausler, Gregory Kelly, Sven Miller, Isabel Anez, Melissa Heller, Rosella Delgado, Caitlin Orr, Wendy Kohlmann, Anne Naumer, Jennie Vagher, Sophie H. Cahill, Luke D. Maese, John Karanicolas, Judy E. Garber, Maureen E. Murphy, Kara N. Maxwell. Variation at the R181 residue of p53 confers loss of p53 DNA binding cooperativity with the retention of mitochondrial-associated apoptosis [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 603.

  PublisherDOI

• Remote delivery of cancer genetic testing in veterans with metastatic prostate cancer: A Million Veteran Program pilot study

  Cancer · 2026-01-30

  articleOpen access

  BACKGROUND: Germline pathogenic variants can inform targeted therapy for metastatic prostate cancer (mPC), and improve cancer early detection and risk reduction for family members. Guidelines recommend germline genetic testing be offered to all men with mPC, yet uptake of testing is only 10%-12%. METHODS: This prospective study enrolled veterans participating in the VA Million Veteran Program (MVP) with a diagnosis of mPC. Veterans were contacted by mail with option to opt-out of future contact. Eligible veterans who did not opt-out were mailed study information and received a follow-up phone call to establish interest in germline testing. Participants provided verbal consent and were mailed a saliva collection kit for a CLIA-level multigene cancer predisposition gene panel test. Results were disclosed to the patient and oncology provider. All steps were performed with genetic counseling support. RESULTS: Of 2104 eligible patients, 1952 veterans with mPC did not opt out. Of these, 681 (35%) provided consent and 459 (24%) completed testing. Of those who were approached 63% were White and 25% were Black. Fifty-nine (13%) of those completing testing carried a germline pathogenic variant in a cancer risk gene. Of the 37 eligible for targeted therapy, 14 received targeted therapy, 18 did not yet have an indication for that therapy, and five were deceased without having received targeted therapy. CONCLUSIONS: Participant completion of remote germline testing was facilitated at rates higher than the 10% previously reported. Remote genetic testing can augment uptake of testing in large, integrated health care systems.

  PublisherDOI

• Abstract 5287: Parent-of-Origin-Aware genomic analysis in hereditary cancer: identifying the side of the family at risk using only the proband’s blood sample

  Cancer Research · 2026-04-03

  article

  Abstract Background: Determining the parent of origin (PofO) of a variant in hereditary cancer guides counseling, risk management, recurrence risk assessment, and variant classification. In conditions involving genes with PofO effects, such as SDHD, SDHAF2 and MAX, this information can determine whether disease will manifest. Current approaches rely on family-based testing, yet uptake among eligible first-degree relatives remains low, with fewer than 30% undergoing testing, creating a major barrier in hereditary cancer.To address this gap, we developed Parent-of-Origin-Aware Genomic Analysis (POAga), a method that integrates chromosome-scale haplotyping with DNA methylation at differentially imprinted regions to assign PofO without parental data. To validate POAga, we applied it to individuals with hereditary cancer and known segregation of their pathogenic variants, and compared the predicted PofO with the established segregation to assess concordance and limitations. Methods: Blood samples are being collected from individuals with pathogenic variants in hereditary cancer genes, representing broad ranges of ages, ancestries, and cancer histories. Parental segregation was previously known or established through confirmatory testing. Predicted PofO is compared with true segregation to assess concordance. All samples undergo Strand-seq and long-read sequencing under an REB-approved protocol. Results: To date, 285 samples with 290 pathogenic variants have been analyzed across the following genes: BRCA2 (n=46), BRCA1 (n=42), MSH2 (n=34), SDHD (n=29), MLH1 (n=27), MSH6 (n=26), PMS2 (n=20), PALB2 (n=15), TP53 (n=14), ATM (n=14), CDH1 (n=9), CHEK2 (n=3), EPCAM (n=2), SDHAF2 (n=2), MUTYH (n=2), CDKN2A (n=1), POT1 (n=1), RAD51D (n=1), and SDHC (n=1). PofO was assigned for 250 variants, with 98.4% concordance (246/250). PofO could not be determined for 40 variants (13.8%, 40/290), mainly due to insufficient allele-specific methylation at imprinted regions or extended homozygosity that impeded phasing. Misassignments were rare and mainly due to stochastic phasing errors, unresolved inversions, or random allelic methylation at imprinted regions. Conclusion: POAga achieves clinical-grade accuracy in assigning PofO from a single blood sample in hereditary cancer. This directly addresses a major barrier in clinical genetics, particularly when parental samples are unavailable. For genes with PofO effects, this information can determine whether disease will manifest. By enabling reliable segregation without parental testing, POAga helps direct clinical efforts toward those truly at risk and improves the clinical interpretation of variants. Ongoing analyses will refine its performance and support its adoption as a transformative tool in hereditary cancer genomics. Citation Format: Lilian Cordova, Vahid Akbari, Tiffany Leung, Kieran O’Neill, Katherine Dixon, Alexandra Roston, Eugene Cheung, Chuyi Zheng, Millicent Sharman, Alshanee Sharma, Steve Bilobram, Yaoqing Shen, Janine Senz, Yanni Wang, Daniel Chan, Alexandra Fok, Jennifer Nuk, Quang Hong, Robin Coope, Eric Chuah, Simon Chan, Hyun-Wu Lee, Yongjun Zhao, Miruna Bala, Karen Mungall, Andrew Mungall, Richard Moore, Nur Diana Binte Ishak, Siao Ting Chong, Ee Ling Chew, Ashley McDonald, Anna Martinez, Gregory Kelly, Rosella Delgado, Caitlin Orr, Joanne Yuen Yie Ngeow, Kara N. Maxwell, Stephen B. Gruber, Dean Regier, Alice Virani, Louis Lefebvre, Fabio Feldman, Marco Marra, Sophie Sun, Stephen Yip, Peter Lansdorp, Steven John Jones, Kasmintan Schrader. Parent-of-Origin-Aware genomic analysis in hereditary cancer: identifying the side of the family at risk using only the proband’s blood sample [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 5287.

  PublisherDOI

Recent grants

• A genotype-phenotype study of tumors from patients with inherited mutations in DNA repair genes

  NIH · $924k · 2018–2023

Frequent coauthors

• Katherine L. Nathanson

  University of Pennsylvania

  100 shared

• Susan M. Domchek

  University of Pennsylvania

  100 shared

• Ryan Hausler

  University of Pennsylvania

  63 shared

• Heena Desai

  University of Pennsylvania

  51 shared

• Jacquelyn Powers

  University of Pennsylvania

  49 shared

• Bradley Wubbenhorst

  University of Pennsylvania

  47 shared

• Isla P. Garraway

  APLA Health

  41 shared

• Anh N. Le

  Philadelphia College of Osteopathic Medicine

  41 shared

Labs

• Maxwell LabPI