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Principal Investigator: Laura Fejerman
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $423,619
Funding agency: National Cancer Institute
PROJECT SUMMARY
Breast cancer is the most common cancer in women and the second leading cause of cancer death in the United
States (US). Although women included in the US Census racial/ethnic categories Hispanic/Latina (H/L) and
Asian American/Pacific Islander (AA/PI) have relatively low breast cancer incidence compared to non-Hispanic
White (NHW) women, multiple studies have reported a higher proportion of human epidermal growth factor
receptor positive (HER2+) tumors in these groups (18-30%) compared to NHWs (14-18%). Expression of HER2
is clinically significant because it determines if a patient can receive targeted treatment. HER2+ disease,
independent of hormone receptor (HR) status, is also associated with poor outcome compared to the most
common HR+ HER2- subtype. The use of European-centric data to predict cancer risk and prognosis in non-
Europeans remains a critical barrier for equity in the implementation of precision medicine. Overall, there is a
gap in knowledge regarding the genetic factorsand molecular correlates relevant to the etiology of HER2+ breast
cancer in diverse populations. Supported by a) our previous work showing a consistent association between
Indigenous American ancestry and HER2+ subtypes in H/L breast cancer patients, b) the higher proportion of
HER2+ tumors described in AA/PI and Asian populations, c) the closer genetic distance between these
populations relative to European groups, and d) promising preliminary data, we hypothesize that germline
variants more common in Indigenous American and Asian genomes contribute to the higher risk of HER2
amplification/expression in breast tumors of individuals with these ancestries. To test this hypothesis, we propose
to integrate and leverage our own existing studies for a total of 17,049 cases (~4,200 HER2+) and 15,409
controls for discovery, and the NCI’s Confluence Project Data for replication (~600,000 cases and controls
combined). Our main goal is to discover germline genetic variants contributing to the higher incidence of HER2+
breast cancer in women of Latin American and Asian heritage. To achieve this goal, we will 1) identify germline
variation associated with HER2+ breast cancer in H/L and Asian women and replicate across diverse ancestries,
2) develop, validate, and test trans-ancestry and ancestry-specific polygenic risk scores for HER2+ disease, and
3) identify genes associated with HER2+ breast cancer risk in H/L and Asian women. The results of our study
will lead to the discovery of genetic factors contributing to the observed HER2 subtype-ancestry association in
women of Indigenous American and Asian ancestry for improved prediction, and provide a better understanding
of HER2+ tumor etiology, which could lead to improved precision prevention strategies and the development of
new targeted treatments for HER2+ disease.
Terms: <Active Follow-up><African><Allelism Test><American><American Indian Females><American Indian Women><Anti-ERB-2><Anti-HER2/c-erbB2 Monoclonal Antibody><Anti-c-ERB-2><Anti-c-erbB2 Monoclonal Antibody><Anti-erbB-2><Anti-erbB2 Monoclonal Antibody><Anti-p185-HER2><Asian><Asian Americans><Asian Females><Asian Women><Asian ancestry><Asian descent><Asian group><Asian individual><Asian people><Asian population><Asians><Body Tissues><Breast Cancer><Breast Cancer Genetics><Breast Cancer Patient><Breast Cancer Risk Factor><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><Cancer Cause><Cancer Etiology><Cancer Prognosis><Cancers><Categories><Caucasian Females><Caucasian Women><Causality><Censuses><Cessation of life><Chinese><Colombian><Complementation Test><Data><Death><Development><Diagnosis><Disease><Disorder><EGF Receptor><EGFR><ERBB Protein><ERBB2><ERBB2 gene><Ensure><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Equity><Ethnic Origin><Ethnicity><Etiology><European><Frequencies><GWA study><GWAS><Gene Expression><Gene variant><Genes><Genetic><Genetic Complementation Test><Genetic Polymorphism><Genetic study><Genome><Genotype><Germ Lines><Germ-Line Mutation><Germline Mutation><Goals><HER -2><HER-2><HER1><HER2><HER2 Genes><HER2 Monoclonal Antibody><HER2/neu><HR positive><Herceptin><Hereditary Mutation><Hispanic><Hispanic Populations><Hispanic group><Hispanic individual><Hispanic people><Hispanics><Hormone Receptor><Human><Human Genetics><Incidence><Indigenous American><Indigenous American Women><Individual><Knowledge><Latin American><Latina><Latina Population><Latinas><Malaysian><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Medicine><Mexican><MoAb HER2><Modeling><Modern Man><Modernization><Molecular><NEU Oncogene><NEU protein><Native American Females><Native American Women><Network Analysis><Non-Hispanic><Nonhispanic><Not Hispanic or Latino><Oncogene ErbB2><Outcome><Pacific Islander><Participant><Pathway Analysis><Patients><Pattern><Pertuzumab><Peruvian><Population><Population Heterogeneity><Preventative strategy><Prevention strategy><Preventive strategy><Public Health><Race><Races><Reporting><Research><Sampling><Singapore><TCGA><TGF-alpha Receptor><TKR1><Testing><The Cancer Genome Atlas><Tissues><Trans Test><Transforming Growth Factor alpha Receptor><Trastuzumab><United States><Urogastrone Receptor><Variant><Variation><White Females><White Women><Woman><Work><active followup><allele variant><allelic variant><black female><black women><breast cancer genomics><breast cancer risk><c-erb-2 Monoclonal Antibody><c-erbB-1><c-erbB-1 Protein><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><cancer risk><causation><clinical significance><clinically significant><cohort><complementation analysis><complementation approach><developmental><disease causation><diverse populations><erbB-1><erbB-1 Proto-Oncogene Protein><erbB-2 Genes><erbBl><follow up><follow-up><followed up><followup><genetic predictors><genetic variant><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><germ-line defect><germline variant><global gene expression><global transcription profile><herstatin><heterogeneous population><high risk><hormone receptor +><hormone receptor-positive><improved><in silico><individualized prevention><insight><lapatinib><malignancy><malignant breast tumor><mammary tumor><migration><neoplasm/cancer><neu Genes><personalized prevention><polygenic risk score><polymorphism><population diversity><precision medicine><precision prevention><precision-based medicine><proto-oncogene protein c-erbB-1><racial><racial background><racial origin><rhuMAb HER2><rhuMAb2C4><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptome><transcriptomics><treatment strategy><tumor><whole genome association analysis><whole genome association studies><whole genome association study>