{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:54:22Z","timestamp":1781585662471,"version":"3.54.5"},"reference-count":19,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      <jats:bold>H<\/jats:bold>\n                      ereditary cancer risk assessment has predominantly focused on HER2\u2010negative breast cancer (BC), with limited characterization of germline pathogenic variants (GPVs) in HER2\u2010positive disease. This study aimed to delineate the prevalence, clinicopathological correlates, and clinical implications of GPVs in a cohort of HER2\u2010positive BC patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrospectively reviewed BC patients who had undergone genetic testing at the Sun Yat\u2010sen University Cancer Center from 2014 to 2024. GPV profiles, clinicopathological features, and survival outcomes were compared between HER2\u2010positive and HER2\u2010negative patients, with additional stratified analysis in HER2\u2010positive GPV carriers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 1692\u2009\n                      <jats:sc>BC<\/jats:sc>\n                      patients, 1,499 patients met NCCN high\u2010risk criteria. In multigene panel testing, GPVs were identified in 18.1% (52\/288) of HER2\u2010positive BC and 22.4% (269\/1,201) of HER2\u2010negative BC patients. HER2\u2010positive GPV carriers exhibited distinct molecular profiles, with higher frequencies of\n                      <jats:italic>BRCA2<\/jats:italic>\n                      (23\/52, 44.2%) and\n                      <jats:italic>TP53<\/jats:italic>\n                      (14\/52, 26.9%) mutations and a lower\n                      <jats:italic>BRCA1<\/jats:italic>\n                      prevalence (6\/52, 11.5%) compared to HER2\u2010negative carriers (\n                      <jats:italic>BRCA2<\/jats:italic>\n                      : 106\/269, 37.9%;\n                      <jats:italic>TP53<\/jats:italic>\n                      : 9\/269, 3.3%;\n                      <jats:italic>BRCA1<\/jats:italic>\n                      : 117\/269, 43.5%). Clinically, HER2\u2010positive carriers were diagnosed at a younger median age, had higher hormone receptor (HR) positivity, and less frequently reported a family history of\n                      <jats:italic>BRCA<\/jats:italic>\n                      \u2010related cancers. GPVs were not associated with increased locoregional recurrence or distant metastasis in HER2\u2010positive BC but significantly elevated the risk of contralateral BC and other secondary primary cancers\u2014a risk particularly pronounced in\n                      <jats:italic>TP53<\/jats:italic>\n                      carriers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>HER2\u2010positive BC patients harbored a distinct GPV spectrum compared to HER2\u2010negative patients. While GPVs did not worsen primary BC\u2010specific outcomes, they conferred a significantly increased risk of second primary cancers, underscoring the clinical utility of multigene panel testing for comprehensive risk stratification and long\u2010term management in this population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Study Limitations<\/jats:title>\n                    <jats:p>This retrospective, single\u2010center study comprised a clinically enriched high\u2010risk cohort, which may limit the generalizability of prevalence estimates. The extended inclusion period and evolving classification standards, despite reannotation, represent inherent methodological constraints.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.71865","type":"journal-article","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T04:44:55Z","timestamp":1778906695000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Germline Pathogenic Variants in\n                    <scp>HER2<\/scp>\n                    \u2010Positive Breast Cancer: Spectrum and Clinical Implications in a High\u2010Risk Chinese Cohort"],"prefix":"10.1002","volume":"15","author":[{"given":"Lijia","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Sun Yat\u2010Sen University Cancer Center  Guangzhou P. R. 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R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daining","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Sun Yat\u2010Sen University Cancer Center  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Dun","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Sun Yat\u2010Sen University Cancer Center  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Sun Yat\u2010Sen University Cancer Center  Guangzhou P. R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9788-8389","authenticated-orcid":false,"given":"Jun","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Sun Yat\u2010Sen University Cancer Center  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Sun Yat\u2010Sen University Cancer Center  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2920-9671","authenticated-orcid":false,"given":"Zhongyu","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Sun Yat\u2010Sen University Cancer Center  Guangzhou P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine Sun Yat\u2010Sen University Cancer Center  Guangzhou P. R. 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