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Comprehensive genomic characterization of HER2-low and HER2-0 breast cancer.

ABSTRACT: The molecular underpinnings of HER2-low and HER2-0 (IHC 0) breast tumors remain poorly defined. Using genomic findings from 1039 patients with HER2-negative metastatic breast cancer undergoing next-generation sequencing from 7/2013-12/2020, we compare results between HER2-low (n = 487, 47%) and HER2-0 tumors (n = 552, 53%). A significantly higher number of ERBB2 alleles (median copy count: 2.05) are observed among HER2-low tumors compared to HER2-0 (median copy count: 1.79; P = 2.36e-6), with HER2-0 tumors harboring a higher rate of ERBB2 hemideletions (31.1% vs. 14.5%). No other genomic alteration reaches significance after accounting for multiple hypothesis testing, and no significant differences in tumor mutational burden are observed between HER2-low and HER2-0 tumors (median: 7.26 mutations/megabase vs. 7.60 mutations/megabase, p = 0.24). Here, we show that the genomic landscape of HER2-low and HER2-0 tumors does not differ significantly, apart from a higher ERBB2 copy count among HER2-low tumors, and a higher rate of ERBB2 hemideletions in HER2-0 tumors.

SUBMITTER: Tarantino P

PROVIDER: S-EPMC10657399 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Comprehensive genomic characterization of HER2-low and HER2-0 breast cancer.

Tarantino Paolo P Gupta Hersh H Hughes Melissa E ME Files Janet J Strauss Sarah S Kirkner Gregory G Feeney Anne-Marie AM Li Yvonne Y Garrido-Castro Ana C AC Barroso-Sousa Romualdo R Bychkovsky Brittany L BL DiLascio Simona S Sholl Lynette L MacConaill Laura L Lindeman Neal N Johnson Bruce E BE Meyerson Matthew M Jeselsohn Rinath R Qiu Xintao X Li Rong R Long Henry H Winer Eric P EP Dillon Deborah D Curigliano Giuseppe G Cherniack Andrew D AD Tolaney Sara M SM Lin Nancy U NU

Nature communications 20231118 1

The molecular underpinnings of HER2-low and HER2-0 (IHC 0) breast tumors remain poorly defined. Using genomic findings from 1039 patients with HER2-negative metastatic breast cancer undergoing next-generation sequencing from 7/2013-12/2020, we compare results between HER2-low (n = 487, 47%) and HER2-0 tumors (n = 552, 53%). A significantly higher number of ERBB2 alleles (median copy count: 2.05) are observed among HER2-low tumors compared to HER2-0 (median copy count: 1.79; P = 2.36e-6), with HE ...[more]

PMID: 37980405

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Project description:PurposeTo investigate the clinicopathological characteristics and prognostic factors of early-stage breast cancer (EBC) with human epidermal growth factor receptor 2 (HER2)-low expression.MethodsThe clinicopathological data and follow-up information of EBC patients with HER2-low and HER2-0 expression treated at the Breast Disease Center of Peking University First Hospital from January 2014 to December 2017 were analyzed. The prognosis between HER2-low and HER2-0 expression groups and with different hormone receptor (HR) expression were compared by statistics. Meanwhile, the expression of Ki67, androgen receptor (AR), TOPIIa, P53, PTEN, and CK5/6 were also analyzed with the HER2-low expression and prognosis.ResultsRetrospectively analyzed 1253 cases of EBC, including 583 (46.5%) cases of HER2-low breast cancer (BC) and 366 (29.2%) HER2-0 BC cases. Among the HER2-low BC patients, 487 (83.5%) were HR-positive, while 96 (16.5%) were HR-negative. Among the HER2-0 BC patients, 265 (72.4%) were HR-positive, while 101 (27.6%) were HR-negative. Median follow-up time was 53 months. The 5-year disease-free survival of HER2-low BC patients was 90.2% (95% confidence interval [CI]: 87.2-93.1), and the 5-year overall survival was 95.4% (95% CI: 93.3-97.6). Cox regression analysis showed that T stage, lymphovascular invasion, and/or perineural invasion were prognostic factors of HER2-low BC patients. However, the 5-year disease-free survival and overall survival of patients in the HER2-low and HER2-0 groups were not significantly different in all patients, but a tendency of better prognosis in HER2-low group was seen in HR-negative tumors.ConclusionHER2-low EBC patients accounted for 46.5% of the patient population. T stage, lymphovascular invasion, and/or perineural invasion were factors affecting the prognosis of BC patients with low HER2 expression. No significant difference in prognosis was noted between HER2-low and HER2-0 EBC patients. But in HR-negative tumors, a tendency of better prognosis was seen in HER2-low versus HER2-0.

Project description:BackgroundNovel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates prompt the identification of the HER2-low subtype. However, the biological significance of HER2-low expression in breast cancer is unclear.MethodsClinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database and genomic analysis of early breast cancer patients from TCGA was also analyzed.FindingsFirst, the clinicopathological characteristics of HER2-low patients were profoundly influenced by HR status and no difference of prognosis was observed between HER2-low and HER2-zero patients when paired by HR status, but notably HER2-low patients showed similar metastatic patterns to HER2-positive patients in the HR-positive (HR+ ) subgroup, with more brain and initial lung metastases and more cases of de novo stage IV breast cancer than HER2-zero patients. Second, among patients with primary HER2-low or HER2-zero tumors, the discordance of HER2 status between primary and metastatic tumors was significant, with 48.4% of patients with HER2-zero primary tumors exhibiting HER2-low phenotype in metastatic tumors in the HR+ subgroup. Third, within HR+ and HR-negative subtypes, HER2-low and HER2-zero tumors showed no substantial differences in mutation alterations and copy number variations. Forth, germline BRCA2 mutations were observed only in HER2-low patients in our NGS database, especially in HR+ HER2-low tumors. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, which provided novel insights into heterogeneity in HER2-low breast cancer.ConclusionsAfter correcting for HR expression, only marginal differences in clinical and molecular phenotypes were determined between HER2-low and HER2-zero breast cancer. Therefore, HER2-low breast cancer is insufficient to be defined as a distinct molecular entity, but rather a heterogenous disease.

Dataset Information

Comprehensive genomic characterization of HER2-low and HER2-0 breast cancer.

Publications

Comprehensive genomic characterization of HER2-low and HER2-0 breast cancer.

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