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Unveiling the traits of HER2-low breast cancer: a comparative analysis of IHC1+ vs IHC2+/ISH-negative subgroups – insights from a 3-year cohort study

2025-11-07Research article Open access
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dc.contributor.authorCorreia, Jorge
dc.contributor.authorPulido, Catarina
dc.contributor.authorAlbuquerque, Joana
dc.contributor.authorPrazeres, Gil
dc.contributor.authorMargarido, Inês
dc.contributor.authorCâmara, Mariana
dc.contributor.authorNeto, Rita
dc.contributor.authorFernandes, Gonçalo
dc.contributor.authorGodinho, João
dc.contributor.authorNave, Mónica
dc.contributor.authorMascarenhas, Francisco
dc.contributor.authorEstudante, Isabel
dc.contributor.authorLopes, Paulina
dc.contributor.authorCatarino, Ana
dc.contributor.authorPassos-Coelho, José Luís
dc.date.accessioned2025-12-15T11:40:41Z
dc.date.available2025-12-15T11:40:41Z
dc.date.issued2025-11-07
dc.description.abstractBackground: Half of all breast cancer (BC) cases fall into the HER2-low category, defined as immunohistochemistry (IHC) 1+ or IHC 2+ in situ hybridization negative (ISH-). Two-thirds of these cases are IHC1+, while one-third is IHC2+/ISH-. New anti-HER2 antibody-drug conjugates (ADCs) have emerged as treatment options for metastatic or unresectable HER2-low BC patients. However, the heterogeneity between IHC1+ and IHC2+/ISH- subgroups and the clinical implications of varying HER2-low expression remain unclear. Objectives: This study aimed to compare demographic and clinicopathological differences between IHC1+ and IHC2+/ISH- subgroups and evaluate their response to neoadjuvant chemotherapy (NACT) in a cohort of patients with HER2-low BC. Methods: All consecutive patients diagnosed with HER2-low invasive BC between 2018 and 2020 at our institution were included in this retrospective cohort study. Clinicopathological characteristics were compared between IHC1+ and IHC2+/ISH- subgroups. Pathologic complete response (pCR) rates were assessed in patients undergoing NACT, and a multivariable logistic regression model was used to identify factors associated with pCR. Results: A total of 222 patients were included, evenly divided between IHC1+ (n=105, 47%) and IHC2+/ISH- (n=117, 53%) tumors, with no significant differences in baseline characteristics. Both subgroups predominantly comprised female patients (99% IHC1+ vs. 98% IHC2+/ISH-), postmenopausal (55% vs. 58%), with early-stage BC (94% vs. 98%) and estrogen receptor (ER)-positive tumors (90% vs. 90%). Around two-thirds had grade 2 tumors (63% vs. 64%), and the median Ki-67 index was 20% in both subgroups. Most BC were classified as luminal B-like (56% vs. 58%), followed by luminal A-like (35% vs. 34%), and TNBC (9% vs. 8%). Among the 43 patients with HER2-low BC who received NACT, 36% of IHC1+ patients achieved pCR, compared to only 5% in the IHC2+/ISH- subgroup (p = 0.021). Multivariable analysis revealed that IHC2+/ISH- status (vs. IHC1+) was significantly associated with lower odds of pCR (OR=0.07, 95% CI: 0.00–0.51, p = 0.025), while higher baseline Ki-67 and ER-negative status showed non-significant trends toward higher pCR rates after adjustment for other variables. Conclusion: Despite similar clinicopathological features, IHC2+/ISH- status was independently associated with lower pCR rates compared to IHC1+. These findings suggest that HER2-low subgroups may influence response to NACT and should be considered in multivariable prediction models, potentially informing stratified treatment approaches in the era of anti-HER2 ADCs.eng
dc.identifier.citationCorreia, J., Pulido, C., Albuquerque, J., & Prazeres, G. et al. (2025). Unveiling the traits of HER2-low breast cancer: a comparative analysis of IHC1+ vs IHC2+/ISH-negative subgroups – insights from a 3-year cohort study. Frontiers in Oncology, 15, Article 1675075. https://doi.org/10.3389/fonc.2025.1675075
dc.identifier.doi10.3389/fonc.2025.1675075
dc.identifier.eid105022649728
dc.identifier.issn2234-943X
dc.identifier.other199ab361-e3f6-4ea8-bf6b-586eaf430e8d
dc.identifier.pmcPMC12634363
dc.identifier.pmid41278278
dc.identifier.urihttp://hdl.handle.net/10400.14/55891
dc.identifier.wos001619084000001
dc.language.isoeng
dc.peerreviewedyes
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAntibody-drug conjugate (ADC)
dc.subjectHER2-low breast cancer
dc.subjectIHC
dc.subjectISH
dc.subjectPCR
dc.subjectPrognostic biomarkers
dc.subjectReal-world cohort study
dc.titleUnveiling the traits of HER2-low breast cancer: a comparative analysis of IHC1+ vs IHC2+/ISH-negative subgroups – insights from a 3-year cohort studyeng
dc.typeresearch article
dspace.entity.typePublication
oaire.citation.titleFrontiers in Oncology
oaire.citation.volume15
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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