HER2-low status and response to neoadjuvant chemotherapy in HER2 negative early breast cancer

Leite, Luciana de Moura; Cesca, Marcelle Goldner; Tavares, Monique Celeste; Santana, D. Maciel; Saldanha, Erick Figueiredo; Guimarães, Paula Tavares; Sá, Daniella Dias Silva; Simões, M.F.; Viana, Rafael Lima; Rocha, Francisca Giselle; Loose, Simone Klog; Silva, Sinara Figueiredo; Pirolli, Rafaela; Fogassa, Camilla Albina Zanco; Mattos, Bruna Raphaeli Silva; Campos, Fernando Augusto Batista; Sanches, Solange Moraes; Lima, Vladmir Cláudio Cordeiro de; Pondé, Noam

doi:10.1007/s10549-021-06365-7

Cited by 111 publications

(93 citation statements)

References 30 publications

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“…A number of studies emerged in the past years have identified differences between HER2-low and HER2-0 disease, currently classified as HER2− disease, suggesting that HER2-low tumors constitute a distinct nosological entity [ 6 - 8 ]. In this study, the HER2-low subgroup was prevalent representing 56.9% of all patients, which is in agreement with previous reports, whose frequency ranged from 45% to 55% [ 6 , 8 , 14 , 16 ]. There was a slightly higher proportion of HER2 2+/ISH non-amplified in our study, which is opposite to the previous series where the vast majority of HER2-low patients had an IHC 1+.…”

Section: Discussionsupporting

confidence: 93%

“…The results were consistent with previous data, concerning HR expression, HER2-low tumors expressing a higher level of HR (65-83%) [ 6 - 8 , 14 ]. Specifically, a study about molecular analysis including PAM50 gene expression features of HER2-low BC found that ERBB2 levels are predominant in HR+/HER2-low tumors compared with TNBC/HER2-low tumors [ 6 ].…”

Section: Discussionsupporting

confidence: 93%

“…The effect of HER2-low status on the prognosis remains debatable among several studies. A number of series corroborate our findings [ 6 , 8 , 14 , 21 ] but others suggested worse outcomes for HER2-low in localized node-positive and luminal early BC, although these studies compared HER2-0/HER2 1+ versus HER2 2+/ISH negative patients [ 18 , 22 ]. Another cohort of 3,689 patients with a vast majority of advanced BC did not achieve a prognostic impact for HER2-low status on OS [ 6 ].…”

Section: Discussionsupporting

confidence: 85%

“…This has resulted in the presumption that HER2-low BC might constitute a different disease category, from other luminal and TNBC, with particular clinical characteristics and therefore potential for novel targeted therapies [ 14 ]. Consequently, this can be especially demanding for clinical pathologists, who are mostly focused on identifying HER2+ tumors (IHC score 3+ or IHC 2+/ISH positive) [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Impact of Human Epidermal Growth Factor Receptor 2 (HER2) Low Status in Response to Neoadjuvant Chemotherapy in Early Breast Cancer

Alves¹,

Gil²,

Matos³

et al. 2022

Cureus

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impact of Human Epidermal Growth Factor Receptor 2 (HER2) Low Status in Response to Neoadjuvant Chemotherapy in Early Breast Cancer

Alves¹,

Gil²,

Matos³

et al. 2022

Cureus

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“…However, studies currently present conflicting results. While a recent pooled analysis of 2310 patients from 4 neoadjuvant clinical trials showed better disease-free survival (DFS) and overall survival (OS) in HER2-low BC [ 11 ], other studies in the non-metastatic setting [ 12 – 14 ] and metastatic setting [ 15 – 17 ] did not observe any significant differences. In contrast, two older studies reported inferior DFS in non-metastatic BCs that were HER2 IHC 2+ ISH− compared with those which were HER2 IHC 1+ or 0 [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis

Tan

Ong

Lee

et al. 2022

BMC Med

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Background HER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC). Methods Patients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) (n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH−) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH− status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort (n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS. Results ABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82–0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76–0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85–0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79–0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83–0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78–0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH− and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59–0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found. Conclusions HER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC.

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Clinical, Epidemiologic, and Pathologic Significance of ERBB2-Low Expression in Breast Cancer

Khoury,

Mendicino,

Payne Ondracek

et al. 2024

JAMA Netw Open

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ImportanceIt is unclear whether breast cancer (BC) with low ERBB2 expression (ERBB2-low) is a distinct clinical, pathological, and epidemiological entity from BC classified as no ERBB2 expression (ERBB2-negative).ObjectiveTo evaluate the clinical, pathological, and epidemiologic features of BC with ERBB2-low expression compared with ERBB2-negative BC in a large population study.Design, Setting, and ParticipantsThis cohort study was conducted as part of the Pathways Study, a prospective, racially and ethnically diverse cohort study of women with BC enrolled between 2006 and 2013 in Kaiser Permanente Northern California (KPNC). The hematoxylin and eosin slides underwent centralized pathology review, including the percentage of tumor infiltrating lymphocytes (TILs). Breast biomarker results were extracted from pathology reports, and women were included if they had a documented ERBB2 value that was not classified ERBB2-positive. Data were analyzed from February 2023 through January 2024.ExposureClinical and tumor characteristics associated with BC and ERBB2-low or ERBB2-negative status.Main Outcome and MeasuresERBB2-low was defined as immunohistochemistry score of 1+ or 2+ (negative by in situ hybridization); ERBB2-negative was defined as immunohistochemistry score of 0+. Other data were collected by self-report or extraction from electronic health records, including BC risk factors, tumor characteristics, treatment modality, and survival outcomes, with recurrence-free survival (RFS) as the primary outcome and overall survival (OS) and BC-specific mortality (BCSM) as secondary outcomes. The clinical, pathological, and epidemiological variables were compared between ERBB2-low and ERBB2-negative BC.ResultsOf 2200 eligible patients (all female; with mean [SD] age, 60.4 [11.9] years), 1295 (57.2%) had tumors that were ERBB2-low. Hormone receptors were positive in 1956 patients (88.9%). The sample included 291 Asian patients (13.2%), 166 Black patients (7.5%), 253 Hispanic patients (11.5%), 1439 White patients (65.4%), and 51 patients (2.3%) who identified as other race or ethnicity (eg, American Indian or Alaska Native and Pacific Islander). Within the hormone receptor–negative group, patients whose tumors had ERBB2-low staining, compared with those with ERBB2-negative tumors, had better OS (hazard ratio [HR], 0.54; 95% CI, 0.33-0.91; P = .02), RFS (HR, 0.53; 95% CI, 0.30-0.95; P = .03), and BCSM (HR, 0.43; 95% CI, 0.22-0.84; P = .01). In multivariable survival analysis stratified by hormone receptor status and adjusted for key covariates, patients with ERBB2-low and hormone receptor–negative tumors had lower overall mortality (HR, 0.48; 95% CI, 0.27-0.83; P = .009), RFS (HR, 0.45; 95% CI, 0.24-0.86; P = .02), and BCSM (subdistribution HR, 0.21; 95% CI, 0.10-0.46; P &lt; .001) compared with patients with ERBB2-negative and hormone receptor–negative tumors. Within the hormone receptor–negative subtype, patients with ERBB2-low and high TILs tumors had better survival across all 3 outcomes compared with patients with ERBB2-negative and low TILs tumors. Additionally, patients with ERBB2-low and low TILs tumors had better BCSM (subdistribution HR, 0.36; 95% CI, 0.14-0.92; P = .03).Conclusions and RelevanceThese findings suggest that there were clinical, pathological, and epidemiological differences between ERBB2-low and ERBB2-negative BC, raising the possibility that ERBB2-low might be a unique biologic entity.

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HER2-low status and response to neoadjuvant chemotherapy in HER2 negative early breast cancer

Cited by 111 publications

References 30 publications

Impact of Human Epidermal Growth Factor Receptor 2 (HER2) Low Status in Response to Neoadjuvant Chemotherapy in Early Breast Cancer

Impact of Human Epidermal Growth Factor Receptor 2 (HER2) Low Status in Response to Neoadjuvant Chemotherapy in Early Breast Cancer

HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis

Clinical, Epidemiologic, and Pathologic Significance of ERBB2-Low Expression in Breast Cancer

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