Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis

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This study aimed to analyze and compare the clinical and histopathological features of HER2-positive breast carcinomas across three subgroups: Group 1: Triple-positive (ER+/PR+/HER2+), Group 2:ER-positive only (ER+/PR-/HER2+), and Group 3: HER2-enriched (ER-/PR-/HER2+). Methods This was a single-institution, retrospective, cross-sectional study conducted over 42 months (January 2021–June 2024) at a tertiary care center comprising of 117 HER2-positive breast carcinoma cases. The demographic, clinical, and histopathological parameters were studied retrospectively. Statistical analysis was performed via SPSS Version 29.0, employing ANOVA and chi-square tests, with p < 0.05 considered significant. Results Among 117 HER2-positive breast cancer patients, left and right breast involvement was nearly equal. Most were diagnosed via core biopsy (83.8%), with the upper outer quadrant most commonly affected (42.9%). Invasive breast carcinoma of no special type was the predominant subtype. The HER2-enriched group (Group 3) had the highest mean age (57.28 years; p = 0.001) and the most Grade 3 tumors (36.1%; p = 0.005). Although Group 2 (ER-positive) had the largest mean tumor size (4.31 cm), the difference was not statistically significant (p = 0.143). Lymphovascular invasion, necrosis, Ductal carcinoma in situ (DCIS), and skin involvement showed no significant differences across groups. ANOVA showed significant variation in age and grade, and post-hoc analysis confirmed that Group 1 vs Group 3 differed significantly in both age (p = 0.001) and grade (p = 0.004). Conclusion HER2-positive breast carcinomas show variability by HR status. The HER2-enriched subtype is associated with older age, higher histological grade, and advanced nodal stage, suggesting a more aggressive phenotype. Recognizing these patterns aids in accurate prognostication and guiding individualized therapy. 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F1000Research 2025, 14 :1246 ( https://doi.org/10.12688/f1000research.171847.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis [version 1; peer review: 2 approved] Anuradha Calicut Kini Rao 1 , Kanthilatha Pai 1 , Swathi Prabhu https://orcid.org/0000-0002-0742-5373 1 , Naurin Kasem 1 , Karthik S Udupa 2 Anuradha Calicut Kini Rao 1 , Kanthilatha Pai 1 , [...] Swathi Prabhu https://orcid.org/0000-0002-0742-5373 1 , Naurin Kasem 1 , Karthik S Udupa 2 PUBLISHED 13 Nov 2025 Author details Author details 1 Department of Pathology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India 2 Department of Medical Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India Anuradha Calicut Kini Rao Roles: Conceptualization, Data Curation, Investigation, Methodology, Supervision, Validation, Writing – Review & Editing Kanthilatha Pai Roles: Conceptualization, Supervision, Validation, Writing – Review & Editing Swathi Prabhu Roles: Data Curation, Formal Analysis, Investigation, Methodology, Resources, Writing – Original Draft Preparation Naurin Kasem Roles: Data Curation, Investigation Karthik S Udupa Roles: Supervision, Validation OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Manipal Academy of Higher Education gateway. This article is included in the Oncology gateway. Abstract Background HER2-positive breast carcinomas are a heterogeneous group with various clinicopathological characteristics depending on hormone receptor (HR) status. This study aimed to analyze and compare the clinical and histopathological features of HER2-positive breast carcinomas across three subgroups: Group 1: Triple-positive (ER+/PR+/HER2+), Group 2:ER-positive only (ER+/PR-/HER2+), and Group 3: HER2-enriched (ER-/PR-/HER2+). Methods This was a single-institution, retrospective, cross-sectional study conducted over 42 months (January 2021–June 2024) at a tertiary care center comprising of 117 HER2-positive breast carcinoma cases. The demographic, clinical, and histopathological parameters were studied retrospectively. Statistical analysis was performed via SPSS Version 29.0, employing ANOVA and chi-square tests, with p < 0.05 considered significant. Results Among 117 HER2-positive breast cancer patients, left and right breast involvement was nearly equal. Most were diagnosed via core biopsy (83.8%), with the upper outer quadrant most commonly affected (42.9%). Invasive breast carcinoma of no special type was the predominant subtype. The HER2-enriched group (Group 3) had the highest mean age (57.28 years; p = 0.001) and the most Grade 3 tumors (36.1%; p = 0.005). Although Group 2 (ER-positive) had the largest mean tumor size (4.31 cm), the difference was not statistically significant ( p = 0.143). Lymphovascular invasion, necrosis, Ductal carcinoma in situ (DCIS), and skin involvement showed no significant differences across groups. ANOVA showed significant variation in age and grade, and post-hoc analysis confirmed that Group 1 vs Group 3 differed significantly in both age ( p = 0.001) and grade ( p = 0.004). Conclusion HER2-positive breast carcinomas show variability by HR status. The HER2-enriched subtype is associated with older age, higher histological grade, and advanced nodal stage, suggesting a more aggressive phenotype. Recognizing these patterns aids in accurate prognostication and guiding individualized therapy. READ ALL READ LESS Keywords breast carcinoma, HER2-positive, HER2-enriched, Luminal B Corresponding Author(s) Swathi Prabhu ( [email protected] ) Close Corresponding author: Swathi Prabhu Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Rao ACK et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Rao ACK, Pai K, Prabhu S et al. Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis [version 1; peer review: 2 approved] . F1000Research 2025, 14 :1246 ( https://doi.org/10.12688/f1000research.171847.1 ) First published: 13 Nov 2025, 14 :1246 ( https://doi.org/10.12688/f1000research.171847.1 ) Latest published: 13 Nov 2025, 14 :1246 ( https://doi.org/10.12688/f1000research.171847.1 ) Introduction Breast cancer ranks as the most prevalent cancer among women globally, accounting for approximately 25% of all female cancer cases. In India, it holds the top position among cancers affecting women, constituting approximately 28.2% of all female cancers. By 2022, approximately 216,000 new cases are projected to be diagnosed across the country. 1 , 2 Luminal A breast cancers are traditionally believed to have a favorable prognosis, whereas triple-negative breast cancers (TNBCs) are associated with poor outcomes. However, clinical observations revealed that some Luminal A tumors exhibited aggressive behavior, whereas certain TNBC cases presented relatively better outcomes. These inconsistencies led to the exploration and development of more refined molecular subtyping of breast cancer. 3 Among all breast cancer subtypes, HER2-positive tumors have drawn particular attention because of the availability of targeted therapy with trastuzumab. As a result, HER2-enriched cancers have been extensively studied in literature. In recent years, the classification has further evolved with the recognition of HER2-low and HER2-ultralow tumors, driven by the development of novel antibody–drug conjugates such as trastuzumab deruxtecan. 4 HER2 status in breast cancer is determined according to the ASCO/CAP guideline criteria via immunohistochemistry (IHC) and in situ hybridization (ISH). A positive HER2 IHC score is defined as 3+, which indicates complete, intense, circumferential membranous staining in more than 10% of the tumor cells. This staining should be easily visible at low magnification and should be observed in a homogenous and contiguous population of invasive tumor cells. A patient is considered HER2-positive if the IHC score is 3+ or if the IHC score is 2+ (equivocal) with a positive HER2 ISH result. Additionally, a tumor is classified as HER2 positive if HER2 ISH is positive, regardless of the IHC result. 1 Approximately 20–25% of breast cancers are HER2-positive, and among these, nearly half also express hormone receptor (HR). A growing body of research indicates that the clinical characteristics, biological behavior, treatment response, and prognosis of HER2-positive breast cancers are influenced by their HR status. 5 HR-positive HER2-positive breast tumors are associated with better survival outcomes than HR-negative HER2-positive tumors. Tumors that are positive for either the estrogen receptor (ER) or progesterone receptor (PR) alone tend to behave differently from those that are dual-positive (ER and PR) or dual-negative, indicating biological heterogeneity within HER2-positive subtypes. 6 – 8 We conducted a retrospective cross-sectional study on HER2-positive breast carcinoma patients diagnosed over a period of 42 months at a tertiary care hospital. The patients were divided into three groups on the basis of HR status: group 1: triple-positive (ER+, PR+, HER2+), group 2: ER-positive only (ER+, PR−, HER2+), and group 3: HER2-enriched (ER−, PR−, HER2+). The objective of this study was to evaluate and compare the clinicopathological features across these molecular subtypes. Our findings provide insights into the biological behavior and morphological spectrum of HER2-positive breast cancers in relation to HR expression. Materials and methods This was a single institutional, cross-sectional, retrospective observational analysis involving cases received at the pathology laboratory of a tertiary care hospital for a duration of 42 months (January 2021-June 2024). After applying the relevant inclusion and exclusion criteria ( Figure 1 ), 117 patients were included in the study group. Patients whose HER2- status was negative/those whose clinicopathological data were insufficient, or whose IHC status was unknown were excluded. The demographic data included the age of the patient, the location within the breast, and the laterality; the morphological data included the size of the tumor, the histopathologic grade, lymphovascular invasion (LVI), perineural invasion (PNI), necrosis, ductal carcinoma in situ (DCIS), skin involvement, TNM stage and Ki67. Clinical TNM staging was used when only core biopsies were available, and pathological TNM staging was used for breast conserving surgery (BCS) and modified radical mastectomy (MRM) cases. Molecular subtyping was performed based on the IHC assessment of HR status and HER2 positivity, and the latter was tested via the ISH technique in a reference laboratory in cases in which HER2 was equivocal on IHC. Figure 1. Methodology with inclusion and exclusion criteria. The total cases included in our study were 117. Patients A total of 117 newly diagnosed HER2-positive breast carcinoma cases diagnosed between January 2021 and June 2024, spanning a period of 42 months, were studied. HER2 positivity was defined based on the ASCO/CAP guidelines as either IHC 3+ or with ISH amplification. The inclusion and exclusion criteria were employed for selection, and the cases were further divided into three study groups according to hormone receptor status ( Table 1 ). Table 1. The table shows three study groups according to hormone receptor status. Groups Estrogen receptor (IHC) Progesterone receptor (IHC) Group 1 (TP) Positive Positive Group 2 (ER-positive only) Positive Negative Group 3 (HER2-enriched) Negative Negative Statistics SPSS Statistics for Windows, Version 29.0. (Armonk, NY: IBM Corp.). To describe the data, descriptive statistics, frequency analysis, and percentage analysis were used for categorical variables, and the mean and SDs were used for continuous variables. To identify significant differences in the multivariate analysis, one-way ANOVA was used. To determine the significance of the differences in qualitative categorical data the chi-square test was used. For both of the above statistical tools, a probability value of 0.05 is considered significant. Results A total of 117 HER2-positive breast carcinomas were analyzed. Among the 117 patients, 59 (50.4%) involved the left breast, and 58 (49.6%) involved the right breast, showing an almost equal distribution between the two sides. The tumors were located in the upper outer quadrant in 50 patients, accounting for 42.9% of the total. The upper inner quadrant was involved in 23 patients (19.6%), whereas the lower outer quadrant was affected in 19 patients (16.2%). The lower inner quadrant was involved in 11 patients (9.4%), and the central quadrant was involved in 8 patients (6.8%). Tumors involving all quadrants were observed in 6 patients, accounting for 5.1% of the total. The majority of patients (83.8%) were diagnosed with core biopsy. BCS accounted for 8.6% of the samples, whereas MRM accounted for 7.6% of the samples. The study cohort of HER2-positive breast carcinoma was divided into three groups on the basis of HR status. Group 1 (Triple-positive) included 53 patients who were positive for both ER and PR. Group 2 (ER-positive only) comprised 28 patients who were positive for ER, negative for PR. Group 3 (HER2-enriched) consisted of 36 patients who were negative for both ER and PR. When the subgroup analysis was performed across the three groups, the mean age was significantly greater in the HER2-enriched group (57.28 years) than in the other groups (p = 0.001). The largest tumor size was detected in the ER-positive only group (4.31 cm), although this difference was marginally significant statistically (p = 0.143). The T2 stage was the most common stage across all groups, with a greater proportion in the HER2-enriched group (58.3%) (p = 0.061). Nodal involvement (N1) was more common in the HER2-enriched group (50%), but the difference was not significant (p = 0.266) ( Table 2 ). Table 2. Clinical characteristics of HER2-enriched patients across various groups (n = 117). Clinical parameters Luminal B HER2-enriched Group 1, n = 53 (Triple-positive) Group 2, n = 28 (ER-positive only) Group 3, n = 36 (HER2-enriched) Age, y * (p = 0.001) 48.98 (9.20) 52.61 (10.51) 57.28 (10.86) Laterality (p = 0.707) Right, n (%) 27 (50.9) 12 (42.9) 19 (52.8) Left, n (%) 26 (49.1) 16 (57.1) 17 (47.2) Tumor size, cm (p = 0.143) 3.34 (2.38) 4.31 (2.51) 3.42 (1.50) Tumor stage (p = 0.061) T1, n (%) 13(24.5) 1 (3.6) 4 (11.1) T2, n (%) 18 (34) 11 (39.3) 21 (58.3) T3, n (%) 13 (24.5) 9 (32.1) 5 (13.9) T4, n (%) 9 (17) 7 (25) 6 (16.7) Nodal stage (p = 0.266) N0, n (%) 25 (47.2) 12 (42.9) 13 (36.1) N1, n (%) 20 (37.7) 10 (35.7) 18 (50.0) N2, n (%) 7 (13.2) 4 (14.3) 1 (2.8%) N3, n (%) 1 (1.9%) 2 (7.1%) 4 (11.1) * Values are expressed as the mean ± SD or median with range, unless otherwise specified. ER, Estrogen receptor. When histopathological features were analyzed among the three groups, the predominant subtype across all groups was invasive breast carcinoma, not otherwise specified (IBC NOS), which was observed in 96.2% of the patients in group 1 (Triple-positive), 92.8% of those in group 2 (ER-positive only), and 88.9% of those in group 3 (HER2-enriched). Rare histological variants included micropapillary and mucinous features in group 1, medullary features in group 2, and apocrine/apocrine-like features in group 3 ( Table 3 ). The SBR grade distribution showed statistically significant difference (p = 0.005), with group 1 showing a predominance of grade 2 tumors (62.3%), group 2 having the highest proportion of grade 2 tumors (92.9%) and very few grade 3 tumors, and group 3 having the highest proportion of grade 3 tumors (36.1%). Other features, such as LVI, PNI, associated DICS, necrosis, and skin involvement, did not differ significantly between the groups. Table 3. Histopathological features of patients across various groups (n = 117). Group 1(n = 53) Group 2(n = 28) Group 3(n = 36) p-value Histopathological subtypes Apocrine breast carcinoma, n (%) 0 0 1 (2.8) IBC with apocrine features, n (%) 0 0 (0) 3 (8.3) IBC with medullary features, n (%) 0 1 (3.6) 00 (0%) IBC with micropapillary features, n (%) 1 (1.9) 1 (3.6) IBC with mucinous differentiation, n (%) 1 (1.9) 0 0 IBC NOS, n (%) 51 (96.2) 26 (92.8) 32 (88.9) SBR grade 0.005 Grade 1, n (%) 13 (24.5) 0 (0) 3 (8.3) Grade 2, n (%) 33 (62.3) 26 (92.9) 20 (55.6) Grade 3, n (%) 7 (13.2) 2 (7.1) 13 (36.1) LVI present, n (%) 9 (17) 6 (21.4) 6 (16.7) 0.859 PNI present, n (%) 3 (5.7) 0 (0) 4 (11.1) 0.176 DCIS, n (%) 14 (26.4) 6 (21.4) 10 (27.8) 0.834 Necrosis, n (%) 14 (26.4) 7 (25) 11 (30.6) 0.866 Skin Involvement, n (%) 10 (18.9) 7 (25) 6 (16.7) 0.694 Ki67 proliferation index, (mean) * 43.42 (23.5) 44.93 (22.94) 50.19 (23.80) 0.4 * Values are expressed as the mean ± SD or median with range, unless otherwise specified. Table 4. Summary of ANOVA and post hoc Pairwise Comparisons for Clinicopathological Variables Among the three groups of HER2 -positive breast carcinomas. Variable ANOVA p value Post hoc Group Comparison Mean Difference (I–J) p value 95% Confidence Interval Age 0.001 group 1 vs group 2 -3.626 0.274 -9.202 to 1.950 group 1 vs group 3 -8.2966 0.001 -13.452 to -3.142 group 2 vs group 3 -4.6706 0.16 -10.685 to 1.344 SBR grade 0.004 group 1 vs group 2 -0.5256 0.081 -1.101 to 0.050 group 1 vs group 3 -0.728 0.004 -1.260 to -0.196 group 1 vs group 3 -0.2024 0.719 -0.823 to 0.418 When ANOVA was performed, statistically significant differences were observed in the mean age (p = 0.001) and SBR score (p = 0.004) among the three groups. However, there was no significant difference in tumor size (p = 0.143) or the Ki67 index (p = 0.400) between the groups. Post hoc analysis revealed a significant difference in age between group 1 and group 3 (p = 0.001), with group 3 being older. Similarly, SBR scores were significantly higher in group 3 than in group 1 (p = 0.004). No significant differences were observed between the other group pairs for either variable ( Table 4 ). Discussion HER2-positive breast cancers are driven by amplification of the HER2 gene located on chromosome 17q. The HER2 protein is a receptor tyrosine kinase that activates signaling pathways such as the RAS and PI3K-AKT pathways, promoting tumor growth and survival. These tumors may or may not express hormone receptors. In addition to gene amplification, they often exhibit complex chromosomal alterations and a high number of genetic mutations. The differences in gene expression profiles among these tumors are largely determined by hormone receptor status and the expression of estrogen related genes. 9 HER2 status can be identified via IHC or ISH. Although HER2-positive cancers were once associated with poor prognosis, the development of targeted therapies has significantly improved outcomes, with more than half of patients now achieving remission. Nonetheless, resistance to these therapies can occur, and new treatment strategies are actively being explored. 10 , 11 In the present study, IBC,NST was the most frequent histologic subtype across all groups, which is consistent with prior literature describing it as the predominant morphology in HER2-positive tumors. 12 A review of the available literature revealed increased HER2 expression in grade 2/grade 3 tumors, apocrine carcinomas (51%) and apocrine-like carcinomas (47%). 13 , 14 Akashi et al. reported that non-Luminal HER2 (NLH- or HER2-enriched) patients frequently presented with comedonecrosis, whereas Luminal HER2 patients tended to have more central scarring. Moreover, NLH patients presented higher rates of tumor-infiltrating lymphocytes and demonstrated greater healing capabilities than Luminal B patients did. These histopathological distinctions and differences in immune responsiveness highlight the complexity and diversity of HER2-positive breast cancer subtypes. 15 Taucher et al. reported a significant correlation between HER2 overexpression and ER and PR receptor-negative status. Additionally, they reported greater HER2 overexpression in SBR grade 3 lesions and younger patients. Notably, in individuals with positive ER and PR status and with SBR grade 1/grade 2 disease, the likelihood of HER2-positivity was estimated to be approximately 6.1%. 16 A study by Omranipour reported that HER2-positivity was associated with larger tumor size and PR negativity, indicating more aggressive tumor characteristics. Similarly, in our study, HR-negative/HER2-positive tumors also presented greater proliferation (Ki67) and more high-grade histology than HR-positive/HER2-positive tumors did. Both studies highlight the link between hormone receptor negativity, particularly PR loss, and aggressive features in HER2-positive breast cancers. However, while Omranipour focused on predictors of HER2 positivity in a broader breast cancer population, our study specifically compared clinicopathological characteristics within HER2-positive patients on the basis of HR status. These findings consistently support the heterogeneity of HER2-positive breast cancers related to hormone receptor expression. 17 Cong et al. reported that the majority of breast cancers were invasive carcinomas of no special type, mostly grade 2, with a tumor size >2 cm and frequent lymph node involvement and that HER2 amplification or overexpression was associated with greater Ki67, larger tumor size, higher grade, stage, and the Nottingham Prognostic Index. In comparison, our study similarly revealed invasive carcinoma as the predominant histology, with HR-negative/HER2-positive tumors showing higher histological grade and Ki67 levels, reflecting more aggressive tumor biology. Both studies demonstrated a clear link between HER2 positivity and markers of tumor proliferation and aggressiveness. 18 Tamaki et al. reported that HER2-positive tumors were generally of higher histological grade and that specific morphological patterns, such as scirrhous carcinoma, were more frequent in ER/PR-positive tumors, whereas solid-tubular and papillotubular patterns were also observed in HER2-enriched cases. In contrast, our study did not identify any distinct histopathological pattern among HER2-positive tumors on the basis of HR status. Like Tamaki et al., we observed that HR-negative/HER2-positive tumors tended to have higher-grade histology, but the morphological features were heterogeneous and lacked a consistent pattern. 19 Hashmi et al. analyzed the demographic and pathologic features of HER2 positive and luminal HER2-positive breast carcinomas. Compared with luminal cancers, HER2-inherent breast cancers are of higher grade and have a higher Ki67 index on IHC. However, all the patients had similar TNM staging. No significant associations were noted for demographics, tumor-infiltrating lymphocytes, LVI or PNI, DCIS, or Paget’s disease. 20 Our study also did not reveal any association with LVI or PNI. Harish Sadashiv et al. studied 186 cases of breast carcinoma and reported that higher stages (T3, T4) were more common among patients with HER2-enriched and triple-negative subtypes (51.5% and 65.2%, respectively). The HER2-enriched subtype had a greater proportion of lymph-node metastases. However, in their study, LVI, which is associated with increased metastatic potential, was significantly greater in the luminal B (OR 4.27 95% CI 2, 9.2) and triple-negative breast carcinoma (TNBC) (OR 4.26 95% CI 2.11, 8.61) subtypes. 21 Puneet Somal et al analyzed 1625 cases received in a tertiary care center in North India, spread across a 6-year period. They studied clinicopathological characteristics across different molecular subtypes of breast carcinoma. They reported that Luminal B subtype was the most common subtype, accounting for approximately 42% of cases, with 17.78% of HER2-positive luminal B cases 15.69% of HER2-enriched cases, and the remaining subtypes. No significant differences were noted among the various groups with respect to age, although TNBC was present in a slightly younger age group. All cases across the molecular subtypes had a greater number of patients in the T2 stage. 22 This study also analyzed the clinicopathological features of two subgroups of Luminal B HER2-positive tumors: triple positive (TP) and ER-positive only. PR-positivity is known to affect overall survival (OS) and breast cancer-related survival in luminal B patients. The triple-positive subgroup shows better survival and OS than the PR-negative subgroups (ER+/PR-/HER2+ and ER+/PR-/HER2-) irrespective of HER2 status. 23 The absence of PR is thought to be the result of a defective ER or the overexpression of growth factor receptors, particularly EGFR. PR-negative cases are also noted to be resistant to hormonal therapy and not as responsive to NACT as HER2-enriched or triple-negative breast cancers. 19 Luminal B breast cancers with absence of PR expression were found to have a shorter OS and a greater association with distant metastasis, than were PR-positive patients, irrespective of HER2 status. 20 In the present study, the ER-positive only subgroup (group 2), was associated with worse prognostic indicators such as LVI and skin involvement, than both the TP subgroup and the HER2-enriched group, corroborating earlier findings by researchers. 24 In our study, HR-negative/HER2-positive tumors had a greater proportion of Grade 3 SBR histology than did HR-positive/HER2-positive tumors, which were mostly Grade 2. Other features, including LVI, PNI, DCIS, necrosis, and skin involvement, were not significantly different between the groups. Ki67 was slightly higher in HR-negative/HER2-positive tumors, reflecting a trend toward increased proliferation. Conclusion This study highlights the clinicopathological heterogeneity within HER2-positive breast carcinomas when stratified by hormone receptor status. The HER2-enriched subgroup was associated with significantly older age and higher histological grade, indicating a more aggressive tumor phenotype. In contrast, the triple-positive subgroup and the ER-positive only subgroup presented lower-grade tumors and a younger age profile. While a larger tumor size, higher nodal stage was seen to be associated with HER2-enriched subtype, these were marginally significant statistically. The Ki67 index and other pathological features did not differ significantly among the groups. However, the observed variations in age and tumor grade underscore the importance of molecular subtyping for prognostication and treatment planning. Integrating hormone receptor status with HER2 positivity is essential for personalized management and outcome prediction in patients with breast cancer. Limitations The p value might not be representative because of the low number of cases. Hence, larger study groups are recommended for appropriate values. Ethical considerations The study has been approved by the Kasturba Medical College and Kasturba Hospital Institutional Ethics Committee (IEC) (Ref: IEC1:191/2024) with date of approval 18/06/2024. Consent As the study is retrospective does not involve any intervention of subjects and uses lab based coded data collection; Consent waived by the ethics committee. Data availability Underlying data Figshare: Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis. DOI: https://doi.org/10.6084/m9.figshare.26868448.v2 25 The project contains the following underlying data: Copy of FISH POSITIVE.xlsx (Anonymised excel sheet of clinical, pathological, immunohistochemical and treatment aspects of cases and controls) Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Reporting guidelines Figshare: STROBE CHECKLIST_HER2POSITIVE BREAST CANCERS DOI: https://doi.org/10.6084/m9.figshare.30281356.v1 26 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Acknowledgements None. References 1. Wolff AC, Somerfield MR, Dowsett M, et al. : Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-College of American Pathologists Guideline Update. J. Clin. Oncol. 2023 Aug 1; 41 (22): 3867–3872. Epub 2023 Jun 7. PubMed Abstract | Publisher Full Text 2. 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Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 13 Nov 2025 ADD YOUR COMMENT Comment Author details Author details 1 Department of Pathology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India 2 Department of Medical Oncology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India Anuradha Calicut Kini Rao Roles: Conceptualization, Data Curation, Investigation, Methodology, Supervision, Validation, Writing – Review & Editing Kanthilatha Pai Roles: Conceptualization, Supervision, Validation, Writing – Review & Editing Swathi Prabhu Roles: Data Curation, Formal Analysis, Investigation, Methodology, Resources, Writing – Original Draft Preparation Naurin Kasem Roles: Data Curation, Investigation Karthik S Udupa Roles: Supervision, Validation Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 13 Nov 2025, 14:1246 https://doi.org/10.12688/f1000research.171847.1 Copyright © 2025 Rao ACK et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Rao ACK, Pai K, Prabhu S et al. Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis [version 1; peer review: 2 approved] . F1000Research 2025, 14 :1246 ( https://doi.org/10.12688/f1000research.171847.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 13 Nov 2025 Views 0 Cite How to cite this report: Bhat A. Reviewer Report For: Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis [version 1; peer review: 2 approved] . F1000Research 2025, 14 :1246 ( https://doi.org/10.5256/f1000research.189505.r454043 ) The direct URL for this report is: https://f1000research.com/articles/14-1246/v1#referee-response-454043 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 12 Mar 2026 Archana Bhat , Father Muller Medical College, Mangaluru, Karnataka, India Approved VIEWS 0 https://doi.org/10.5256/f1000research.189505.r454043 The authors have studied HER2-positive breast carcinomas and compared the clinicopathological features across three subgroups: Triple-positove, ER-positive only, and HER2-enriched groups. They observed statistically significant differences in the mean age (p = 0.001) and SBR score (p = 0.004) ... Continue reading READ ALL The authors have studied HER2-positive breast carcinomas and compared the clinicopathological features across three subgroups: Triple-positove, ER-positive only, and HER2-enriched groups. They observed statistically significant differences in the mean age (p = 0.001) and SBR score (p = 0.004) among the three groups. However, there was no significant difference in tumor size (p = 0.143) or the Ki67 index (p = 0.400) between the groups. Post hoc analysis revealed a significant difference in age between group 1 and group 3 (p = 0.001), with group 3 being older. Similarly, SBR scores were significantly higher in group 3 than in group 1 (p = 0.004). However, the authors mention no details on the method of Ki67 evaluation (? eyeballing method) which may impact the results as majority of the cases (83.8%) included are core-biopsies. Another concern is regarding the assessment of lymphovascular invasion, perineural invasion, DCIS, in the core biopsy specimens, which may not be entirely representative as compared to BCS samples (8.6%) and MRM (7.6%) of the total samples. The statistically significant association for SBR grade but not for Ki67 needs to be explored further to check if HER2 status has any association with glandular/ tubule formation. This study is a good attempt to highlight the clinicopathologic heterogeneity within HER2-positive breast carcinomas and subgroups. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly References 1. Tamaki M, Kamio T, Kameoka S, Kojimahara N, et al.: The relevance of the intrinsic subtype to the clinicopathological features and biomarkers in Japanese breast cancer patients. World Journal of Surgical Oncology . 2013; 11 (1). Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Renal Pathology, Cytopathology, Medical education, Pulmonary Pathology, Oncopathology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Bhat A. Reviewer Report For: Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis [version 1; peer review: 2 approved] . F1000Research 2025, 14 :1246 ( https://doi.org/10.5256/f1000research.189505.r454043 ) The direct URL for this report is: https://f1000research.com/articles/14-1246/v1#referee-response-454043 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Saldanha P. Reviewer Report For: Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis [version 1; peer review: 2 approved] . F1000Research 2025, 14 :1246 ( https://doi.org/10.5256/f1000research.189505.r454044 ) The direct URL for this report is: https://f1000research.com/articles/14-1246/v1#referee-response-454044 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 02 Feb 2026 Prema Saldanha , Department of Pathology, Yenepoya Medical College, Deralakatte, Karnataka, India Approved VIEWS 0 https://doi.org/10.5256/f1000research.189505.r454044 Identification of HER2-positive breast cancers is crucial due to the availability of targeted therapies. However, these tumours exhibit significant clinico-pathological heterogeneity, variation in hormone receptor status and differences in gene expression profiles. This study by Rao ACK, et al, ... Continue reading READ ALL Identification of HER2-positive breast cancers is crucial due to the availability of targeted therapies. However, these tumours exhibit significant clinico-pathological heterogeneity, variation in hormone receptor status and differences in gene expression profiles. This study by Rao ACK, et al, has identified the clinical and histopathological characteristics in the three subgroups based on the hormone receptor status. This knowledge is important for prognostication as well as for guiding the selection of treatment modalities in individual patients. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes References 1. Rao A, Pai K, Prabhu S, Kasem N, et al.: Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis. F1000Research . 2025; 14 . Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Histopathology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Saldanha P. Reviewer Report For: Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis [version 1; peer review: 2 approved] . F1000Research 2025, 14 :1246 ( https://doi.org/10.5256/f1000research.189505.r454044 ) The direct URL for this report is: https://f1000research.com/articles/14-1246/v1#referee-response-454044 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 13 Nov 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 1 13 Nov 25 read read Prema Saldanha , Yenepoya Medical College, Deralakatte, India Archana Bhat , Father Muller Medical College, Mangaluru, India Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Bhat A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 12 Mar 2026 | for Version 1 Archana Bhat , Father Muller Medical College, Mangaluru, Karnataka, India 0 Views copyright © 2026 Bhat A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors have studied HER2-positive breast carcinomas and compared the clinicopathological features across three subgroups: Triple-positove, ER-positive only, and HER2-enriched groups. They observed statistically significant differences in the mean age (p = 0.001) and SBR score (p = 0.004) among the three groups. However, there was no significant difference in tumor size (p = 0.143) or the Ki67 index (p = 0.400) between the groups. Post hoc analysis revealed a significant difference in age between group 1 and group 3 (p = 0.001), with group 3 being older. Similarly, SBR scores were significantly higher in group 3 than in group 1 (p = 0.004). However, the authors mention no details on the method of Ki67 evaluation (? eyeballing method) which may impact the results as majority of the cases (83.8%) included are core-biopsies. Another concern is regarding the assessment of lymphovascular invasion, perineural invasion, DCIS, in the core biopsy specimens, which may not be entirely representative as compared to BCS samples (8.6%) and MRM (7.6%) of the total samples. The statistically significant association for SBR grade but not for Ki67 needs to be explored further to check if HER2 status has any association with glandular/ tubule formation. This study is a good attempt to highlight the clinicopathologic heterogeneity within HER2-positive breast carcinomas and subgroups. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly References 1. Tamaki M, Kamio T, Kameoka S, Kojimahara N, et al.: The relevance of the intrinsic subtype to the clinicopathological features and biomarkers in Japanese breast cancer patients. World Journal of Surgical Oncology . 2013; 11 (1). Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Renal Pathology, Cytopathology, Medical education, Pulmonary Pathology, Oncopathology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Bhat A. Peer Review Report For: Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis [version 1; peer review: 2 approved] . F1000Research 2025, 14 :1246 ( https://doi.org/10.5256/f1000research.189505.r454043) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1246/v1#referee-response-454043 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Saldanha P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 02 Feb 2026 | for Version 1 Prema Saldanha , Department of Pathology, Yenepoya Medical College, Deralakatte, Karnataka, India 0 Views copyright © 2026 Saldanha P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Identification of HER2-positive breast cancers is crucial due to the availability of targeted therapies. However, these tumours exhibit significant clinico-pathological heterogeneity, variation in hormone receptor status and differences in gene expression profiles. This study by Rao ACK, et al, has identified the clinical and histopathological characteristics in the three subgroups based on the hormone receptor status. This knowledge is important for prognostication as well as for guiding the selection of treatment modalities in individual patients. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes References 1. Rao A, Pai K, Prabhu S, Kasem N, et al.: Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis. F1000Research . 2025; 14 . Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Histopathology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Saldanha P. Peer Review Report For: Histopathological and Clinical Features of HER2-Positive Breast Cancers across Hormone Receptor Subgroups: A Cross-Sectional Analysis [version 1; peer review: 2 approved] . F1000Research 2025, 14 :1246 ( https://doi.org/10.5256/f1000research.189505.r454044) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-1246/v1#referee-response-454044 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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