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Purpose: The objective of the current research was to assess the clinicopathological characteristics and long-term prognosis of triple-negative breast cancer (TNBC) patients with human epidermal growth factor receptor 2 (HER2)-low status following breast surgery. Methods: A total of 202 TNBC patients treated at Qingdao Central Hospital from January 2010 to December 2019 were included, comprising 71 HER2-low and 131 HER2-zero patients. Propensity score matching (PSM) was applied to minimize differences between the cohorts. Results: HER2-low TNBC patients had lower histological grade, lower Ki-67 expression levels, and a higher prevalence of hypertension compared to HER2-zero TNBC patients. Before and after PSM, the HER2-low group consistently exhibited a lower recurrence rate and longer RFS compared to HER2-zero TNBC patients. HER2-low status was validated as an independent low-risk factor for RFS both pre-PSM (HR 0.354, 95% CI 0.178–0.706, p = 0.003) and post-PSM (HR 0.405, 95% CI 0.185–0.886, p = 0.024). No statistically significant differences in mortality rate and OS were observed, both before and after PSM. Conclusions: HER2-low and HER2-zero TNBC patients show significant clinicopathological differences. Compared to HER2-zero, HER2-low status is linked to better long-term prognosis and serves as an independent low-risk factor for RFS in TNBC patients. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions To evaluate the evolution when breast cancer (BC) is classified as three clinical profiles and five clinical profiles by incorporating human epidermal growth factor 2 (HER2)‐low to the biomarkers’ profile.BC with distant metastasis that has document hormonal receptors (HR) (positive, negative) and HER2 (positive, low, zero) results were included (n = 161). Cases were categorised into three clinical profiles (HR‐positive/HER2‐negative, HER2‐positive and TNBC) and five (HR‐positive/HER2‐zero, HR‐positive/HER2‐low, HR‐negative/HER2‐zero, HR‐negative/HER2‐low, HR‐positive or negative/HER2‐positive). Evolution occurred in 22.4% cases when three clinical profiles were analysed and 36.6% considering five clinical profiles. There were no statistically significant differences among the three clinical profiles in overall survival (OS). When five clinical profiles were analysed, HR‐negative/HER2‐zero had the worst OS with HzR = 6.82 and 95% confidence interval (CI) =1.19, 39.23, P = 0.031. In the multivariable analysis, ER‐positive was associated with HER2 discordance less than oestrogen receptor (ER)‐negative with odds ratio (OR) = 0.354 and 95% CI = 0.14–0.88, P = 0.025. In the multivariable analysis, patients with Eastern Cooperative Oncology Group 2+ had worse OS with hazard ratio (HzR) = 5.54 and 95% CI = 2.4–12.79, P < 0.0001. HR concordant had better OS with HzR = 0.34 and 95% CI = 0.2–0.63, P = 0.0004. HER2 conversion from low to zero had worse OS than HER2 concordance with HzR 2.66 and 95% CI = 1.21–5.83, P = 0.015.Five‐profile classification provides a more accurate idea about the rate of potential change in treating BC in the metastatic setting. [ABSTRACT FROM AUTHOR]

Objective: The aim of this paper was to assess the differences in clinicopathological characteristics, efficacy and prognosis of neoadjuvant chemotherapy (NAC) in human epidermal growth factor receptor2(HER2)-zero and HER2-low hormone receptor (HR)-negative breast cancer (BC) patients, and the impact of HER2-evolution on prognosis before and after NAC. Methods: 319 triple negative breast cancer (TNBC) patients who completed NAC and surgery from August 2014 to August 2018 at Tianjin Medical University Cancer Institute and Hospital were included. Clinicopathological features, efficacy of NAC and assessment of prognosis were retrospectively analysed. The evolution of HER2-zero to HER2-low after NAC is defined as HER2-gain, the evolution of HER2-low to HER2-zero after NAC is defined as HER2-loss, and HER2 unchanged after NAC is defined as HER2-stable. Results: In HR-negative BC, the pathological complete response (pCR) rate was significantly higher in HER2-zero compared with HER2-low patients, and the difference was statistically significant (38.9% vs 23.2%, p = 0.004), but there was no significant difference in the prognosis between the two groups. The overall rate of HER2-evolution after NAC was 19.7%, and there was a significant correlation between HER2-loss and histological grading, whereas HER2-gain was significantly associated with Ki-67 expression. In terms of prognosis, HER2-gain was better compared to the other two groups. Conclusion: In this study, we found that HER2-low HR-negative BC showed different clinicopathological features and response to NAC compared with HER2-zero, as well as HER2-evolution before and after NAC had a significant impact on prognosis. [ABSTRACT FROM AUTHOR]

Objective: With the approval of trastuzumab deruxtecan for the treatment of unresectable/metastatic HER2-low breast cancer, human epidermal growth factor receptor 2 (HER2)-low has emerged as a clinically actionable biomarker. There is an urgent need for a deeper understanding of HER2-low breast cancer patients. Therefore, this study was conducted to explore the clinicopathological characteristics, the evolution of HER2-low status, and its impact on the prognosis of hormone receptor (HoR)-negative/HER2-low metastatic breast cancer (MBC) patients. Methods: This pooled analysis included 350 metastatic triple-negative breast cancer (mTNBC) patients who received first-line platinum-based chemotherapy at Fudan University Shanghai Cancer Center from November 2007 to July 2022. Patients were categorized into HER2-0 and HER2-low groups based on their HER2 status. Baseline clinicopathological characteristics, evolution of HER2 status between primary and metastatic lesions, and treatment efficacy were compared between the two groups. Results: Among the 350 mTNBC patients, 34.9% (122/350) were HER2-low and 65.1% (228/350) were HER2-0. Significant differences were observed between HER2-low and HER2-0 patients in terms of age and menopausal status. HER2-low patients were older (54 vs. 49 years, p =0.002) and had a lower proportion of premenopausal patients (32.8% vs. 52.6%, p <0.001) compared to HER2-0 patients. No significant differences were observed in progression-free survival (PFS) and overall survival (OS) between HER2-low and HER2-0 patients receiving first-line platinum-based chemotherapy (mPFS: 7.43 vs. 8.30 months, p =0.389, HR=1.11, 95% CI 0.88-1.40; mOS: 25.37 vs. 26.63 months, p =0.907, HR=1.02, 95% CI 0.76-1.37). Additionally, 32.3% (41/127) of patients exhibited discordant HER2 status between primary and metastatic lesions, primarily evolving from HER2-0 to HER2-low. Notably, patients with discordant HER2 status had significantly longer PFS compared to those with concordant status (mPFS: 11.07 vs. 7.53 months, p =0.020). The Cox multivariate analysis showed that HER2 status consistency (p =0.026) was an independent predictor of PFS. Conclusion: In mTNBC patients, those with HER2-low status had similar responses to platinum-based chemotherapy as HER2-0 patients. There was significant discordance in HER2 status between primary and metastatic lesions. Patients with discordant HER2 status had better responses to platinum-based chemotherapy. Therefore, for patients with HER2-0 primary lesions, re-evaluation of HER2 status in metastatic lesions through biopsy may offer new treatment opportunities. [ABSTRACT FROM AUTHOR]

Aims: Recently, human epidermal growth factor 2 (HER2)‐low (i.e. HER2 score 1+ or 2+ without amplification) breast cancer patients became eligible for trastuzumab–deruxtecan treatment. To improve assay standardisation and detection of HER2‐low in a quantitative manner, we conducted an external quality assessment‐like study in the Netherlands. Dynamic range cell lines and immunohistochemistry (IHC) calibrators were used to quantify HER2 expression and to assess interlaboratory variability. Methods and results: Three blank slides with a dynamic range cell line and an IHC calibrator were stained with routine HER2 assays by 35 laboratories. Four different antibody clones were used: 19 (54.3%) 4B5, six (17.1%) A0485, five (14.3%) DG44 (HercepTest) and five (14.3%) SP3. Laboratories used two different detection kits for 4B5 assays: 14 (73.7%) ultraView and five (26.3%) OptiView. Variability of HER2 expression in cell lines, measured with artificial intelligence software, was median (min–max) = negative core 0.5% (0.0–57.0), 1+ core 4.3% (1.6–71.3), 2+ core 42.8% (30.4–92.6) and 3+ core 96.2% (91.8–98.8). The calibrators DG44 and 4B5 OptiView had the highest analytical sensitivity, closely followed by 4B5 ultraView. SP3 was the least sensitive. Calibrators of A0485 assays were not analysable due to background staining. Conclusions: As assays were validated for detecting HER2‐amplified tumours, not all assays and antibodies proved suitable for HER2‐low detection. Some tests showed distinct expression in the negative cell line. Dynamic range cell line controls and quantitative analysis using calibrators demonstrated more interlaboratory variability than commonly appreciated. Revalidation of HER2 tests by laboratories is needed to ensure clinical applicable HER2‐low assays. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the prevalence and characteristics of different HER2 categories among patients with advanced breast cancer (aBC) and describe treatment patterns and outcomes of those with HER2-low disease. Methods: A retrospective cohort study was conducted via chart review at the Huntsman Cancer Institute, including patients diagnosed with aBC (stages IIIB, IIIC and IV) between 2010 and 2019. All patients with IHC1+ were considered HER2-low unless FISH was positive. Patients with IHC2+ were only classified as HER2-low if a negative FISH was documented. The prevalence and characteristics of each HER2 category were reported. Treatment patterns and survival outcomes of HER2-low patients who received first line treatment in 2017 or later were presented. Results: A total of 240 of 414 patients (58%) with aBC were HER2-low, with the majority of patients (83%) classified as hormone receptor (HR)-positive. In first line, most HR-positive patients received endocrine therapy with chemotherapy for stage IIIB/IIIC (47%) and with CDK4/6 inhibitors for stage IV breast cancer (50%) Most HR-negative patients received chemotherapy alone (92% for stage IIIB/IIIC, 60% for stage IV). In second line, chemotherapy alone was the most common modality (21.4% for HR-positive; 45.5% for HR-negative). Median overall survival was 37.7 months while median progression-free survival from first line was 18.0 months, decreasing to 8.0 months in second line. Conclusion: A substantial proportion of patients previously classified as HER2-negative have low but detectable HER2 expression and may benefit from novel HER2-directed agents, which have demonstrated clinical benefit in this population post-chemotherapy. [ABSTRACT FROM AUTHOR]

We investigated frequencies of HER2-low breast cancer (BC) (immunohistochemistry [IHC] 1+ or 2+ without gene amplification) before and after IHC conditions were modified in order to understand the impact of IHC staining conditions on frequencies of HER2-low BC. Primary BC cases diagnosed at the Yeungnam University Hospital (YUH, n = 728) or Keimyung University Dongsan Hospital (KUDH, n = 290) in 2022 were reviewed, and data on HER2 status and IHC conditions were collected (cohort 1). Both institutions used the 4B5 antibody for HER2 IHC but had different staining protocols. After modifications of the IHC conditions at both institutions, primary BC cases (YUH, n = 324 and KUDH, n = 135) diagnosed from April to July 2023 (cohort 2) were reviewed to assess any changes in the frequency of HER2 status. In cohort 1, of the 728 cases diagnosed at YUH, 556 (76.4%) were HER2-zero, 76 (10.4%) were HER2-low, and 96 (13.2%) were HER2-positive, and of the 290 cases diagnosed at KUDH, 135 (46.6%) were HER2-zero, 82 (28.3%) were HER2-low, and 73 (25.2%) were HER2-positive. Modifications in HER2 IHC staining conditions dramatically increased the frequencies of HER2-low BC in cohort 2 (YUH 38.9% and KUDH 49.6%), but they did not result in significant changes in the HER2-positive rates (YUH 15.4% and KUDH 25.2%) compared to cohort 1. In conclusion, minor modifications in HER2 IHC staining conditions significantly affected the frequency of HER2-low BC but had little impact on the HER2-positivity rate. Each pathology laboratory should verify IHC conditions using control slides (including 1+) to enable the accurate identification of HER2-low BC. [ABSTRACT FROM AUTHOR]

Background: HER2-positivity is an essential marker for therapeutic decisions, while HER2 expression is heterogenous. In recent years, there has been increasing recognition of a subgroup of breast cancer patients who have low levels of HER2 expression, also known as HER2-low because trastuzumab deruxtecan offers clinical benefit for patients with HER2-low metastatic breast cancer. Despite the growing interest in HER2-low breast cancer, there is limited research on how multigene assays can help differentiate between HER2-low and HER2-negative breast cancer. Among HR + HER2- breast cancer, we compared genomic characteristics between HER2-low and HER2-zero using the 21-gene assay. Methods: A retrospective review of clinical records was performed in 2,295 patients who underwent Oncotype DX® test in two hospitals between 2013 and 2020. Patients were classified into two groups as the HER2-zero and HER2-low based on HER2 immunohistochemistry. In cases with HER2 2+, no amplification of HER2 gene was confirmed by silver in situ hybridization. High genomic risk was defined as cases with 21-gene recurrence score (RS) > 25. Multivariable binary logistic-regression analysis was performed. Results: Of these, 944 (41.1%) patients were assigned to the HER2-zero group, while 1351 (58.9%) patients were assigned to the HER2-low group. The average Recurrence Score (RS) was found to be 17.802 in the HER2-zero breast cancer group and 18.503 in the HER2-low group, respectively (p-value < 0.005). When comparing the proportion of high RS between the two groups, the HER2-zero group had a high RS rate of 12.4% (117 out of 944), while the HER2-low group had a high RS rate of 17.0% (230 out of 1351) (p = 0.002). The HER2 score identified by qRT-PCR was 8.912 in the HER2-zero group and 9.337 in the HER2-low group (p < 0.005). In multivariable analysis, HER2-low status was found to be an independent factor for high RS, with an odds ratio of 1.517 (1.172–1.964), independent of ER, PR, and Ki67. Within the subgroup of patients with invasive ductal carcinoma, the high RS rates were 19% in the HER2-low group and 14% in the HER2-zero group. However, when considering all patients, there were no significant differences observed in recurrence-free survival and overall survival between the HER2-low and HER2-zero groups. Conclusion: Within HR + HER2- breast cancer, HER2-low tumors are associated with high RS, especially for histologically invasive ductal carcinoma. A prognostic influence of HER2-low expression among HR + HER2- breast cancer remains as an area that requires further study. [ABSTRACT FROM AUTHOR]

Background: Until recently, targeted therapies have failed to benefit patients with human epidermal growth factor receptor 2 (HER2)-low-expressing breast cancer (BC). Nevertheless, antibody–drug conjugates (ADCs) have reshaped their prognosis. Objectives: We performed a systematic review and meta-analysis to assess the effectiveness of ADCs in patients with HER2-low advanced/metastatic (a/m) BC. Design: This study is a systematic review and meta-analysis. Data sources: We searched PubMed, Embase, and Cochrane databases as well as the American Society of Clinical Oncology, European Society for Medical Oncology, and San Antonio Breast Cancer Symposium conference proceedings. Methods: Studies evaluating ADCs (trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), MRG002, and RC48-ADC) in patients with HER2-low a/mBC were included. We used R software (v.4.2.2) and random effects models for all analyses. Heterogeneity was assessed using the I 2 test. Results: Overall, 14 studies were included (five real-world studies and nine clinical trials (CTs)), with 2883 HER2-low a/mBC patients: 808 received treatment of physician's choice (TPC), and 2075 ADCs. Most were treated with T-DXd (n = 1691), followed by SG (n = 310), MRG002 (n = 56), and RC48-ADC (n = 18). Patients treated with T-DXd achieved a significantly higher objective response rate (ORR), disease control rate (DCR), and clinical benefit rate (CBR) than those receiving other ADCs. In the pooled analysis of four randomized CTs, ADCs statistically prolonged progression-free survival (n = 1828, hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.36–0.68, I 2 = 82%, p < 0.001) and overall survival (n = 1546, HR 0.70, 95% CI 0.57–0.86, I 2 = 43%, p < 0.001) compared with TPC. Patients on ADCs also achieved a greater antitumor response than TPC, including better ORR (odds ratio (OR), 3.7, 95% CI 2.5–5.6, I 2 = 59%, p < 0.001), DCR (OR, 2.7, 95% CI 2.1–3.5, I 2 = 0%, p < 0.001), and CBR (OR, 3.6, 95% CI 2.6–5.2, I 2 = 56%, p < 0.01). Conclusion: Our systematic review and meta-analysis confirms the efficacy of ADCs in HER2-low a/m BC patients over TPC. Future studies should focus on bringing ADCs into earlier lines of therapy in this population. Trial registration: This study was registered in PROSPERO (CRD42024452962). [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer among women and a leading cause of cancer-related deaths. PIK3CA gene mutations, which are often present in advanced HR+ breast cancer, can be targeted by alpelisib. However, data on PIK3CA mutations in Chile are limited. Here, we aim to assess the mutational status of PIK3CA in metastatic breast cancer tissues from Chilean patients and describe their clinicopathological characteristics and survival outcomes. We analyzed 102 formalin-fixed, paraffin-embedded metastatic breast cancer samples from 96 patients diagnosed at three Chilean hospitals between 2007 and 2023. PIK3CA mutations were identified using targeted sequencing, and clinicopathological data were collected. We evaluated associations between mutational status, clinicopathological features, and survival. The median age at diagnosis was 56 years. The most common metastatic sites were liver (29.4%), bone (17.6%), and lung/pleura (16.7%). Most patients were HR+ HER2− (83.3%), with 57.3% showing HER2-low status. PIK3CA mutations were present in 40.6% of patients, mainly in exons 7, 9, and 20. No significant associations were found between PIK3CA mutations and clinicopathological characteristics or survival. Our study reveals a high frequency of PIK3CA mutations in HR+ metastatic breast cancer, consistent with global data. The majority of mutations are targetable with alpelisib. The proportion of HER2-low status patients suggests potential benefits from novel HER2-targeted therapies. These findings highlight the need for routine molecular diagnostics in Chile to improve personalized treatment and address economic and access challenges. [ABSTRACT FROM AUTHOR]

Background: HER2-low populations constitute a heterogeneous group, and the cytotoxic anticancer agent efficacy based on HER2 status remains unclear. This study evaluated the clinicopathological features and outcomes of patients with advanced breast cancer showing HER2-low expression treated with eribulin or capecitabine, two treatment options after anthracycline and taxane treatment. Methods: We retrospectively evaluated patients who were treated with eribulin or capecitabine between 2011 and 2015. HER2 status was evaluated according to the ASCO/CAP guidelines. Results: No significant difference was observed in overall survival (OS; eribulin: hazard ratio [HR], 0.66; 95% CI 0.40–1.10; capecitabine: HR, 0.76; 95% CI 0.45–1.30) or progression-free survival (PFS; eribulin: HR, 1.13; 95% CI 0.72–1.78; capecitabine: HR, 0.90; 95% CI 0.56–1.44) between patients receiving eribulin (HER2-null: 35, HER2-low: 44) and those receiving capecitabine (HER2-null: 41, HER2-low: 33). Subgroup analysis revealed no significant differences in OS between the two groups in the hormone-positive and -negative populations for eribulin and capecitabine. HER2-null and HER2-low patients showed objective response rates (ORRs) of 22.5% and 9.1% (p = 0.09) overall, and 32.0% and 10.5% (p = 0.03), respectively, in hormone-positive cases among eribulin-treated patients. No response was observed in hormone-negative patients. Capecitabine treatment in HER2-null and HER2-low patients had overall ORRs of 26.8% and 15.2% (p = 0.23), respectively, with 27.3% and 16.1% (p = 0.28) for hormone-positive cases; and 25.0% and 0% (p = 1.0), respectively, for hormone-negative cases. Conclusions: Eribulin and capecitabine sensitivity may vary based on HER2 expression in patients with HER2-low and HER2-null breast cancer. Prognosis was similar between the HER2-low and the HER2-null groups. [ABSTRACT FROM AUTHOR]

Introduction: Until recently, the available human receptor epidermal growth factor 2 (HER2) targeted agents were ineffective for treating patients with HER2-low expressing breast cancer (defined as immunohistochemical expression of 1+ or 2+ without amplification). The development of novel and potent HER2-directed antibody-drug conjugates, affective at treating HER2-low expressing breast cancers, have changed the way we think about HER2-low expression and expanded the treatment options for many patients with advanced disease. Areas covered: In this review, we summarize the current management of HER2-low breast cancer and commonly encountered challenges such as treatment sequencing and toxicity management. Expert opinion: trastuzumab deruxtecan (T-DXd) is a treatment option for patients with advanced, HER2-low breast cancer, irrespective of the hormone receptor status. The current optimal place in treatment algorithms is after the first line of chemotherapy, both in HR-positive and triple-negative breast cancer; however, other agents are available in this setting and risks and benefits for each should be considered in shared decision making. Up to 10–15% of patients receiving T-DXd develop interstitial lung disease. Patient and clinician education are key to safely implement T-DXd in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Human epidermal growth factor receptor 2 (HER2)-low breast cancer, consisted of carcinomas with HER2 protein 1+ or 2+ without gene amplification, has been considered a biologically heterogeneous disease. Limited research separately investigated the prognostic significance of HER2 2+ without gene amplification, and no evidence can be identified in older patients. In this dedicated cohort of older patients with HER2-negative and high-risk breast cancer, we analyzed the real-world prognosis after standard adjuvant chemotherapy, and investigated the associations of survival with HER2 2+ without gene amplification. Patients and Methods: From January 2016 to December 2021, older patients (≥ 65 years) with breast cancer were reviewed, and HER2-negative/high-risk disease receiving standard adjuvant chemotherapy was included. HER2-negativity was defined as immunohistochemistry (IHC) score 0, 1+ or 2+ without gene amplification by fluorescent in situ hybridization (FISH). Cox proportional hazards regression analyses were performed to assess the associations of HER2 2+/FISH-negativity with disease-free survival (DFS), which was estimated by the Kaplan–Meier method and compared by the Log rank test. Results: This cohort consisted of 121 consecutive older patients. With a median follow-up of 46 months, 12 patients had a DFS event. By univariate and multivariate analyses, HER2 2+/FISH-negativity was the only independent predictor for worse DFS (hazard ratio 5.56; P=0.046). Patients with HER2 2+/FISH-negativity had significantly poorer DFS compared with those with HER2 0 or 1+ (Log rank test, P=0.029). In both hormone receptor (HR)-positive (Log rank test, P=0.052) and HR-negative (Log rank test, P=0.125) subgroups, HER2 2+/FISH-negativity showed a marginally significant adverse influence on DFS. Conclusion: In older patients with HER2-negative/high-risk breast cancer undergoing standard adjuvant chemotherapy, our findings suggest that HER2 2+/FISH-negativity has an independent negative impact on prognosis. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to develop an AI algorithm for automated HER2 scoring in urothelial bladder cancer (UBCa) and assess the interobserver agreement using both manual and AI-assisted methods based on breast cancer criteria. Methods and Results: We utilized 330 slides from two institutions for initial AI development and selected 200 slides for the ring study, involving six pathologists (3 senior, 3 junior). Our AI algorithm achieved high accuracy in two independent tests, with accuracies of 0.94 and 0.92. In the ring study, the AI-assisted method improved both accuracy (0.66 vs 0.94) and consistency (kappa=0.48; 95 % CI, 0.443–0.526 vs kappa=0.87; 95 % CI, 0.852–0.885) compared to manual scoring, especially in HER2-low cases (F1-scores: 0.63 vs 0.92). Additionally, in 62.3 % of heterogeneous HER2-positive cases, the interpretation accuracy significantly improved (0.49 vs 0.93). Pathologists, particularly junior ones, experienced enhanced accuracy and consistency with AI assistance. Conclusions: This is the first study to provide a quantification algorithm for HER2 scoring in UBCa to assist pathologists in diagnosis. The ring study demonstrated that HER2 scoring based on breast cancer criteria can be effectively applied to UBCa. Furthermore, AI assistance significantly improves the accuracy and consistency of interpretations among pathologists with varying levels of experience, even in heterogeneous cases.

Abstract Background HER2-positivity is an essential marker for therapeutic decisions, while HER2 expression is heterogenous. In recent years, there has been increasing recognition of a subgroup of breast cancer patients who have low levels of HER2 expression, also known as HER2-low because trastuzumab deruxtecan offers clinical benefit for patients with HER2-low metastatic breast cancer. Despite the growing interest in HER2-low breast cancer, there is limited research on how multigene assays can help differentiate between HER2-low and HER2-negative breast cancer. Among HR + HER2- breast cancer, we compared genomic characteristics between HER2-low and HER2-zero using the 21-gene assay. Methods A retrospective review of clinical records was performed in 2,295 patients who underwent Oncotype DX® test in two hospitals between 2013 and 2020. Patients were classified into two groups as the HER2-zero and HER2-low based on HER2 immunohistochemistry. In cases with HER2 2+, no amplification of HER2 gene was confirmed by silver in situ hybridization. High genomic risk was defined as cases with 21-gene recurrence score (RS) > 25. Multivariable binary logistic-regression analysis was performed. Results Of these, 944 (41.1%) patients were assigned to the HER2-zero group, while 1351 (58.9%) patients were assigned to the HER2-low group. The average Recurrence Score (RS) was found to be 17.802 in the HER2-zero breast cancer group and 18.503 in the HER2-low group, respectively (p-value

Abstract Background Bidirectional crosstalk between HER2 and estrogen receptor (ER) pathways may influence outcomes and the efficacy of endocrine therapy (ET). Low HER2 expression levels (HER2-low) have emerged as a predictive biomarker in patients with breast cancer (BC). Methods PALLAS is an open, international, phase 3 study evaluating the addition of palbociclib for 2 years to adjuvant ET in patients with stage II-III ER-positive/HER2-negative BC. To assess the impact of HER2 expression on patient outcomes in the phase III PALLAS trial, we analyzed (1) the association between rate of HER2-low with demographic and clinicopathological parameters, (2) the prognostic value of HER2-low status on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) HER2 expression’s value as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH). All pathologic evaluation was performed locally. Prognostic and predictive power of HER2 were assessed with Cox models. Results From the original PALLAS intention-to-treat population (N = 5753), 5304 patients (92.2%) were included in this analysis. Among these, 2254 patients (42.5%) were classified as having HER2 IHC 0 (HER2-0), and 3050 (57.5%) as having HER2-low disease (1838 with IHC 1 + and 1212 with IHC 2 +). Median follow-up was 59.8 months. HER2-low prevalence varied significantly across 21 participating countries (range 16.7% to 75.6%; p

Abstract Background This study aims to analyze potential differences in clinicopathology, efficacy of neoadjuvant therapy (NAT), and clinical outcome among HER2-null, HER2-ultralow and HER2-low breast cancers. Methods Consecutive cases of HER2-negative breast cancer that received NAT were included. They were classified as HER2-null (no staining), HER2-ultralow (incomplete faint staining in ≤ 10% of tumour cells) and HER2-low (HER2-1 + or HER2-2+, in situ hybridisation negative). Subgroup analysis was performed based on the HER2 expression level. Results Out of 302 patients, 215 (71.19%) were HER2-low, 59 (19.54%) were HER2-ultralow, and 28 (9.27%) were HER2-null. In comparison to the HER2-ultralow group, the HER2-low group exhibited higher expression frequencies of ER (p

Abstract Background The novel anti-HER2 antibody drug conjugates (ADCs) can effectively improve the long-term survival of patients with HER2-low expression breast cancer. However, pathological responses to neoadjuvant therapy (NAT) within HER2-low expression breast cancer, the relationship between pathological response and prognosis and the transformation of HER2 status are all now poorly understood. Methods The patients with HER2-0 and HER2-low expression breast cancer receiving NAT at Harbin Medical University Cancer Hospital between Jan. 2014 and Nov. 2018 were retrospectively explored. HER2 low expression refers to the IHC 1 + or 2 + and FISH negative. The Kappa test was utilized for analyzing the consistency rate of HER2 expression. To evaluate disease-free survival (DFS) and overall survival (OS), this research employed both the Kaplan-Meier analysis and the Cox regression. Results In this study, 178 patients with HER2-0 and 344 patients with HER2-low expression breast cancer were included. In comparison with the HER2-0 group, it is shown that patients in the HER2-low group have more possibility to be younger compared to those 50 years old (P

Background: Human epidermal growth factor receptor 2 (HER2)-low has emerged as a potential new entity in breast cancer (BC). Data on this subset are limited, and prognostic results are controversial, evidencing the need of further data in a BC real-world cohort. Methods: Patients with HER2-negative stage I–III BC diagnosed between 2006 and 2016 were retrospectively reviewed in a single cohort from the Catalan Institute of Oncology Badalona. Demographics and clinicopathological characteristics were examined via medical charts/electronic health records. We aim to describe and compare HER2-0/HER2-low populations through Chi-square or Fisher test, and explore its prognostic impact using Kaplan–Meier curves and Cox regression models. Results: From a cohort of 1755 BC patients, 1401 invasive HER2-negative, stage I–III cases were evaluated. 87% were hormone receptor (HR)-positive versus 13% triple negative (TNBC). Overall, 43% were HER2-0 and 57% HER2-low (61% immunohistochemistry (IHC) 1+ and 39% IHC 2+). Comparing HER2-low versus HER2-0, HER2-low showed higher proportion of estrogen receptor (ER)-positive (91.6% vs 79.9%, p ⩽ 0.001) and progesterone receptor (PR)-positive (79.8% vs 68.9%, p ⩽ 0.001) cases. HER2-0 exhibited higher proportion of TNBC (20.1% vs 8.4%, p = 0.001), grade III tumors (28.8% vs 23.5%, p = 0.039), and higher Ki67 median value (26.47% vs 23.88%, p = 0.041). HER2-low was associated with longer time to distant recurrence (TTDR) compared to HER2-0 (67.8 vs 54.1 months; p = 0.015) and better BC-related survival (19.2 vs 16.3 years; p = 0.033). In the multivariable analysis, HER2-low was not an independent prognostic factor for TTDR and BC-related survival. ER expression showed a strong association with longer TTDR (Hazard Ratio: 0.425, p ⩽ 0.001) and improved BC-related survival (Hazard Ratio: 0.380, p ⩽ 0.001). PR expression was also associated with longer TTDR (Hazard Ratio: 0.496, p ⩽ 0.001), and improved BC-related survival (Hazard Ratio: 0.488, p ⩽ 0.001). Histological grade III was significantly associated with shorter TTDR (Hazard Ratio: 1.737, p = 0.002). Positive nodal status was the strongest factor correlated with worse BC-related survival (Hazard Ratio: 2.747, p ⩽ 0.001). Conclusion: HER2-low was significantly associated with HR-positive disease, whereas HER2-0 group had higher incidence of TNBC, histological grade III and higher Ki67%. Although HER2-low group was associated with longer TTDR and improved BC-related survival, these findings could be explained by the greater proportion of favorable prognostic features in this subgroup compared to HER2-0. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Breast cancer with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 1+ or 2+ with negative in‐situ hybridisation (ISH) (HER2‐low) can now be targeted by HER2 antibody drug conjugates. We set out to compare HER2 status between matched primary invasive breast carcinoma (IBC) and distant metastases (DM) with clinical–pathological correlation, with specific interest in HER2‐low.Biomarker studies and clinical–pathological features of primary IBC with matched DM diagnosed between 2021 and 2022 were retrospectively analysed. HER2 status was assessed per 2023 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for IHC (4B5) and ISH (IQFISH pharmDX). Bilateral breast primaries were excluded. HER2 IHC 0 to 1+ were reassessed.One hundred and forty‐seven cases of primary IBC with matched DM were identified. Biomarkers were performed on core biopsy (n = 74) and resection (n = 73). One hundred and twenty‐six (86%) were initially classified as ‘HER2‐negative’; of these, 67 (46%) were reclassified as HER2‐low. Patients with HER2‐positive primaries were younger (P = 0.01) and had an increased incidence of micropapillary carcinoma (P = 0.02). HER2‐low primaries also had an increased incidence of micropapillary carcinoma (P = 0.02) and oestrogen receptor (ER) positivity (P = 0.02) compared to HER2 0. One hundred and sixty‐nine matched DM cases excluding bone metastasis were identified (range = one to seven metastases per IBC). The most common sites of metastases were liver (50 of 169, 30%), lung (36 of 169; 21%), distant lymph node (26 of 169, 15%); 138 DM cases (82%) were previously classified as ‘HER2‐negative’, and 62 (37%) were reclassified as HER2‐low. Like HER2‐low primaries, HER2‐low metastases were frequently ER‐positive (52 of 62; 84%) (P = 0.02). Brain metastases were more frequently HER2‐positive (five of 32; 16%) (P = 0.04). Comparing HER2 status in matched primaries and DM, HER2 status was discordant in 62 cases (37%). Most changes occurred from HER2‐low to HER2 0 (33 of 169, 20%), HER2 0 to HER2‐low (17 of 169, 10%) and HER2‐low to positive (10 of 169, 6%). All HER2‐low to HER2 0 changes were HER2 1+ to 0. In 30 patients with multiple DM sites (47 cases), HER2 status among different DM samples was discordant in 16 patients (53%), mainly from HER2‐low to HER2 0 (16 of 47, 34%).A significant proportion of previous ‘HER2‐negative’ primaries and DM cases were reclassified as HER2‐low. Discordant HER2 status between IBC primary and metastasis and between different DM sites demonstrated tumour heterogeneity and highlights the need for HER2 retesting in distant metastasis. [ABSTRACT FROM AUTHOR]

Background: Bidirectional crosstalk between HER2 and estrogen receptor (ER) pathways may influence outcomes and the efficacy of endocrine therapy (ET). Low HER2 expression levels (HER2-low) have emerged as a predictive biomarker in patients with breast cancer (BC). Methods: PALLAS is an open, international, phase 3 study evaluating the addition of palbociclib for 2 years to adjuvant ET in patients with stage II-III ER-positive/HER2-negative BC. To assess the impact of HER2 expression on patient outcomes in the phase III PALLAS trial, we analyzed (1) the association between rate of HER2-low with demographic and clinicopathological parameters, (2) the prognostic value of HER2-low status on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) HER2 expression's value as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH). All pathologic evaluation was performed locally. Prognostic and predictive power of HER2 were assessed with Cox models. Results: From the original PALLAS intention-to-treat population (N = 5753), 5304 patients (92.2%) were included in this analysis. Among these, 2254 patients (42.5%) were classified as having HER2 IHC 0 (HER2-0), and 3050 (57.5%) as having HER2-low disease (1838 with IHC 1 + and 1212 with IHC 2 +). Median follow-up was 59.8 months. HER2-low prevalence varied significantly across 21 participating countries (range 16.7% to 75.6%; p < 0.001) and was more frequent in patients enrolled in North America (63.1%) than in Europe (53.4%) or other regions (53.4%) (p < 0.001). HER2 status was not significantly associated with iDFS in a multivariable Cox model (hazard ratio 0.93, 95% confidence interval 0.81 – 1.06). No significant interaction was observed between treatment arm and HER2 status for iDFS (p = 0.43). Similar results were obtained for DRFS and OS. Conclusions: In this large, prospective, global patient cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib between HER2-0 and HER2-low tumors. Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes. [ABSTRACT FROM AUTHOR]

This article presents a study on the development and validation of an ultrasound-based radiomics nomogram for predicting HER2-low expression breast cancer. The study included 222 patients with breast cancer, and machine learning methods were used to extract radiomics features from ultrasound images. The features were then used to construct a prediction model, which was validated using a training cohort and a test cohort. The nomogram, incorporating radiomics features and clinical risk factors, showed high prediction value for HER2-low expression breast cancer. This non-invasive approach could be useful for early detection and clinical therapy planning. [Extracted from the article]

Purpose: Notable effectiveness of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 (HER2)–low advanced breast cancer (BC) has focused pathologists' attention. We studied the incidence and clinicopathologic characteristics of HER2-low BC, and the effects of immunohistochemistry (IHC) associated factors on HER2 IHC results. Materials and Methods: The Breast Pathology Study Group of the Korean Society of Pathologists conducted a nationwide study using real-world data on HER2 status generated between January 2022 and December 2022. Information on HER2 IHC protocols at each participating institution was also collected. Results: Total 11,416 patients from 25 institutions included in this study. Of these patients, 40.7% (range, 6.0% to 76.3%) were classified as HER2-zero, 41.7% (range, 10.5% to 69.1%) as HER2-low, and 17.5% (range, 6.7% to 34.0%) as HER2-positive. HER2-low tumors were associated with positive estrogen receptor and progesterone receptor statuses (p < 0.001 and p < 0.001, respectively). Antigen retrieval times (≥ 36 minutes vs. < 36 minutes) and antibody incubation times (≥ 12 minutes vs. < 12 minutes) affected on the frequency of HER2 IHC 1+ BC at institutions using the PATHWAY HER2 (4B5) IHC assay and BenchMark XT or Ultra staining instruments. Furthermore, discordant results between core needle biopsy and subsequent resection specimen HER2 statuses were observed in 24.1% (787/3,259) of the patients. Conclusion: The overall incidence of HER2-low BC in South Korea concurs with those reported in previously published studies. Significant inter-institutional differences in HER2 IHC protocols were observed, and it may have impact on HER2-low status. Thus, we recommend standardizing HER2 IHC conditions to ensure precise patient selection for targeted therapy. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) is one of the most common gynecologic malignancies with increasing morbidity. The prognosis for patients diagnosed with early-stage EC remains favorable; however, for patients with recurrent or metastatic EC, the prognosis is poor and treatment options, until recently, are limited. Antibody drug conjugates (ADCs) represent innovative strategies in cancer treatment; however, there are less investigations regarding their efficacy in EC. This report describes an EC case with low human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) expression score (IHC 2+) that experienced recurrent metastasis in the abdominal and peritoneal following post-surgical chemotherapy and radiotherapy. Subsequently, the commencement of HER2- targeted ADC, disitamab vedotin (RC48; 2.5 mg/kg), administered intravenously every two weeks, was initiated. The tumor lesions shrunk markedly after three cycles of treatment and disappeared by the completion of ten cycles of therapy. The patient is still in remission at present. The current findings imply the potential efficacy of HER2-targeted ADCs for patients with HER2-low metastatic EC. [ABSTRACT FROM AUTHOR]

Background: This study aims to analyze potential differences in clinicopathology, efficacy of neoadjuvant therapy (NAT), and clinical outcome among HER2-null, HER2-ultralow and HER2-low breast cancers. Methods: Consecutive cases of HER2-negative breast cancer that received NAT were included. They were classified as HER2-null (no staining), HER2-ultralow (incomplete faint staining in ≤ 10% of tumour cells) and HER2-low (HER2-1 + or HER2-2+, in situ hybridisation negative). Subgroup analysis was performed based on the HER2 expression level. Results: Out of 302 patients, 215 (71.19%) were HER2-low, 59 (19.54%) were HER2-ultralow, and 28 (9.27%) were HER2-null. In comparison to the HER2-ultralow group, the HER2-low group exhibited higher expression frequencies of ER (p < 0.001), PR (p < 0.001), and AR (p = 0.004), along with a greater prevalence of the luminal subtype (p < 0.001). The HER2-ultralow group also demonstrated a higher prevalence of lymph node metastasis compared to the HER2-null group (p = 0.026). Varied rates of pathologic complete response (pCR) were observed among the three subgroups: HER2-null, HER2-ultralow, and HER2-low, with rates of 35.71%, 22.03%, and 12.56%, respectively. Only the HER2-low subgroup exhibited a significant difference compared to HER2-null (p = 0.001). Despite variations in pCR rates, the three subgroups exhibited comparable disease-free survival (DFS) (p = 0.571). Importantly, we found HER2-low patients with better treatment response (RCB-0/I) exhibited significantly better DFS than those with significant residual disease (RCB-II/III) (P = 0.036). The overall rate of HER2 immunohistochemical score discordance was 45.24%, mostly driven by the conversion between HER2-0 and HER2-low phenotype. Notably, 32.19% of cases initially classified as HER2-0 phenotype on baseline biopsy were later reclassified as HER2-low after neoadjuvant therapy, and it is noteworthy that 22 out of these cases (78.57%) originally had an HER2-ultralow status in the pretreatment biopsy sample. Conclusions: Our results demonstrate the distinct clinicopathological features of HER2-low and HER2-ultralow breast tumors and confirm that RCB is an effective predictor of prognosis in HER2-low populations for the first time. Notably, our findings demonstrate high instability in both HER2-low and HER2-ultralow expression from the primary baseline biopsy to residual disease after NAT. Furthermore, this study is the first to investigate the clinicopathological feature and the effectiveness of NAT for HER2-ultralow breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: HER2-low breast cancer is a newly recognized subtype that has shown promising responses to treatment with antibody–drug conjugates (ADCs). However, there is still little known about its clinical and molecular characteristics. In this study, we examined the clinical and pathological features, survival rates, and expression of HER2-related genes in Colombian patients with HER2-low breast cancer, comparing them to HER2-negative and positive groups. We found that HER2-low tumors were better differentiated and had a lower proliferation index compared to HER2-positive tumors. Additionally, compared to HER2-negative cases, HER2-low patients had higher mRNA expression of the ERBB2 gene and longer overall survival rates. Despite these findings, there were no significant differences in survival when adjusted for estrogen receptor status and clinical stage. These results highlight the need for further research on HER2-low breast cancer to optimize treatment strategies for this unique group. HER2-low tumors have shown promise in response to antibody–drug conjugates (ADCs) in recent clinical trials, underscoring the need to characterize this group's clinical phenotype. In this study, we aimed to explore the clinicopathological features, survival rates, and HER2 amplicon mRNA expression of women affected with HER2-low breast cancer, compared with HER2-negative and HER2-positive groups. We included 516 breast cancer patients from Colombia, for whom we compared clinicopathological features, mRNA expression of three HER2 amplicon genes (ERBB2, GRB7 and MIEN1), survival and risk of mortality between HER2-low cases (1+ or 2+ with negative in situ hybridization (ISH) result) with HER2-positive (3+ or 2+ with positive ISH test) and HER2-negative (0+) cases. A higher proportion of patients with better-differentiated tumors and a lower proliferation index were observed for HER2-low tumors compared to the HER2-positive group. Additionally, HER2-low tumors showed higher mRNA expression of the ERBB2 gene and longer overall survival rates compared to HER2-negative cases. Nonetheless, a Cox-adjusted model by ER status and clinical stage showed no statistically significant differences between these groups. Our results show differences in important clinicopathological features between HER2-low and both HER2-positive and negative tumors. Given this unique phenotype, it is crucial to evaluate the potential advantages of ADC therapies for this emerging subtype of breast cancer. [ABSTRACT FROM AUTHOR]

Background: The novel anti-HER2 antibody drug conjugates (ADCs) can effectively improve the long-term survival of patients with HER2-low expression breast cancer. However, pathological responses to neoadjuvant therapy (NAT) within HER2-low expression breast cancer, the relationship between pathological response and prognosis and the transformation of HER2 status are all now poorly understood. Methods: The patients with HER2-0 and HER2-low expression breast cancer receiving NAT at Harbin Medical University Cancer Hospital between Jan. 2014 and Nov. 2018 were retrospectively explored. HER2 low expression refers to the IHC 1 + or 2 + and FISH negative. The Kappa test was utilized for analyzing the consistency rate of HER2 expression. To evaluate disease-free survival (DFS) and overall survival (OS), this research employed both the Kaplan-Meier analysis and the Cox regression. Results: In this study, 178 patients with HER2-0 and 344 patients with HER2-low expression breast cancer were included. In comparison with the HER2-0 group, it is shown that patients in the HER2-low group have more possibility to be younger compared to those 50 years old (P < 0.014), have more premenopausal patients (P < 0.001), a higher proportion of hormone receptor (HR) positive patients (P < 0.001), and less proportion of stage III V patients (P < 0.034). When NAT was finished, the pCR rate became 23.6% in the HER2-0 group while 22.1% in the HER2-low group, and there was also a higher pCR rate in HR- patients in comparison with that in HR + patients (P < 0.01). Considering HER2 expression inconsistency, the overall HER2 inconsistency rate was 30.4% (Kappa = 0.431, P < 0.01). Among patients initially diagnosed as HER2-0, 34% (N = 61) were re-diagnosed as HER2-low after NAT. After stratification by HR expression status, HR+/HER2-0 patients transformed to HER2-low after NAT in 37%, and 32% of HR- patients changed from HER2-0 to HER2-low. In this survival analysis, there were both better DFS rates (P = 0.009) and OS rates (P = 0.026) in the HR-/HER2-low patients in comparison with the HR-/HER2-0 patients, while the HER2-0 and HER2-low patients in the HR + group had no significant survival difference. Additionally, for non-pCR patients, there was better DFS (P = 0.029) and OS (P = 0.038) in the HER2-low group in comparison with that of the HER2-0 group, while no significant survival difference exists between pCR patients. Conclusion: After HR stratification, there are unique clinical characteristics and prognostic outcomes in HER2-low expression breast cancer, which indicates the potential to become a specific molecular subtype of breast cancer. The significant instability of HER2-low expression status between primary tumor and residual invasive disease suggests that multiple detections of HER2 status should be emphasized in NAT strategies. [ABSTRACT FROM AUTHOR]

Background: The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is currently the standard first-line treatment for patients with metastatic hormone receptor positive (HR+), and HER2-negative (HER2-) breast cancer. However, the impact of HER2 status on the prognosis of patients receiving CDK4/6i and ET remains unclear. The meta-analysis was conducted to evaluate different outcomes between HER2-low and HER2-zero patients in advanced HR+ breast cancer receiving CDK4/6i and ET. Methods: A systematic search was performed in PubMed and EMBASE databases for relevant published literature. Objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) were pooled by fixed or random effects models. Results: Overall, 12 studies with 3567 patients were eligible for analysis. The pooled analysis suggested that no significant differences were observed in terms of ORR and OS between HER2-low and HER2-zero patients who underwent CDK4/6i and ET. Similarly, no significant difference in PFS was found between HER2-low and HER2-zero patients who underwent post-line CDK4/6i and ET or first-line Palbociclib and ET. However, in patients who received mixed-line (not a single treatment line) or first-line CDK4/6i and ET, the PFS was significantly shorter in the HER2-low subgroup than in the HER2-zero subgroup (mixed-line: HR = 1.36; 95% CI = 1.11–1.65; P = 0.002; first-line: HR = 1.14; 95% CI = 1.01– 1.28; P = 0.04). A similar phenomenon was observed in patients who received mixed-line or post-line Palbociclib and ET (mixed-line: HR = 1.60; 95% CI = 1.09–2.34; P = 0.02; post-line: HR = 1.43; 95% CI = 1.03–2.00; P = 0.03). Conclusion: These results indicated that HER2-low status did not have a significant association with ORR and OS, but it may have a worse impact on PFS in patients who received mixed-line or first-line CDK4/6i and ET, as well as mixed-line or post-line palbociclib plus ET. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the distribution and changes of HER2 status in untreated tumours, in residual disease and in metastasis, and their long-term prognostic implications. Methods: This is a population-based cohort study of patients treated with neoadjuvant chemotherapy for breast cancer during 2007–2020 in the Stockholm–Gotland region which comprises 25% of the entire Swedish population. Information was extracted from the National Breast Cancer Registry and electronic patient charts to minimize data missingness and misclassification. Results: In total, 2494 patients received neoadjuvant chemotherapy, of which 2309 had available pretreatment HER2 status. Discordance rates were 29.9% between primary and residual disease (kappa = 0.534), 31.2% between primary tumour and metastasis (kappa = 0.512) and 33.3% between residual disease to metastasis (kappa = 0.483). Adjusted survival curves differed between primary HER2 0 and HER2-low disease (p < 0.001), with the former exhibiting an early peak in risk for death which eventually declined below the risk of HER2-low. Across all disease settings, increasing the number of biopsies increased the likelihood of detecting HER2-low status. Conclusion: HER2 status changes during neoadjuvant chemotherapy and metastatic progression, and the long-term behaviours of HER2 0 and HER2-low disease differ, underscoring the need for obtaining tissue biopsies and for extended follow-up in breast cancer studies. [ABSTRACT FROM AUTHOR]

Objectives: To develop and validate machine learning models for human epidermal growth factor receptor 2 (HER2)-zero and HER2-low using MRI features pre–neoadjuvant therapy (NAT). Methods: Five hundred and sixteen breast cancer patients post-NAT surgery were randomly divided into training (n = 362) and internal validation sets (n = 154) for model building and evaluation. MRI features (tumour diameter, enhancement type, background parenchymal enhancement, enhancement pattern, percentage of enhancement, signal enhancement ratio, breast oedema, and apparent diffusion coefficient) were reviewed. Logistic regression (LR), support vector machine (SVM), k-nearest neighbour (KNN), and extreme gradient boosting (XGBoost) models utilized MRI characteristics for HER2 status assessment in training and validation datasets. The best-performing model generated a HER2 score, which was subsequently correlated with pathological complete response (pCR) and disease-free survival (DFS). Results: The XGBoost model outperformed LR, SVM, and KNN, achieving an area under the receiver operating characteristic curve (AUC) of 0.783 (95% CI, 0.733-0.833) and 0.787 (95% CI, 0.709-0.865) in the validation dataset. Its HER2 score for predicting pCR had an AUC of 0.708 in the training datasets and 0.695 in the validation dataset. Additionally, the low HER2 score was significantly associated with shorter DFS in the validation dataset (hazard ratio: 2.748, 95% CI, 1.016-7.432, P = .037). Conclusions: The XGBoost model could help distinguish HER2-zero and HER2-low breast cancers and has the potential to predict pCR and prognosis in breast cancer patients undergoing NAT. Advances in knowledge: HER2-low–expressing breast cancer can benefit from the HER2-targeted therapy. Prediction of HER2-low expression is crucial for appropriate management. MRI features offer a solution to this clinical issue. [ABSTRACT FROM AUTHOR]

Aims: Human epidermal growth factor receptor 2 (HER2) expression is an important biomarker in breast cancer (BC). Most BC cases categorised as HER2‐negative (HER2−) express low levels of HER2 [immunohistochemistry (IHC) 1+ or IHC 2+/in‐situ hybridisation not amplified (ISH−)] and represent a clinically relevant therapeutic category that is amenable to targeted therapy using a recently approved HER2‐directed antibody–drug conjugate. A group of practising pathologists, with expertise in breast pathology and BC biomarker testing, outline best practices and guidance for achieving consensus in HER2 IHC scoring for BC. Methods and results: The authors describe current knowledge and challenges of IHC testing and scoring of HER2‐low expressing BC and provide best practices and guidance for accurate identification of BCs expressing low levels of HER2. These expert pathologists propose an algorithm for assessing HER2 expression with validated IHC assays and incorporate the 2023 American Society of Clinical Oncology and College of American Pathologist guideline update. The authors also provide guidance on when to seek consensus for HER2 IHC scoring, how to incorporate HER2‐low into IHC reporting and present examples of HER2 IHC staining, including challenging cases. Conclusions: Awareness of BC cases that are negative for HER protein overexpression/gene amplification and the related clinical relevance for targeted therapy highlight the importance of accurate HER2 IHC scoring for optimal treatment selection. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2)‐enriched breast cancer benefits significantly from anti‐HER2 targeted therapies. This highlights the critical need for precise HER2 immunohistochemistry (IHC) interpretation serving as a triage tool for selecting patients for anti‐HER2 regimens. Recently, the emerging eligibility of patients with HER2‐low breast cancers for a novel HER2‐targeted antibody–drug conjugate (T‐DXd) adds challenges to HER2 IHC scoring interpretation, notably in the 0–1+ range, which shows high interobserver and interlaboratory staining platform variability. In this review, we navigate evolving challenges and suggest practical recommendations for HER2 IHC interpretation. [ABSTRACT FROM AUTHOR]

Background: There are limited data on the role of multigene tests and their correlation with immunohistochemistry (IHC), especially on core biopsy. MammaTyper is a quantitative conformite Europeeanne (CE) marked, National Institute for Health and Care excellence (NICE) approved, in in vitro diagnostic quantitative real‐time polymerase chain reaction (RT‐qPCR) test for assessment of mRNA expression of four biomarkers (ESR1, PGR, ERBB2, MKI67). Methods: We evaluated the concordance of MammaTyper with oestrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 by IHC on 133 core needle biopsies of breast cancer. HER2 was positive if IHC 3+ or 2+ and fluorescence in situ hybridization (FISH)‐amplified. Global and hotspot Ki67 expression was analysed using a cutoff of ≥20% assessed manually and by digital image analysis. Agreements were expressed as overall percent agreement (OPA), positive percent agreement (PPA), negative percent agreement (NPA), and Cohen's kappa. Results: RT‐qPCR results of ESR1 were highly concordant with IHC with OPA of 94.7% using 1% cutoff and 91.7% when the low ER‐positive category was included. The PPA and NPA between RT‐qPCR and IHC for PR was 91.5% and 88.0%, respectively, when using the 1% cutoff. For ERBB2/HER2, the OPA was 95% and the PPA was 84.6%. 40 of 72 HER2 IHC score 0 tumours were classified as ERBB2 low. Best concordance between MKI67 by MammaTyper and Ki67 IHC was achieved using hotspot digital image analysis (OPA: 87.2%, PPA: 90.6%, NPA: 80%). Conclusion: RT‐qPCR‐based assessment of the mRNA expression of ESR1, PGR, ERBB2, and MKI67 showed high concordance with IHC, suggesting that the MammaTyper test on core needle biopsies represents a reliable, efficient, and reproducible alternative for breast cancer classification and refining HER2 low categorisation. [ABSTRACT FROM AUTHOR]

Background/Aim: "HER2-low" is an emerging subtype of breast cancer, with a documented role in predicting response to treatment with novel antibody-drug conjugates. It is defined based on immunohistochemistry, but increasing evidence is challenging this approach as appropriate for identifying the HER2-low subgroup, due to both interobserver variability and limitations of the method itself. Patients and Methods: We retrospectively analyzed data from 430 patients from our departmental databases who had been subjected to an Oncotype-DX score and assessed the correlation of the Oncotype-DX HER2 single-gene score with the HER2 expression on immunohistochemistry. The Oncotype-DX Recurrence Score was also evaluated in the HER2-0 versus HER2-low subgroups. Results: The HER2 single-gene score was found to accurately correlate with the HER2 result on immunohistochemistry, with a statistically significant difference both between HER2-0 and HER2 +1 tumors (p<0.0001), as well as between HER2 +1 and +2 tumors (p<0.0001). There was no statistically significant difference in the recurrence score between the HER2-0 and the HER2-low subgroups. Conclusion: Oncotype-DX single-gene scores for HER2 are a potential surrogate marker for assessing the precise HER2 status, with better reproducibility and less interobserver variance compared to immunohistochemistry. The use of rt-PCR emerges as an alternative method of assessment of the HER2-low subgroup. [ABSTRACT FROM AUTHOR]

Background: In the global phase 3 DESTINY-Breast04 study (NCT03734029), the anti-human epidermal growth factor 2 (HER2) antibody–drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated a statistically significant improvement in progression-free survival (PFS) and overall survival (OS), with manageable safety compared with treatment of physician's choice (TPC) in patients with HER2-low metastatic breast cancer (mBC) who had received 1–2 prior lines of chemotherapy. Methods: This subgroup analysis examined the efficacy and safety of T-DXd versus TPC in 213 patients from Asian countries and regions who were enrolled in the DESTINY-Breast04 trial and randomized to T-DXd (n = 147) or TPC (n = 66). Results: Median PFS with T-DXd and TPC was 10.9 and 5.3 months, respectively, in Asian patients with hormone receptor-positive mBC, and 10.9 and 4.6 months, respectively, in the overall Asian population. In both populations, median OS was not reached with T-DXd and was 19.9 months with TPC. The objective response rate was higher with T-DXd versus TPC in all Asian patients. Median treatment duration was 8.4 months with T-DXd and 3.5 months with TPC. The most common grade ≥ 3 drug-related treatment-emergent adverse events in Asian patients treated with T-DXd were neutropenia (16.3%), anemia (12.9%), and leukopenia (11.6%); the incidences of neutropenia and leukopenia were higher with TPC versus T-DXd. Adjudicated drug-related interstitial lung disease or pneumonitis with T-DXd was 14.3%; the majority of events were grade 1–2. Conclusions: T-DXd demonstrated clinically meaningful survival benefits versus TPC in Asian HER2-low mBC patients, regardless of hormone receptor status, with no new safety signals. Clinical trial registration number: ClinicalTrials.gov, NCT03734029. [ABSTRACT FROM AUTHOR]

Background: Breast cancer presents diverse molecular subtypes affecting treatment strategies. Human epidermal growth factor receptor 2 (HER2)-low, hormone receptor-positive (HR+) breast cancer poses a challenge due to limited targeted therapies. Current neoadjuvant treatment primarily utilizes chemotherapy, with conflicting results regarding efficacy in patients with HER2-low breast cancer. Trastuzumab deruxtecan (T-DXd) shows promise in HER2-low metastatic disease, and preliminary evidence suggests synergy with endocrine therapy. Objective: This editorial explores the hypothesis that neoadjuvant T-DXd with or without endocrine therapy offers efficacy in the clinical management of HR+/HER2-low breast cancer. Methods: We propose a phase II study with two treatment arms: T-DXd + letrozole and T-DXd alone. The primary endpoint is the radiological complete response rate. Secondary endpoints include pathological complete response rate, safety, event-free survival, and overall survival. Exploratory analyses will compare the arms to identify potential for optimizing treatment efficacy and minimizing side effects. Conclusions: This study design allows for initial assessment of T-DXd with or without endocrine therapy in the treatment of HER2-low breast cancer. The findings may pave the way for personalized treatment strategies and inform future research, potentially leading to a chemotherapy-sparing approach. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to evaluate the utility of radiomic features from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in distinguishing HER2-low from HER2-zero breast cancer. Patients and methods: We retrospectively analyzed 118 MRI cases, including 78 HER2-low and 40 HER2-zero patients confirmed by immunohistochemistry or fluorescence in situ hybridization. From each DCE-MRI case, 960 radiomic features were extracted. These features were screened and reduced using intraclass correlation coefficient, Mann-Whitney U test, and least absolute shrinkage to establish rad-scores. Logistic regression (LR) assessed the model's effectiveness in distinguishing HER2-low from HER2-zero. A clinicopathological MRI characteristic model was constructed using univariate and multivariate analysis, and a nomogram was developed combining rad-scores with significant MRI characteristics. Model performancewas evaluated using the receiver operating characteristic (ROC) curve, and clinical benefit was assessed with decision curve analysis. Results: The radiomics model, clinical model, and nomogram successfully distinguished between HER2-low and HER2-zero. The radiomics model showed excellent performance, with area under the curve (AUC) values of 0.875 in the training set and 0.845 in the test set, outperforming the clinical model (AUC = 0.691 and 0.672, respectively). HER2 status correlated with increased rad-score and Time Intensity Curve (TIC). The nomogram outperformed both models, with AUC, sensitivity, and specificity values of 0.892, 79.6%, and 82.8% in the training set, and 0.886, 83.3%, and 90.9% in the test set. Conclusions: The DCE-MRI-based nomogram shows promising potential in differentiating HER2-low from HER2-zero status in breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)‐low‐expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. Methods: Women aged ≤40 years with newly diagnosed early‐stage HER2‐negative BC (HER2‐0 and HER2‐low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi‐square test and Student t‐test were used to describe variable distribution between HER2‐0 and HER2‐low. Associations with HER2‐low status were assessed with logistic regression. Kaplan–Meier method and Cox regression analysis were used to assess disease‐free survival (DFS) and overall survival. Statistical significance was considered for p ≤.05. Results: Of 3547 included patients, 32.3% had HER2‐low BC, representing 46.3% of hormone receptor–positive and 21.3% of triple‐negative (TN) tumors. HER2‐low vs. HER2‐0 BC were more often of grade 1/2 (p <.001), hormone receptor–positive (p <.001), and node‐positive (p =.003). BRCA2 PVs were more often associated with HER2‐low than BRCA1 PVs (p <.001). HER2‐low versus HER2‐0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76–0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64–0.95) and overall survival (HR, 0.65; 95% CI, 0.46–0.93) in the TN subgroup. Luminal A–like tumors in HER2‐low (p =.014) and TN and luminal A‐like in HER2‐0 (p =.019) showed the worst DFS. Conclusions: In young patients with HER2‐negative BC and germline BRCA1/2 PVs, HER2‐low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal‐like disease. HER2‐low status was associated with a modestly improved prognosis. Approximately 32% of human epidermal growth factor receptor 2 (HER2)‐negative breast cancer in an international multicenter cohort of 3547 women ≤40 years old with germline BRCA1/2 pathogenic variants was HER2‐low, and more frequently associated with hormone receptor–positive disease and BRCA2 variants than triple‐negative and BRCA1. HER2‐low status was associated with slightly better outcomes than HER2‐0, especially in triple‐negative tumors, without prognostic differences according to BRCA1 vs. BRCA2 variants, though within HER2‐low disease, luminal A–like tumors displayed worse disease‐free survival than luminal B–like and triple negative tumors. [ABSTRACT FROM AUTHOR]

Breast cancer has become the most prevalent malignant tumor worldwide and remains one of the leading causes of cancer-related mortality among women globally. The prognosis for patients with metastatic breast cancer remains poor, necessitating the exploration of novel therapeutic strategies to improve survival rates. In the era of precision medicine, antibody-drug conjugates (ADCs) have gained significant attention as a targeted therapeutic strategy in breast cancer treatment. ADCs, a relatively new treatment for breast cancer, deliver cytotoxic drugs (payloads), directly into the tumor space, turning chemotherapy into a targeted agent, which enables patients to experience significant improvements with manageable drug toxicity. For the treatment of breast cancer, there are three ADCs approved for breast cancer treatment: Trastuzumab emtansine (T-DM1), Trastuzumab Deruxtecan (T-Dxd) targeting HER-2, and Sacituzumab Govitecan (SG) targeting Trop-2. Recent clinical studies have demonstrated that the benefits of ADC therapies extend beyond HER2-positive breast cancer toinclude hormone receptor (HR)-positive breast cancer, triple-negative breast cancer (TNBC), and HER2-low expressing breast cancer. Notably, the DESTINY-Breast series of studies, particularly focusing on T-Dxd, encompass neoadjuvant, adjuvant, and multiple lines of therapy for advanced breast cancer. This marks the advent of a comprehensive ADC era in breast cancer treatment. This review summarizes the efficacy and adverse effects of ADC therapies that have completed or are currently undergoing phase I-III clinical trials. Additionally, it analyzes potential combination strategies to overcome ADC resistance, aiming to provide clinicians with a comprehensive clinical guide to the use of ADCs in breast cancer treatment.

ER-low and HER2-low breast cancers have emerged as clinically significant subtypes that challenge traditional diagnostic categories and treatment paradigms. These subtypes, representing a spectrum of disease, exhibit distinct biological behaviors, therapeutic responses, and prognostic outcomes. HER2-low breast cancer, defined by low HER2 protein expression (IHC score of 1+ or 2+ without HER2 gene amplification), has achieved clinical significance, particularly following the DESTINY-Breast trials, which demonstrated the efficacy of trastuzumab deruxtecan (T-DXd) in the population of patients with advanced HER2-low disease. Similarly, ER-low breast cancer, characterized by low estrogen receptor expression (in 1%–10 % invasive tumor cells), poses unique challenges due to its intermediate biological behavior and uncertain response to endocrine therapies. The identification of these subtypes is further complicated by inconsistencies in testing methodologies, which can lead to misclassification and impact treatment decisions. As our understanding of these subtypes improves, the need for standardized diagnostic approaches and individualized therapeutic decisions becomes increasingly urgent. Ongoing research and collaboration between pathologists and oncologists are essential for refining diagnostic criteria and improving outcomes for patients with breast cancers characterized by low expression of these theragnostic biomarkers. This review aims to consolidate current knowledge on HER2-low and ER-low breast cancers, focusing on the challenges associated with their identification, the implications for treatment, and future directions in clinical management. By examining recent studies and interlaboratory assessments, this review emphasizes the critical need for accurate and reproducible testing and reporting, and for the development of tailored therapeutic strategies for these “low” expression cancers.

For the past 2 decades, pathologists have been accustomed to reporting the HER2 status of breast cancer as either positive or negative, based on HER2 IHC. Today, however, there is a clinical imperative to employ a 3-tier approach to interpreting HER2 IHC that can also identify tumours categorised as HER2-low. Meeting this need for a finer degree of discrimination may be challenging, and in this article, we consider the potential for the integration of computational approaches to support pathologists in achieving accurate and reproducible HER2 IHC scoring as well as outlining some of the practicalities involved.

Objective: The aim of this paper was to assess the differences in clinicopathological characteristics, efficacy and prognosis of neoadjuvant chemotherapy (NAC) in human epidermal growth factor receptor2(HER2)-zero and HER2-low hormone receptor (HR)-negative breast cancer (BC) patients, and the impact of HER2-evolution on prognosis before and after NAC.Methods: 319 triple negative breast cancer (TNBC) patients who completed NAC and surgery from August 2014 to August 2018 at Tianjin Medical University Cancer Institute and Hospital were included. Clinicopathological features, efficacy of NAC and assessment of prognosis were retrospectively analysed. The evolution of HER2-zero to HER2-low after NAC is defined as HER2-gain, the evolution of HER2-low to HER2-zero after NAC is defined as HER2-loss, and HER2 unchanged after NAC is defined as HER2-stable.Results: In HR-negative BC, the pathological complete response (pCR) rate was significantly higher in HER2-zero compared with HER2-low patients, and the difference was statistically significant (38.9% vs 23.2%, p = 0.004), but there was no significant difference in the prognosis between the two groups. The overall rate of HER2-evolution after NAC was 19.7%, and there was a significant correlation between HER2-loss and histological grading, whereas HER2-gain was significantly associated with Ki-67 expression. In terms of prognosis, HER2-gain was better compared to the other two groups.Conclusion: In this study, we found that HER2-low HR-negative BC showed different clinicopathological features and response to NAC compared with HER2-zero, as well as HER2-evolution before and after NAC had a significant impact on prognosis.

ObjectiveWith the approval of trastuzumab deruxtecan for the treatment of unresectable/metastatic HER2-low breast cancer, human epidermal growth factor receptor 2 (HER2)-low has emerged as a clinically actionable biomarker. There is an urgent need for a deeper understanding of HER2-low breast cancer patients. Therefore, this study was conducted to explore the clinicopathological characteristics, the evolution of HER2-low status, and its impact on the prognosis of hormone receptor (HoR)-negative/HER2-low metastatic breast cancer (MBC) patients.MethodsThis pooled analysis included 350 metastatic triple-negative breast cancer (mTNBC) patients who received first-line platinum-based chemotherapy at Fudan University Shanghai Cancer Center from November 2007 to July 2022. Patients were categorized into HER2-0 and HER2-low groups based on their HER2 status. Baseline clinicopathological characteristics, evolution of HER2 status between primary and metastatic lesions, and treatment efficacy were compared between the two groups.ResultsAmong the 350 mTNBC patients, 34.9% (122/350) were HER2-low and 65.1% (228/350) were HER2-0. Significant differences were observed between HER2-low and HER2-0 patients in terms of age and menopausal status. HER2-low patients were older (54 vs. 49 years, p=0.002) and had a lower proportion of premenopausal patients (32.8% vs. 52.6%, p

PurposeHER2 overexpression has a central role in breast cancer carcinogenesis and is associated with poor prognosis if untreated. Lately, identification of HER2-low breast cancer has been proposed to select patients for novel HER2-directed chemotherapy and includes cancers with immunohistochemistry 1 + or 2 + with negative FISH, encompassing approximately 55-60% of all breast carcinomas. In early-stage breast cancer, the prognostic significance of HER2 low-disease is less well understood, with a particular paucity of data evaluating the prevalence and implications of HER2-low status in invasive lobular carcinoma (ILC).MethodsWe evaluated 666 stage I-III ILC tumors from a prospectively maintained institutional database, comparing clinicopathologic features and disease-free survival (DFS) using a multivariable Cox proportional hazards model.ResultsHER2-low status was common in this cohort of patients with ILC, but most clinicopathologic features did not differ between HER2-low and HER2-negative cases. However, when adjusting for tumor size, number of positive nodes, ER/PR status, and local therapy received, patients with HER2-low status had worse disease-free survival (DFS) than those with HER2-negative tumors (hazard ratio 2.0, 95% confidence interval 1.0-4.1, p = 0.05).ConclusionThis difference in DFS supports the notion that HER2-low and HER2-negative early stage ILC may differ clinically, despite similar clinicopathologic features. Further investigation into the potential benefit of HER2 targeted therapy in HER2-low early-stage breast cancer, and specifically lobular cancer, is warranted to ensure optimal outcomes in this distinct tumor subtype.

HER2-Low is defined as low levels of HER2 expression, based on a score of 1+ on immunohistochemical (IHC) assay or as an IHC score of 2+ and negative results on in situ hybridization (ISH or FISH). They are a heterogeneous population of breast cancers that vary in prognosis and sensitivity to systemic treatments. The frequency and clinical characteristics of pathogenic germline variants (PGVs) in HER2-Low breast cancer (BC) patients is not defined. We analyzed results from patients with BC who underwent multi-gene panel testing (MGPT) (maximum 145 genes) between 2018–2019. We reclassified HER-2 status accordingly. Relationships between the variables of interest were assessed by adopting the proportional regression Cox models. Of a total of 167 BC patients who underwent MGPT, half were hormone-receptor-positive. The median age was 45 years. About two thirds of the patients were in the earlier stage of BC. A total of 57% of the cases were reclassified as HER-2-negative or -Low. PGVs were found in 19% of the patients overall, as follows: seven BRCA1, four BRCA2, two ATM, one ATR, two CFTR, three CHEK2, one FANCA, one MERTK, one MLH1, three MUTYH, one RAD50, three RAD51C, one RECQL4, and two TP53 mutations. In HER2-Low, 26.5% of the patients had PGVs, and in the overall cohort, this was 19.8%. In conclusion, differences in the prevalence of deleterious germline mutations in HER2-Low BC patients compared to non-HER2-Low BC patients were identified. Similar alterations in BRCA were observed in this group of patients compared to the overall cohort. Germline genetic tests should be evaluated in larger cohorts of patients with HER2-Low status to better address the findings.

Abstract Mounting evidence showed that HER2-Low breast cancer patients could benefit from the novel anti-HER2 antibody–drug conjugates (ADCs) treatment, which pointed the way towards better therapy for HER2-Low patients. The purpose of this study was to describe the clinicopathological features, along with chemotherapeutic effects and survival outcomes of HER2-Low and HER2-Zero in TNBC who received neoadjuvant chemotherapy (NACT). We retrospectively evaluated 638 triple-negative breast cancer patients who were treated with neoadjuvant chemotherapy between August 2014 and August 2022. Pathologic complete response (pCR) and survival outcomes were analyzed in HER2-Low cohort, HER2-Zero cohort and the overall patients, respectively. In the entire cohort, 342 (53.6%) patients were HER2-Low and 296 (46.4%) patients were HER2-Zero. No significant difference was found between HER2-Low and HER2-Zero patients based on all the clinical–pathological characteristics. 143 cases (22.4%) achieved pCR after NACT in the overall TNBC patients. The pCR rate of the HER2-Low patients and the HER2-Zero patients was 21.3% and 23.6%, respectively, exhibiting no statistical difference (p = 0.487). The survival of pCR group after NACT significantly improved compared to non-pCR group either in HER2-Low patients or in HER2-Zero patients. Although we found that patients with HER2-Low had longer DFS than patients with HER2-Zero, there was no considerable difference (p = 0.068). However, HER2-Low patients had a dramatically longer OS than HER2-Zero patients (p = 0.012). The data from present study confirmed the clinical importance of HER2-Low expression in TNBC. Further effort is needed to determine whether HER2-Low could be a more favorable prognostic marker for individual treatment.