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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]

Purpose: HER2-low triple-negative breast cancer (TNBC) accounted for up to 34%–39% of primary TNBC and 22.2%–32% of metastatic TNBC. Our study aims to explore the relationship between HER2 expression and clinicopathological characteristics, analyze the impact of HER2 expression on the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in TNBC. Methods: This study involved 191 patients with TNBC who underwent operation after NAC from October 2021 to August 2022. Clinicopathological characteristics and the frequency of pCR were compared between HER2-low and HER2-0 TNBC. Results: 42.2% (81/191) patients in our cohort were HER2-low. They exhibited differences in menopausal status, body mass index (BMI), androgen receptor (AR) expression, and histological grade (P < 0.05). Particularly, in HER2-low TNBC, AR was associated with tumor size, lymph node metastase, histological grade, and the incidence of multifocal disease (P < 0.05). The total pCR rate of entire cohor was 39.8%. Tumor size (P = 0.025), AR status (P = 0.033) and histological grade (P = 0.007) were significantly associated with the pCR rate of them, while the HER2 status did not exert a similar association. The multivariate analysis revealed that BMI (P = 0.004) and histological grade (P < 0.001) were associated with pCR of HER2-low TNBC, while tumor size (P = 0.034) and AR (P = 0.034) were associated with pCR of HER2-0 TNBC, respectively. Conclusions: In our cohort, HER2-low TNBC patients exhibits specific clinical characteristics and response features to NAC. [ABSTRACT FROM AUTHOR]

Purpose: Endocrine therapy (ET) in combination with CDK 4/6 inhibitors (CDK 4/6i) is the standard treatment modality for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (mBC). There is uncertainty about the prognostic and predictive value of HER2-low status and whether HER2-low BC is an individual biologic subtype. In this study, we aimed to investigate the prognostic effect of HER2 expression status on survival in mBC patients treated with first-line ET plus CDK 4/6i. Methods: This multicenter retrospective study included patients with HR + /HER2-negative mBC cancer who were treated with first-line CDK 4/6i in combination with ET from January 2016 to March 2023. Patients were divided into two groups (HER2-low and zero), and survival and safety analyses were performed. Results: A total of 201 patients were included in this study; of these, 73 (36.3%) had HER2-low disease and 128 (63.7%) had HER2-zero. There were 135 patients (67.2%) treated with ribociclib and 66 (32.8%) with palbociclib. Most of the patients (75.1%) received aromatase inhibitors as combination-endocrine therapy. Baseline characteristics were similar between the two groups. The median follow-up was 19.1 months (range: 2.5–78.4). The most common side effect was neutropenia (22.4%). The frequency of grade 3–4 toxicity was similar between the HER2-zero and low patients (32% vs 31.5%; p = 0.939). Visceral metastases were present in 44.8% of patients. Between the HER2-low and zero groups, median PFS (25.2 vs 22.6 months, p = 0.972) and OS (not reached vs 37.5 months, p = 0.707) showed no statistically significant differences. Conclusion: The prognostic value of HER2-low status remains controversial. Our study showed no significant effect of HER2 low expression on survival in patients receiving CDK 4/6i plus ET. [ABSTRACT FROM AUTHOR]

Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitors significantly altered the treatment landscape of hormone-positive (HR+), HER2- metastatic breast cancer (MBC). However, biomarkers predicting long-term benefit and early progression are yet to be defined. Several studies suggested the possibility of diminished efficacy in patients with HER2-low disease. Therefore, we conducted a systematic review and meta-analysis to evaluate the association between low-level HER2 expression and efficacy outcomes (PFS, OS, ORR) with CDK 4/6 inhibitors. Methods: The Pubmed, Web of Science, and Scopus databases were used to systematically filter the published studies from inception to 08 August 2023 for this systemic review. Studies including MBC patients treated with CDK 4/6 inhibitors and reported survival outcomes according to HER2 expression were included. We performed the meta-analyses with the generic inverse-variance method with a fixed-effects model and used HRs with 95% two-sided CIs as the principal summary measure. Results: Nine studies encompassing 2705 patients were included in the analyses. In the pooled analysis of nine studies, the risk of progression and/or death was higher in patients with HER2-low tumors compared to HER2-zero (HR: 1.22, 95% CI 1.10–1.35, p < 0.001). In the pooled analysis of five studies, although the median follow-up was short, the risk of death was higher in the HER2-low group compared to the HER2-zero group (HR: 1.22, 95% CI 1.04–1.44, p = 0.010). Conclusion: The available evidence demonstrates a significantly higher risk of progression or death with CDK 4/6 inhibitors in HER2-low tumors. Further research is needed to improve outcomes in patients with HR+-HER2-low tumors. [ABSTRACT FROM AUTHOR]

Purpose: To investigate potential differences in pathological complete response (pCR) rates and overall survival (OS) between HER2-low and HER2-zero patients with early-stage hormone receptor (HR)-positive and triple-negative breast cancer (TNBC), in the neoadjuvant chemotherapy setting. Methods: We identified early-stage invasive HER2-negative BC patients who received neoadjuvant chemotherapy diagnosed between 2010 and 2018 in the National Cancer Database. HER2-low was defined by immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, and HER2-zero by IHC0. All the methods were applied separately in the HR-positive and TNBC cohorts. Logistic regression was used to estimate the association of HER2 status with pCR (i.e. ypT0/Tis and ypN0). Kaplan–Meier method and Cox proportional hazards model were applied to estimate the association of HER2 status with OS. Inverse probability weighting and/or multivariable regression were applied to all analyses. Results: For HR-positive patients, 70.9% (n = 17,934) were HER2-low, whereas 51.1% (n = 10,238) of TNBC patients were HER2-low. For both HR-positive and TNBC cohorts, HER2-low status was significantly associated with lower pCR rates [HR-positive: 5.0% vs. 6.7%; weighted odds ratio (OR) = 0.81 (95% CI: 0.72–0.91), p < 0.001; TNBC: 21.6% vs. 24.4%; weighted OR = 0.91 (95% CI: 0.85–0.98), p = 0.007] and improved OS [HR-positive: weighted hazard ratio = 0.85 (95% CI: 0.79–0.91), p < 0.001; TNBC: weighted hazard ratio = 0.91 (95% CI: 0.86–0.96), p < 0.001]. HER2-low status was associated with favorable OS among patients not achieving pCR [HR-positive: adjusted hazard ratio = 0.83 (95% CI: 0.77–0.89), p < 0.001; TNBC: adjusted hazard ratio = 0.88 (95% CI 0.83–0.94), p < 0.001], while no significant difference in OS was observed in patients who achieved pCR [HR-positive: adjusted hazard ratio = 1.00 (95% CI: 0.61–1.63), p > 0.99; TNBC: adjusted hazard ratio = 1.11 (95% CI: 0.85–1.45), p = 0.44]. Conclusion: In both early-stage HR-positive and TNBC patients, HER2-low status was associated with lower pCR rates. HER2-zero status might be considered an adverse prognostic factor for OS in patients not achieving pCR. [ABSTRACT FROM AUTHOR]

Purpose: To investigate potential differences in pathological complete response (pCR) rates and overall survival (OS) between HER2-low and HER2-zero patients with early-stage hormone receptor (HR)-positive and triple-negative breast cancer (TNBC), in the neoadjuvant chemotherapy setting. Methods: We identified early-stage invasive HER2-negative BC patients who received neoadjuvant chemotherapy diagnosed between 2010 and 2018 in the National Cancer Database. HER2-low was defined by immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, and HER2-zero by IHC0. All the methods were applied separately in the HR-positive and TNBC cohorts. Logistic regression was used to estimate the association of HER2 status with pCR (i.e. ypT0/Tis and ypN0). Kaplan–Meier method and Cox proportional hazards model were applied to estimate the association of HER2 status with OS. Inverse probability weighting and/or multivariable regression were applied to all analyses. Results: For HR-positive patients, 70.9% (n = 17,934) were HER2-low, whereas 51.1% (n = 10,238) of TNBC patients were HER2-low. For both HR-positive and TNBC cohorts, HER2-low status was significantly associated with lower pCR rates [HR-positive: 5.0% vs. 6.7%; weighted odds ratio (OR) = 0.81 (95% CI: 0.72–0.91), p < 0.001; TNBC: 21.6% vs. 24.4%; weighted OR = 0.91 (95% CI: 0.85–0.98), p = 0.007] and improved OS [HR-positive: weighted hazard ratio = 0.85 (95% CI: 0.79–0.91), p < 0.001; TNBC: weighted hazard ratio = 0.91 (95% CI: 0.86–0.96), p < 0.001]. HER2-low status was associated with favorable OS among patients not achieving pCR [HR-positive: adjusted hazard ratio = 0.83 (95% CI: 0.77–0.89), p < 0.001; TNBC: adjusted hazard ratio = 0.88 (95% CI 0.83–0.94), p < 0.001], while no significant difference in OS was observed in patients who achieved pCR [HR-positive: adjusted hazard ratio = 1.00 (95% CI: 0.61–1.63), p > 0.99; TNBC: adjusted hazard ratio = 1.11 (95% CI: 0.85–1.45), p = 0.44]. Conclusion: In both early-stage HR-positive and TNBC patients, HER2-low status was associated with lower pCR rates. HER2-zero status might be considered an adverse prognostic factor for OS in patients not achieving pCR. [ABSTRACT FROM AUTHOR]

Purpose: HER2-low breast cancer (BC) is a novel entity with relevant therapeutic implications, especially in hormone receptor (HR) positive BC. This study examines whether HER2 mRNA through the 21-gene assay, Oncotype DX (ODX), can refine the diagnosis of HER2-low and HER2-zero, obtained by immunohistochemistry (IHC). Methods: Between Jan 2021 and Jan 2023, 229 consecutive HR-positive HER2-negative early BC (T1-3 N0-1) have been characterised by IHC and ODX. HER2 status by IHC was either zero (IHC-0) or low (IHC-1 + and IHC-2 + /ISH-negative) while HER2-zero was further divided into HER2-null (IHC-0) and HER2-ultralow (IHC-1–10%). HER2 gene expression by ODX was negative if lower 10.7. Results: The distribution of HER2 IHC was as follows: 53.3% HER2-0, 29.25% HER2-1 + , and 17.5% HER2-2 +. The clinicopathological characteristics were similar in the three groups, with higher PgR-negative rate in HER2-zero (13.9% vs 3% vs 5%). The distribution of RS was homogeneous in the three groups with the median HER2 gene expression of 9.20 [IQR: 8.70–9.60]. HER2 gene expression gradually increased as the IHC score, with substantial overlap. After adjusting for confounders, HER2-1 + and HER2 2 + had a significant positive correlation between HER2 gene expression and IHC [OR 1.42, 95% CI 1.21 to 1.68, p < 0.001; OR 1.96, 95% CI 1.61 to 2.37, p < 0.001] compared to the HER2-zero group. HER2 gene expression did not differ between HER2-null and HER2-ultralow subgroups. Conclusion: Due to the substantial overlap, the HER2 gene expression is unable to properly distinguish HER2-low and HER2-zero IHC whose accurate identification is critical in the context of HER2-negative BC. [ABSTRACT FROM AUTHOR]

Purpose: Treatment for HER2-low [defined as ImmunoHistoChemistry (IHC) 1 + or 2 + and negative/normal in Situ Hybridization (ISH)] breast cancer patients is rapidly evolving, yet we lack critical information about the HER2-low population. Methods: We conducted a retrospective cohort study of women aged 18 years or older diagnosed with breast cancer between 2010 and 2016 in North Carolina. Analyses were conducted for the overall cohort and a stage IV sub-cohort. We examined demographic and clinical characteristics, and characterized prevalence of HER2-low disease and healthcare utilization. We estimated adjusted rate ratios for the association between HER2 classifications and utilization outcomes, and hazard ratios for 3-year all cause mortality (stage IV only). Results: The overall and stage IV cohorts included 12,965 and 635 patients, respectively. HER2-low patients represented more than half of both cohorts (59% overall, 53% stage IV). HER2-low patients were more likely than IHC 0 patients to have hormone receptor (HR)-positive disease. In the stage IV cohort, HER2-low patients were more likely to be Black (26% vs. 16% IHC 0, p = 0.0159). In both cohorts, rates of hospitalizations were slightly higher among HER2-low patients. There were no survival differences between HER2-low and IHC 0 among stage IV patients. Conclusion: New treatment options for HER2-low breast cancer may have potential for significant impact at the population level particularly for patients with stage IV disease. In light of racial differences between HER2-low and IHC 0 patients observed in our cohort, research- and practice-based efforts to ensure equitable adoption of new treatment guidelines for patients with HER2-low metastatic breast cancer will be essential. [ABSTRACT FROM AUTHOR]

Objective: This study aims to analyze whether there are any differences in clinicopathological features and prognosis between HER2 ultra-low, HER2-null, and HER2-low expression in Chinese breast cancer (BC) patients. Methods: The clinicopathological data of 1363 HER2-negative BC patients were retrospectively collected (from January 2018 to December 2019). HER2 status was further classified into HER2-null, HER2 ultra-low, and HER2-low. HER2-null expression is defined as infiltrating cancer cells completely free of staining. HER2 ultra-low expression is defined as ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining. HER2-low expression is defined as HER2 immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization (ISH) assay. Results: Of 1363 patients, there were 86 (6.3%) HER2-null patients, 395 (29.0%) HER2 ultra-low patients, and 882 (64.7%) HER2-low patients. HER2 ultra-low patients were different from HER2-low patients in terms of N stage, hormone receptor (HR) status, Ki-67 expression, and type of surgery. There were also significant differences in histologic type and postoperative endocrine therapy between HER2 ultra-low and HER2-null patients. HR+ (81.0%) tumors was more common than HR− (19.0%) in HER2 ultra-low patients. In addition, there was a significant difference in HR status between HER2 ultra-low and HER2-low patients (P = 0.001). The survival analysis showed that HER2 status had no effect on disease-free survival (DFS) in HER2-negative patients (all P > 0.05). However, regardless of HER2 status, HR+ patients had better DFS than HR− patients (P = 0.003). Cox multivariate analysis revealed that age (HR [95% CI] = 0.950 [0.928, 0.972], P < 0.001), HR status (HR [95% CI] = 3.342 [1.658, 6.736], P = 0.001), and postoperative endocrine therapy (HR [95% CI] = 0.048 [0.048, 0.023], P < 0.001) were important influencing factors of DFS in HER2-negative BC patients. Conclusion: HER2 ultra-low BC patients demonstrated distinct clinicopathological features from HER2-null and HER2-low tumors; while, HER2 status (null, ultra-low, or low) had no prognostic value in these HER2-negative BC population. Consistent with the published literature, HR status was an independent prognostic factor for DFS in HER2-negative BC patients. [ABSTRACT FROM AUTHOR]

Purpose: Low HER2 expression is emerging as an actionable target for the treatment of breast cancer (BC) with the antibody drug conjugate Trastuzumab deruxtecan. The aim of the study was to characterize the dynamics of HER2 expression during BC progression. Methods: We evaluated the evolution of HER2 expression in 171 paired primary and metastatic BCs (pBCs/mBCs) by including the HER2-low category. Results: The proportions of HER2-low cases were 25.7% in pBCs and 23.4% in mBCs, respectively, while those of HER2-0 cases were 35.1% and 42.7%, respectively. The overall conversion rate between HER2-0 and HER2-low was 31.7%. HER2-low switching to HER2-0 was more frequent than the reverse (43.2% vs. 23.3%; P = 0.03). Two (3.3%) and 9 (20.5%) cases of pBCs with a HER2-0 and a HER2-low status, respectively, were converted to HER2-positive mBCs. In contrast, 10 (14.9%) HER2-positive pBCs were converted to HER2-0 and an identical number to HER2-low mBCs, respectively, significantly higher than that when compared to the HER2-0 to HER2-positive (P = 0.03), but not HER2-low to HER2-positive conversion. No significant difference was found when comparing the conversion rates among the common organs of relapse. Of the 17 patients with multiorgan metastases, 41.2% had discordance among the different sites of relapse. Conclusions: HER2-low BCs constitute a heterogeneous group of tumors. Low HER2 expression is dynamic, with significant discordance between primary tumors and advanced disease as well as the distant sites of relapse. Repeat biomarker studies from advanced disease are warranted in making appropriate treatment plans in the pursuit of precision medicine. [ABSTRACT FROM AUTHOR]

Purpose: HER2 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). Methods: We 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. Results: HER2-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). Conclusion: This 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. [ABSTRACT FROM AUTHOR]

Purpose: Accurate evaluation of breast cancer on bioptic samples is of fundamental importance to guide therapeutic decisions, especially in the neoadjuvant or metastatic setting. We aimed to assess concordance for oestrogen receptor (ER), progesterone receptor (PR), c-erbB2/HER2 and Ki-67. We also reviewed the current literature to evaluate our results in the context of the data available at present. Methods: We included patients who underwent both biopsy and surgical resection for breast cancer at San Matteo Hospital, Pavia, Italy, between January 2014 and December 2020. ER, PR, c-erbB2, and Ki-67 immunohistochemistry concordance between biopsy and surgical specimen was evaluated. ER was further analysed to include the recently defined ER-low-positive in our analysis. Results: We evaluated 923 patients. Concordance between biopsy and surgical specimen for ER, ER-low-positive, PR, c-erbB2 and Ki-67 was, respectively, 97.83, 47.8, 94.26, 68 and 86.13%. Cohen's κ for interobserver agreement was very good for ER and good for PR, c-erbB2 and Ki-67. Concordance was especially low (37%) in the c-erbB2 1 + category. Conclusion: Oestrogen and progesterone receptor status can be safely assessed on preoperative samples. The results of this study advise caution in interpreting biopsy results regarding ER-low-positive, c-erbB2/HER and Ki-67 results due to a still suboptimal concordance. The low concordance for c-erbB2 1 + cases underlines the importance of further training in this area, in the light of the future therapeutic perspectives. [ABSTRACT FROM AUTHOR]