Low HER2 Expression Research Articles

The impact of HER2-low status on pathological complete response and disease-free survival in early-stage breast cancer

BackgroundThe HER-2 status of breast cancer (BC) has been classified as negative or positive for a long time. Given the efficacy of novel anti-HER2-targeted antibody drug conjugates (ADCs) in HER2-low BC, a distinct subgroup of HER2-low tumors has emerged within BC. The biology and prognostic impact of HER2-low expression are not yet well defined, and inconsistent results were reported. This study aims to evaluate the impact of low HER-2 status on the response to neoadjuvant chemotherapy (NACT) and disease- free survival (DFS) rates.MethodsWe retrospectively analyzed BC patients treated with NACT from 2017 to 2023 in two cancer centers. HER2-negative patients were included. HER-2 low status was defined by IHC + 1 or + 2/ISH non-amplified, and HER2-zero was defined by IHC 0. Pathological complete response (pCR) rates and DFS between HER2-low and HER2-zero populations were compared.Results170 patients were identified. 122 (72%) of these patients were HER2- zero BC, whereas 48 (28%) were HER2-low BC. Overall, pCR was achieved in 35 (20.5%) patients. Of these, pCR was observed in 30 patients (44.6%) from the HER2- zero group, compared to 5 patients (10.4%) from the HER2-low group (p = 0.046), but significance was lost in multivariate analysis. Among the hormone receptor (HR) positive subtype, pCR was achieved 19.8% of HER2-zero tumors and 7.5% of HER2-low tumors (p = 0.08). For HR-negative subtype 34.1% HER2-zero tumors had pCR and 25% of the HER2-low tumors had pCR (p = 0.614). There was no association between DFS and HER2-low status.ConclusionsOur study indicates that HER2-low status had no impact on pCR or DFS.

Targeted PHA Microsphere-Loaded Triple-Drug System with Sustained Drug Release for Synergistic Chemotherapy and Gene Therapy.

The combination of paclitaxel (PTX) with other chemotherapy drugs (e.g., gemcitabine, GEM) or genetic drugs (e.g., siRNA) has been shown to enhance therapeutic efficacy against tumors, reduce individual drug dosages, and prevent drug resistance associated with single-drug treatments. However, the varying solubility of chemotherapy drugs and genetic drugs presents a challenge in co-delivering these agents. In this study, nanoparticles loaded with PTX were prepared using the biodegradable polymer material poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx). These nanoparticles were surface-modified with target proteins (Affibody molecules) and RALA cationic peptides to create core-shell structured microspheres with targeted and cationic functionalization. A three-drug co-delivery system (PTX@PHBHHx-ARP/siRNAGEM) were developed by electrostatically adsorbing siRNA chains containing GEM onto the microsphere surface. The encapsulation efficiency of PTX in the nanodrug was found to be 81.02%, with a drug loading of 5.09%. The chemogene adsorption capacity of siRNAGEM was determined to be 97.3%. Morphological and size characterization of the nanodrug revealed that PTX@PHBHHx-ARP/siRNAGEM is a rough-surfaced microsphere with a particle size of approximately 150 nm. This nanodrug exhibited targeting capabilities toward BT474 cells with HER2 overexpression while showing limited targeting ability toward MCF-7 cells with low HER2 expression. Results from the MTT assay demonstrated that PTX@PHBHHx-ARP/siRNAGEM exhibits high cytotoxicity and excellent combination therapy efficacy compared to physically mixed PTX/GEM/siRNA. Additionally, Western blot analysis confirmed that siRNA-mediated reduction of Bcl-2 expression significantly enhanced cell apoptosis mediated by PTX or GEM in tumor cells, thereby increasing cell sensitivity to PTX and GEM. This study presents a novel targeted nanosystem for the co-delivery of chemotherapy drugs and genetic drugs.

Efficacy of pyrotinib and capecitabine in recurrent breast cancer with a HER2-negative genetic switch following systemic therapy: A case report and literature review

Despite the demonstrated safety and efficacy of pyrotinib and capecitabine in treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, their efficacy in recurrent breast cancer in which the HER2 status has changed to negative remains unexplored. Here, we report a case of a 38-year-old female diagnosed with invasive ductal adenocarcinoma of the left breast, staged as mcT2N0M0. Fluorescence in situ hybridization (FISH) confirmed that the tumor was hormone receptor (HR) positive with low HER2 expression (2+) and a HER2/CEP17 ratio of 3.56. Following neoadjuvant targeted therapy and chemotherapy, she underwent a modified radical mastectomy. Post-surgical histopathological examination revealed a non-pathological complete response, classified as ypT1cypN1M0. The tumor remained HR positive with low HER2 expression (2+), but the FISH result was negative (HER2/CEP17 ratio of 1.65). For 1 year, she was administered dual-targeted therapy with goserelin and exemestane. Sequential therapy with neratinib was initiated; however, it was discontinued due to grade IV diarrhea. Despite ongoing endocrine therapy, she experienced tumor recurrence on the left chest wall. A biopsy of the recurrent lesion revealed it to be HR positive with low HER2 expression (2+) and a negative FISH result (HER2/CEP17 ratio of 1.33). The recurrent lesion responded to combination therapy consisting of pyrotinib and capecitabine, with tolerable adverse events. This case highlights the potential advantages of combining pyrotinib and capecitabine when the HER2 status changes to negative following systemic therapy.

Impact of low HER2 expression on response to CDK4/6 inhibitor treatment in advanced HR + /HER2- breast cancer: a multicenter real-world data analysis.

CDK4/6 inhibitors (CDK4/6i) represent the first-line therapy approach of choice for patients with hormone receptor-positive, HER2-negative advanced breast cancer (HR + /HER-ABC). Approximately 50% of HR + /HER2-ABC displays low HER2 expression (HER2 low). Recent data emerging from the DESTINY-Breast04 trial demonstrated practice-changing efficacy of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in patients with low HER2 expression. Here, we aimed to analyze the impact of low HER2 expression on CDK4/6i therapy response in a well-characterized multicenter HR + /HER-ABC cohort. Patients diagnosed with HR + /HER2-ABC who were treated with CDK4/6i in clinical routine between November 2016 and December 2020 at four certified German Breast Cancer Centers were retrospectively identified. The cohort was stratified according to graduation of positivity in HER2 immunohistochemistry (IHC; HER2 zero = IHC score 0 and HER2 low = IHC score 1 + , 2 + /fluorescence in situ hybridization negative). Subgroups were analyzed with regard to progression-free survival (PFS) following CDK4/6i initiation. The study cohort comprised n = 448 patients. For n = 311 patients, HER2 status from the metastatic site was available. n = 91 (29.3%) cases were HER2 zero and n = 220 cases (70.7%) were HER2 low. There was no significant difference in PFS between the two groups (PFS: 17months versus 18months, log-rank p = 0.42). Further, we examined the influence of HER2 expression changes between primary and metastatic tissue (n = 171; HER2 gain/HER2 loss/HER2 stable expression) on CDK4/6i treatment response. Again, there was no significant difference between these three groups, respectively (PFS: 16months versus 13months versus 17months, log-rank p = 0.86). In our analysis, HER2 status did not have a significant impact on treatment response to CDK4/6i.

Stable or at least once HER2-low status during neoadjuvant chemotherapy confers survival benefit in patients with breast cancer

Background Temporal heterogeneity in human epidermal growth factor receptor 2 (HER2) status may be associated with the prognosis of breast cancer. We aimed to clarify the relationship of HER2-low transition during neoadjuvant therapy with survival outcomes under the new classification of HER2 status. Methods This retrospective study was conducted based on the prospective database of breast cancer patients treated with neoadjuvant therapy from September 2013 to August 2020. Results This analysis enrolled 185 patients, including 44 patients with HER2-zero tumours, 93 patients with HER2-low tumours and 48 patients with HER2-positive tumours after neoadjuvant therapy. Nearly, 57.6% of HER2-zero tumours turned into HER2-low tumours after neoadjuvant therapy, while 25.0% of HER2-low patients changed to HER2-zero or HER2-positive tumours. We found that at least once diagnosis as HER2-low breast cancer was related to hormone receptor status (p < .001) and Ki-67 expression (p = .036). Patients ever diagnosed as HER2-low tumours had favourable clinicopathological features (less Ki-67 expression, lower pathological staging, etc.) as well as significantly better locoregional relapse-free survival (LRFS; p = .007) and overall survival (OS; p = .026) compared with those never exhibiting HER2-low expression. Furthermore, the 6-year OS rates were 94.2% (95% confidence interval (CI) 83.1–98.1), 88.7% (74.4–95.2) and 78.1% (65.4–86.6) for patients with stable, once and none HER2-low expression, respectively (adjusted HR, 0.514 [95%CI, 0.294–0.897], p = .019). Conclusions Our study first indicated in patients across all expression levels of HER2 that stable or at least once HER2-low status may confer favourable attributes including less malignant biological behaviour and long-term survival benefit for breast cancer receiving neoadjuvant therapy.

Clinical characterization, prognostic, and predictive values of HER2-low in patients with early breast cancer in the PALLAS trial (ABCSG-42/AFT-05/BIG-14–13/PrE0109)

BackgroundBidirectional 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).MethodsPALLAS 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.ResultsFrom 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.ConclusionsIn 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.

Comparison of clinicopathological characteristics, efficacy of neoadjuvant therapy, and prognosis in HER2-low and HER2-ultralow breast cancer

BackgroundThis 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.MethodsConsecutive 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.ResultsOut 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.ConclusionsOur 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.

Ultrasound-based radiomics nomogram for predicting HER2-low expression breast cancer.

Accurate preoperative identification of Human epidermal growth factor receptor 2 (HER2) low expression breast cancer (BC) is critical for clinical decision-making. Our aim was to use machine learning methods to develop and validate an ultrasound-based radiomics nomogram for predicting HER2-low expression in BC. In this retrospective study, 222 patients (108 HER2-0 expression and 114 HER2-low expression) with BC were included. The enrolled patients were randomly divided into a training cohort and a test cohort with a ratio of 8:2. The tumor region of interest was manually delineated from ultrasound image, and radiomics features were subsequently extracted. The features underwent dimension reduction using the least absolute shrinkage and selection operator (LASSO) algorithm, and rad-score were calculated. Five machine learning algorithms were applied for training, and the algorithm demonstrating the best performance was selected to construct a radiomics (USR) model. Clinical risk factors were integrated with rad-score to construct the prediction model, and a nomogram was plotted. The performance of the nomogram was assessed using receiver operating characteristic curve and decision curve analysis. A total of 480 radiomics features were extracted, out of which 11 were screened out. The majority of the extracted features were wavelet features. Subsequently, the USR model was established, and rad-scores were computed. The nomogram, incorporating rad-score, tumor shape, border, and microcalcification, achieved the best performance in both the training cohort (AUC 0.89; 95%CI 0.836-0.936) and the test cohort (AUC 0.84; 95%CI 0.722-0.958), outperforming both the USR model and clinical model. The calibration curves showed satisfactory consistency, and DCA confirmed the clinical utility of the nomogram. The nomogram model based on ultrasound radiomics exhibited high prediction value for HER2-low BC.

Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.

Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy. We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety. Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively. Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).

Unveiling the mysteries of HER2-low expression in breast cancer: pathological response, prognosis, and expression level alterations

BackgroundThe 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.MethodsThe 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.ResultsIn 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.ConclusionAfter 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.

Impact of Low HER2 Expression on Neoadjuvant Treatment Response in Early Luminal Breast Cancer

Impact of Low HER2 Expression on Neoadjuvant Treatment Response in Early Luminal Breast Cancer

Challenges and improvements in HER2 scoring and histologic evaluation: insights from a national proficiency testing scheme for breast cancer diagnosis in China

BackgroundIn 2022, our team launched the pioneering national proficiency testing (PT) scheme for the pathological diagnosis of breast cancer, rapidly establishing its credibility throughout China. Aiming to continuously monitor and improve the proficiency of Chinese pathologists in breast pathology, the second round of the PT scheme was initiated in 2023, which will expand the number of participating institutions, and will conduct a nationwide investigation into the interpretation of HER2 0, 1+, and 2+/FISH- categories in China.MethodsThe methodology employed in the current round of PT scheme closely mirrors that of the preceding cycle in 2022, which is designed and implemented according to the “Conformity assessment—General requirements for proficiency testing”(GB/T27043—2012/ISO/IEC 17043:2010). More importantly, we utilized a statistics-based method to generate assigned values to enhance their robustness and credibility.ResultsThe final PT results, published on the website of the National Quality Control Center for Cancer (http://117.133.40.88:3927), showed that all participants passed the testing. However, a few institutions demonstrated systemic biases in scoring HER2 0, 1+, and 2+/FISH- with accuracy levels below 59%, considered unsatisfactory. Especially, the concordance rate for HER2 0 cases was only 78.1%, indicating challenges in distinguishing HER2 0 from low HER2 expression. Meanwhile, areas for histologic type and grade interpretation improvement were also noted.ConclusionsOur PT scheme demonstrated high proficiency in diagnosing breast cancer in China. But it also identified systemic biases in scoring HER2 0, 1+, and 2+/FISH- at some institutions. More importantly, our study highlighted challenges in the evaluation at the extreme lower end of the HER2 staining spectrum, a crucial area for further research. Meanwhile, it also revealed the need for improvements in interpreting histologic types and grades. These findings strengthened the importance of robust quality assurance mechanisms, like the nationwide PT scheme conducted in this study, to maintain high diagnostic standards and identify areas requiring further training and enhancement.

Prognostic significance of low HER2 expression in gastric cancer: a retrospective, single-center analysis

IntroductionMutated human epidermal growth factor receptor 2 (HER2) is an oncogene with critical pathogenic roles in breast cancer. HER2-low-positive breast cancer is a recently described subtype. We aimed to explore the clinical and molecular characteristics of gastric cancer with low HER2 expression, drawing on recent developments in breast cancer subtypes.Materials and methodsThis retrospective study involved 129 patients with HER2-non-amplified gastric cancer treated in Iwate prefectural Iwai Hospital from 2013 to 2019. Tumors were classified as HER2-null or low-positive based on immunohistochemistry score 0 or 1 + or 2 + with HER2 negativity in situ hybridization, respectively. Statistical analyses, including Kaplan–Meier analyses and Cox proportional hazards model were conducted.ResultsLow HER2 expression was present in 26% (33/129) of the patients. Clinicopathological characteristics were not significantly different between the HER2-low and null groups. Kaplan–Meier analysis of overall survival was significantly longer in the HER2-low group than in the HER2-null group (P = 0.01). In multivariate Cox regression analysis, HER2-null status was associated with worse survival (hazard ratio 3.01; 95% confidence interval 1.18–7.65; and P = 0.02).ConclusionThis study highlights the prognostic importance of low HER2 expression in gastric cancer, similar to that observed in HER2-low-positive breast cancer, and suggests reclassification of gastric cancer to improve personalized treatment. Future studies should elucidate the molecular underpinnings of low HER2 expression in gastric cancer to guide novel therapeutic strategies and improve outcomes.

Incidence and Prognostic Values in Human Epidermal Growth Factor Receptor 2-Low Expression Metastatic Breast Cancer in Southeast Asian Population: A 10-Year Retrospective Study.

Breast cancer progression varies across molecular subtypes, and treatment options for human epidermal growth factor receptor 2 (HER2)-low expression tumors are limited compared with those of HER2 overexpression tumors. Comprehensive information regarding the epidemiology and clinical outcomes of metastatic HER2-low expression breast cancer in a Southeast Asian population is lacking. This retrospective cohort study was performed to analyze data from patients with de novo advanced breast cancer, including HER2 expression, tumor stage, and metastatic pattern. Statistical analyses, including chi-square tests and survival analyses, were used to compare HER2-low expression and HER2-negative groups. Of the 491 patients, 21.2% had HER2-low expression, 30% had HER2 overexpression, and 50% had HER2-negative expression. Among the hormone receptor (HR)-positive patients, 34% had HER2-low expression; in the triple-negative patients, the HER2-low incidence was 20.6%. No significant differences in clinical characteristics between HER2-low and HER2-negative groups were observed, except for more HR-positive patients in the HER2-low group. HER2-low patients had a longer overall survival (OS) than HER2-negative patients (43 v 23 months; hazard ratio, 0.7; P < .001), especially in HR-positive patients. After adjusting for HR status, HER2-low patients maintained improved outcomes. HR-positive HER2-low patients showed nonsignificant OS gains compared with HR-positive HER2-negative patients, regardless of first-line chemotherapy or endocrine therapy. This study revealed the incidence and clinical outcomes of HER2-low expression in de novo advanced breast cancer, suggesting favorable outcomes, particularly in HR-positive breast cancer. These findings may inform personalized treatment strategies. Further research into the mechanisms and implications of HER2-low expression in breast cancer is required.

Development and validation of machine learning models for predicting HER2-zero and HER2-low breast cancers.

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). 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). 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). 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. 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.

Analysis of HER2 expression changes from breast primary to brain metastases and the impact of HER2-low expression on overall survival.

There are limited data regarding HER2-low expression dynamics between matched primary tumors and brain metastases (BrMs) in breast cancer. HER2-low expression has emerged as a new therapeutic biomarker for highly active antibody-drug conjugates with emerging intracranial activity. Patients with metastatic breast cancer (MBC) and BrMs seen at an NCI-designated center between 2003-2023 were identified. HER2 expression was defined as HER2-positive (3+,2+/ISH amplified), HER2-low (1+,2+/ISH negative), or HER2-0 by ASCO-CAP guidelines. Estrogen receptor (ER) status was defined as ER≥1%. Multivariate survival analyses by Cox proportional hazard models were determined from time of BrM resection to death or last follow-up between the 3 subtypes, controlling for ER and age. Among 197 matched primary and resected BrMs, 81% exhibited HER2 expression in the brain:61% HER2-positive, 20% HER2-low, and 19% HER2-0. Concordance was high in HER2-positive primary tumors with 100% retaining HER2 expression (97% retained HER2+ expression and 2.7% switched to HER2-low). HER2-0 primaries frequently showed HER2 gain in BrMs to HER2-low (35%) or HER2-positive (5.4%) status. Among 48 HER2-low primary tumors, 52% were discordant for HER2 status in the brain with 21% testing HER2-positive and 31% testing HER2-0. In adjusted analyses, patients with HER2-positive BrMs had significantly lower death risk than patients with HER2-low BrMs (HR=0.41, P=0.0006); no difference was observed between HER2-0 and HER2-low. In this retrospective analysis, HER2 expression is common in breast cancer BrMs, emphasizing the need for improved, non-invasive diagnostics. Patients with HER2-low and HER2-0 BrMs face inferior survival, presenting an unmet clinical need.

Patient characteristics and treatment patterns of patients with locally advanced or metastatic HER2-low breast cancer, a single site descriptive study.

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. 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. 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. 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.

Clinicopathological and prognostic features of HER2-null and HER2-low advanced breast cancer treated with eribulin or capecitabine

BackgroundHER2-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.MethodsWe retrospectively evaluated patients who were treated with eribulin or capecitabine between 2011 and 2015. HER2 status was evaluated according to the ASCO/CAP guidelines.ResultsNo 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.ConclusionsEribulin 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.

Effect of HER2-low status on brain metastasis-free survival and survival after brain metastasis in patients with breast cancer.

The discovery of novel human epidermal growth factor receptor 2 (HER2)-directed antibody‒drug conjugates has accelerated the identification of the HER2-low subtype. However, the biological significance of low HER2 expression in breast cancer brain metastasis (BCBM) is unclear. Patients with HER2-negative BC and brain metastasis were retrospectively screened between February 2012 and November 2023. Brain metastasis-free survival (BMFS) and survival after brain metastasis (SABM) were analyzed according to HER2 expression. A total of 201 female patients, 84 of whom were HER2-low and 117 of whom were HER2-zero, were evaluated. The median BMFS in the entire cohort was 35.6months (95% CI 29.8-41.4). Although HER2-low patients had numerically longer median BMFS than HER2-zero patients (43.7m vs. 30.1m, p = 0.025), multivariate analysis revealed that the difference was not significant (p = 0.167). BMFS between the HER2-low and HER2-zero groups was similar in the hormone receptor (HR)-positive (52.8m vs. 47.6m, p = 0.276) and HR-negative (15.3m vs. 19.7m, p = 0.930) cohorts. The median SABM in the entire cohort was 6.0months (95% CI 3.8-8.1). HER2-low and HER2-zero patients had similar median SAMB (5.4m vs. 6.1m, p = 0.816). The SABM between the HER2-low and HER2-zero groups was similar in the HR-positive (6.3m vs. 8.7m, p = 0.375) and HR-negative (3.3m vs. 4.2m, p = 0.783) cohorts. Low HER2 expression does not affect BMFS or SAMB in brain metastatic breast cancer patients in this real-world population.

Clinical and Biological Significance of HER2-Low in Ductal Carcinoma In Situ of the Breast

BackgroundDuctal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer, with 5-10% of cases progressing into invasive disease. Herein, we investigated the association between HER2-low and clinico-pathological characteristics in DCIS and subsequent ipsilateral loco-regional relapse (LRR). Materials and methodsWe accessed our prospectively maintained institutional database. HER2 status was determined by immunohistochemistry and classified as null (score 0), over-expressed (3+), and low (1+ or 2+); in situ hybridization was not considered since it is not used for routine DCIS diagnostics. ResultsAmong 375 patients with DCIS, median age was 54 (27-88) years, with a primary tumor size < 2.5 cm in 63%, grade III in 33%, and positive hormone receptor status (HR) in 81% of cases; 71% underwent breast-conserving surgery, 34% received adjuvant endocrine and 39% radiotherapy. A total of 197 (52%) had tumors with low HER2 expression, which resulted significantly associated with grade I/II (P < .001), Ki67< 20% (P < .001), and HR-positive status (P < .001). HER2-low distribution varied from 19.61% and 50% in ER negative and ER-low (<10%) to 60% and 69% in ER high (50%-95%) and very high tumors (> 95%) (P < .001). After a median 39-month follow-up (IQR 16-65), cumulative incidences of LRR was 0.054. Among 17 patients with paired primary tumor and LRR, 5 had discordant HER2 status, with an even distribution of increased and decreased HER2 expression. ConclusionsLow HER2 expression in DCIS is associated with features of reduced aggressiveness. Importantly, changes in HER2 expression may occur prompting retesting in recurrent cases, in line with observations in invasive breast cancer.