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BackgroundHER2-low expression breast cancer (BC) accounts for approximately 45%-55% of all BC cases. The purpose of this study was to investigate the prognostic difference between patients with HER2-low expression and HER2-zero BC.MethodsAn electronic search of Pubmed, Embase, Cochrane Library, and Web of Science databases was performed to screen studies that included prognostic comparisons between HER2-zero and HER2-low expression groups. A total of 14 studies involving 52106 patients were included.ResultsOur results indicated that HER2-low expression was associated with a significant benefit in OS among all patients with early BC (HR, 0.83; 95% CI, 0.78–0.88), patients with hormone-receptor positive BC (HR, 0.83; 95% CI, 0.77–0.89), and patients with TNBC (HR, 0.78; 95% CI, 0.70–0.87). HER2-low expression was associated with a significant benefit in DFS among all patients (HR, 0.81; 95% CI, 0.71–0.93), patients with hormone receptor-positive BC (HR, 0.81; 95% CI, 0.72–0.90), but no significant difference in DFS was found in patients with TNBC (HR, 0.87; 95% CI, 0.65–1.17). HER2-low expression was associated with a significant benefit in RFS among all patients (HR, 0.90; 95% CI, 0.85–0.95), patients with hormone receptor-positive BC (HR, 0.90; 95% CI, 0.84–0.96), but no significant difference in RFS was found in patients with TNBC (HR, 0.80; 95% CI, 0.55–1.16).ConclusionsAmong patients with early-stage BC, patients with HER2-low expression BC had better OS in the overall population, hormone receptor-positive and TNBC subgroups. Besides, favorable DFS and RFS were observed in both the overall population and hormone receptor-positive subgroup.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier (CRD 42022349458).

The increasing burden of breast cancer has prompted a wide range of researchers to search for new prognostic markers. Considering that tumor mutation burden (TMB) is low and copy number alteration burden (CNAB) is high in breast cancer, we built a CNAB-based model using a public database and validated it with a Chinese population. We collected formalin-fixed, paraffin-embedded (FFPE) tissue samples from 31 breast cancer patients who were treated between 2010 and 2014 at the National Cancer Center (CICAMS). METABRIC and TCGA data were downloaded via cBioPortal. In total, 2295 patients with early-stage breast cancer were enrolled in the study, including 1427 in the METABRIC cohort, 837 in the TCGA cohort, and 31 in the CICAMS cohort. Based on the ROC curve, we consider 2.2 CNA/MBp as the threshold for the CNAB-high and CNAB-low groupings. In both the TCGA cohort and the CICAMS cohort, CNAB-high had a worse prognosis than CNAB-low. We further simplified this model by establishing a prognostic nomogram for early breast cancer patients by 11 core genes, and this nomogram was highly effective in both the TCGA cohort and the CICAMS cohort. We hope that this model will subsequently help clinicians with prognostic assessments.

Yiran Si,1 Jian Yue,2 Zhaoyang Liu,3 Mo Li,3 Feng Du,4 Xue Wang,2 Zhong Dai,5 Nanlin Hu,1 Jie Ju,1 Songlin Gao,1 Xiaobing Wang,3 Peng Yuan2 1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 3State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 4China Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), The VIPII Gastrointestinal Cancer Division of Medical Department, Peking University Cancer Hospital and Institute, Beijing, 100142, People’s Republic of China; 5Department of Medical Oncology, Cancer Hospital of Huanxing Chaoyang District, Beijing, 100005, People’s Republic of ChinaCorrespondence: Peng YuanDepartment of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Pan Jia Yuan Nan Li, Chao Yang District, Beijing, 100021, People’s Republic of ChinaTel +86 10-87787245Email yuanpeng01@hotmail.comXiaobing WangState Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, #17 Pan Jia Yuan Nan Li, Chao Yang District, Beijing, 100021, People’s Republic of ChinaTel +86 10-87788430Email wangxb@cicams.ac.cnPurpose: Immunologically quiescent of breast cancer cells has been recognized as the key impediment for the breast cancer immunotherapy. In this study, we aimed to investigate the role of nanoparticle-mediated sonodynamic therapy (SDT) in promoting anti-tumor immune of breast cancer cells and its potential immune mechanisms.Materials and Methods: The phase-transformation nanoparticles (LIP-PFH nanoparticles) were in-house prepared and its physiochemical characters were detected. The CCK-8 assay, apoptosis analysis and Balb/c tumor model establishment were used to explore the anti-tumor effect of LIP-PFH nanoparticles triggered by low-intensity focused ultrasound (LIFU) both in vitro and in vivo. Flow cytometry and immunohistochemistry of CD4+T, CD8+T, CD8+PD-1+T in blood, spleen and tumor tissue were performed to represent the change of immune response. Detection of immunogenic cell death (ICD) markers was examined to study the potential mechanisms.Results: LIP-PFH nanoparticles triggered by LIFU could inhibit the proliferation and promote the apoptosis of 4T1 cells both in vitro and in vivo. CD4+T and CD8+T cell subsets were significantly increased in blood, spleen and tumor tissue, meanwhile CD8+PD-1+T cells were reduced, indicating enhancement of anti-tumor immune response of breast cancer cells in the nanoparticle-mediated SDT group. Detection of ICD markers (ATP, high-mobility group box B1, and calreticulin) and flow cytometric analysis of dendritic cell (DC) maturity further showed that the nanoparticle-mediated SDT can promote DC maturation to increase the proportion of cytotoxic T cells by inducing ICD of breast cancer cells.Conclusion: The therapy of nanoparticles-mediated SDT can effectively enhance anti-tumor immune response of breast cancer.Keywords: breast cancer, immune response, phase-transformation nanoparticles, immunogenic cell death, DC maturation

Objective: Anlotinib is a novel tyrosine kinase inhibitor blocking angiogenesis. This study was performed to assess the efficacy and safety of anlotinib in patients with metastatic breast cancer. Methods: Patients with HER2-negative breast cancer, who were pre-treated with anthracycline or taxanes in a neoadjuvant, adjuvant, or metastatic setting, and had treatment failure after at least one prior chemotherapy regimen in the metastatic setting were enrolled. Anlotinib was administered at 12 mg daily for 14 days in a 21-day cycle until disease progression or unacceptable toxicity occurred. Simultaneously, 5–10 mL of venous blood was collected to perform circulating tumor DNA (ctDNA) testing every 2 treatment cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival, safety, and biomarkers. Results: Twenty-six eligible patients were enrolled, with a median age of 56 (30–75) years. The median follow-up time was 10.5 months. The ORR was 15.4%, the DCR was 80.8%, and the median PFS was 5.22 months (95% confidence interval 2.86–6.24). Fourteen (53.8%) patients survived for more than 10 months. The changes in the detectable ctDNA variant allele frequency were consistent with the tumor response. The most common treatment-related adverse events were hypertension (57.7%), thyroidstimulating hormone elevation (34.6%), and hand-foot syndrome (23.1%). Conclusion: Anlotinib showed objective efficacy with tolerable toxicity in heavily pre-treated, metastatic HER2-negative breast cancer. The dynamic changes in the ctDNA variant allele fraction may be predictive of the tumor response.

BackgroundHormone receptor-positive and human epidermal growth factor receptor-2-positive (HR+/HER2+) breast cancer comprise approximately 5-10% of all invasive breast cancers. However, the lack of knowledge regarding the complexity of tumor heterogeneity in HR+/HER2+ disease remains a barrier to more accurate therapies. This study aimed to describe the tumor heterogeneity of HR+/HER2+ breast cancer and to establish a novel indicator to identify the HER2-enriched-like subtype in patients with HR+/HER2+ breast cancer.MethodsFirst, a comprehensive analysis was performed on HR+/HER2+ breast cancer samples from the TCGA (n=141) and METABRIC (n=104) databases. We determined the distribution of PAM50 intrinsic subtypes within the two cohorts and compared the somatic mutational profile and RNA expression features between HER2-enriched and non-HER2-enriched subtypes. We then performed multiplex immunofluorescence to evaluate HER2 and estrogen receptor (ER) expression simultaneously in the third cohort, enrolling 43 cases of early HR+/HER2+ breast cancer from Cancer Hospital, Chinese Academy of Medical Sciences (CAMS). ResultsAll four main intrinsic subtypes were identified in HR+/HER2+ breast cancer, of which the luminal-B subtype was the most common, followed by the HER2-enriched and luminal-A subtypes. Significantly increased TP53 and ERBB3 and decreased PIK3CA somatic mutation frequency were observed in the HER2-enriched subtype compared with the non-HER2-enriched subtype. In addition, the HER2-enriched subtype was characterized by significantly higher ERBB2 and lower ESR1 expression. We then constructed a marker termed rH/E to reflect the relative expression of ERBB2 to ESR1 in each patient. rH/E discriminates the HER2-enriched subtype from the non-HER2 subtypes better than the expression of ERBB2 or ESR1 alone. In the CAMS cohort, we observed four subtypes of tumor cells: ER+/HER2-, ER+/HER2+, ER-/HER2+, and ER-/HER2-. Tumor cell diversity was common, with 86% of patients having all four subtypes of tumor cells. Moreover, rH/E showed a significant prognostic association in the CAMS cohort. ConclusionsThis study furthers our understanding of the complexity of tumor heterogeneity in HR+/HER2+breast cancer, and suggests that the combined analysis of ERBB2 and ESR1 expression may contribute to identifying patients with specific subtypes in this population.

e12550 Background: ER- positive and HER2-positive (double-positive) breast cancers are known to display significant heterogeneity; however, traditional immunohistochemistry (IHC) only reflects inter-tumor heterogeneity. Studies are needed to demonstrate the intra-tumor heterogeneity of ER and HER2 expression and to further explore its impact. Methods: The retrospective study included three double-positive breast cancer cohorts. Data from a total of 141 patients from The Cancer Genome Atlas (TCGA) and 104 patients from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used to investigate the molecular characteristics of double-positive breast cancers at the tissue level via somatic mutation and RNA-seq analyses, while 43 patients treated at our hospital were selected to analyze ER and HER2 expression and localization at a single-cell level using multiple IF. The rH/R was proposed to reflect ER and HER2 expression profiles based on multiple IF or RNA-seq results, as follows: rH/E = HER2+ cell percentage / (ER+ cell percentage + 1) or rH/E = ERBB2 expression quantity / (ESR1 expression quantity + 1). Results: In the first two cohorts, we found that the HER2-enriched subtype displayed unique molecular characteristics, including increased TP53, ERBB3, and PI3KCA mutation rates and the abnormal expression of important signaling pathways (e.g., G2/M cell cycle checkpoint and epithelial mesenchymal transition); The rH/E was a significant index for diagnosing HER2-enriched patients (area under the receiver operating characteristic curve [AUC] = 0.92 and 0.75, both P < 0.0001). In the third cohort, we found that 86 % of the patients contained all four tumor cell types (ER+HER2+, ER+HER2-, ER-HER2+, and ER-HER2- cells); The rH/E was an independent risk factor for recurrence (hazard ratio [HR] = 2.63, P = 0.02) and patients with a rH/E ≥ 1.5 had a significantly shorter 5-year disease-free survival (DFS = 67 % vs. 92 %, P = 0.046). Conclusions: The significant intra- and inter-tumor heterogeneity of double-positive breast cancers is closely related to the prognosis of patients, which is of great significance for precision treatment.