Objective: To investigate the clinical and pathological characteristics of breast cancer with HER2 low expression. Methods: The data from 3 422 patients with invasive breast cancer which archived in Peking Union Medical College Hospital between April 2019 and July 2022 were retrospectively reviewed. Among them, 136 patients were treated with neoadjuvant chemotherapy. The tumor size, histological type, tumor differentiation, lymph node metastasis, Ki-67 index, the status of estrogen receptor, progesterone receptor and HER2 as well as pathological complete response (pCR) rate were collected. Results: The HER2 status of 3 286 patients without neoadjuvant therapy, 616 (616/3 286, 18.7%) score 0, 1 047 (1 047/3 286, 31.9%) score 1+, 1 099 (1 099/3 286,33.4%) score 2+ and 524 (524/3 286,15.9%) score 3+ by immunohistochemistry (IHC). Among the 1 070 IHC 2+ cases, 161 were classified as HER2 positive by reflex fluorescence in situ hybridization (FISH) assay. In our cohort, 1 956 cases of HER2-low (IHC 1+ and IHC 2+/FISH-) breast cancer were identified. Compared to the HER2 IHC 0 group, HER2-low tumors more frequently occurred in patients with hormone receptor (HR) positive (P<0.001), Ki-67 index below 35% (P<0.001), well or moderate differentiation (P<0.001) and over the age of 50 (P=0.008). However, there were no significant differences in histological type, tumor size, and lymph node metastasis between HER2-low and HER2 IHC 0 group. For patients who had neoadjuvant therapy, the pCR rate in the patients with HER2-low was lower than those with HER2 IHC 0 (13.3%, 23.9%), but there was no significant difference. Although HER2-low breast cancers showed a slightly lower pCR rate than HER2 IHC 0 tumors, no remarkable difference was observed between tumors with HER2-low and HER2 IHC 0 regardless of hormone receptor status. Conclusions: The clinicopathological features of HER2-low breast cancers are different from those with HER2 IHC 0. It is necessary to accurately distinguish HER2-low breast cancer from HER2 IHC 0 and to reveal whether HER2-low tumor is a distinct biological entity.
目的： 探讨HER2低表达乳腺癌的特征。 方法： 收集北京协和医院2019年4月至2022年7月3 422例存档的浸润性乳腺癌患者临床资料，其中包括具有完整新辅助化疗信息的患者136例。所分析的指标包括年龄、雌激素受体和孕激素受体状态、HER2状态、Ki-67阳性指数、组织学分型、肿瘤分化、肿瘤大小及淋巴结转移，以及病理完全缓解（pathologic complete response，pCR）率。 结果： 在未接受新辅助治疗的3 286例乳腺癌中，检出免疫组织化学（IHC）0者616例（616/3 286，18.7%）、IHC 1+者1 047例（1 047/3 286，31.9%）、IHC 2+者1 099例（1 099/3 286，33.4%）及IHC 3+者524例（524/3 286，15.9%）。在IHC 2+组中1 070例乳腺癌进行荧光原位杂交（FISH）检测，其中HER2扩增者161例。在本队列中，HER2低表达（IHC 1+和IHC 2+/FISH-）乳腺癌共计1 956例。与HER2 IHC 0组相比，HER2低表达好发于50岁以上（P=0.008）、激素受体阳性（P<0.001）、Ki-67阳性指数<35%（P<0.001）及非低分化（P<0.001）的乳腺癌中。而组织学分型、肿瘤大小及淋巴结转移情况等临床病理特征在HER2低表达和HER2 IHC 0组中差异无统计学意义（P>0.05）。新辅助化疗后，HER2低表达组的pCR率低于HER2 IHC 0组（分别为13.3%和23.9%），但差异无统计学意义（P>0.05）；尽管按激素受体状态分类，也都观察到HER2低表达组的pCR率略低于HER2 IHC 0组，但差异仍无统计学意义（P>0.05）。 结论： HER2低表达组乳腺癌的临床病理特征不同于HER2 IHC 0组。准确区分HER2低表达和HER2 IHC 0并探索其是否为一个独立的生物学实体是有必要的。.

Objective: To investigate the relationship between 21-gene recurrence risk score (21-Gene RS) and the prognosis and clinicopathological features of hormone receptor (HR) positive, HER2-negative early breast cancer patients who did not receive neoadjuvant therapy. Methods: A total of 469 patients with HR positive and HER2-negative early breast cancer who received surgical treatment in the First Affiliated Hospital, Zhejiang University School of Medicine from January 2014 to October 2017 were selected. Their clinicopathological data were retrospectively analyzed. Tumor tissue samples were collected from patients, and the expression of 21-gene was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). The 21-Gene RS was calculated according to the Trial Assigning Individualized Options for Treatment (TAILORx) RS grouping and National Surgical Adjuvant Breast and Bowel Project B-20 (NSABP B-20) RS grouping principles. Patients were divided into low (21-Gene RS<11 or 21-Gene RS<18), intermediate (11≤21-Gene RS<26 or 18≤21-Gene RS<31) and high (21-Gene RS≥26 or 21-Gene RS≥31) risk groups, and the clinicopathological features and prognostic differences of patients in different risk groups were compared. Statistical data were compared by chi-square test. Survival analysis was performed using Kaplan-Meier curve analysis and the differences between groups were compared using Log-rank test. Multivariate analysis was conducted by COX regression analysis. Results: Based on TAILORx RS grouping, the proportions of low-risk, intermediate-risk and high-risk groups among the 469 patients were 18.8% (88/469), 48.2% (226/469) and 33.0% (155/469), respectively. Based on NSABP B-20 RS grouping, the proportion of low-risk, intermediate-risk and high-risk groups were 43.1% (202/469), 37.5% (176/469) and 19.4% (91/469), respectively. The association of 21-Gene RS with histological grading, luminal typing, Ki-67 expression, and chemotherapy and treatment modalities were statistically significant (P<0.05) regardless of TAILORx RS grouping or NSABP B-20 RS grouping. Kaplan-Meier survival curve suggested poor prognosis in high-risk group (P<0.05, Log-rank test). Multivariate COX regression analysis showed that surgical method and 21-Gene RS were risk factors affecting the prognosis of patients. Conclusions: 21-Gene RS is significantly associated with the prognosis of patients with HR-positive, HER2-negative, early-stage breast cancer not receiving neoadjuvant therapy, as well as with their clinicopathological characteristics such as patients\' histologic grade, luminal typing, Ki-67 expression, and whether or not they are treated with chemotherapy or other treatment modalities.The 21-Gene RS threshold of 11 and 26 or 18 and 31 can be used to grade the prognosis in Chinese patients with early-stage breast cancer. More researches are needed to guide the selection of postoperative adjuvant therapy for patients with HR-positive and HER2-negative early-stage breast cancer.
目的： 探讨激素受体阳性、HER2阴性、未接受新辅助治疗的早期乳腺癌患者21基因复发风险评分（21-gene recurrence risk score，21-Gene RS）与患者预后及临床病理特征的关系。 方法： 收集浙江大学医学院附属第一医院2014年1月至2017年10月接受手术治疗的早期激素受体阳性、HER2阴性乳腺癌患者469例，回顾性分析其临床病理资料。收集患者的肿瘤组织标本，进行即时荧光定量逆转录聚合酶链反应（RT-qPCR）检测21基因的表达，计算21-Gene RS并基于个体化治疗方案分配试验（Trial Assigning Individualized Options for Treatment，TAILORx）分组及国家乳腺和肠道外科辅助治疗项目（National Surgical Adjuvant Breast and Bowel Project B-20，NSABP B-20）分组原则，将患者分为低（21-Gene RS<11或21-Gene RS<18）、中（11≤21-Gene RS<26或18≤21-Gene RS<31）和高危组（21-Gene RS≥26或21-Gene RS≥31），比较不同风险分组患者的临床病理特征和预后差别。使用卡方检验比较计数资料，Kaplan-Meier曲线分析进行生存分析，Log-rank检验方法进行组间差异比较，COX回归分析进行多因素分析。 结果： 469例乳腺癌患者，基于TAILORx RS分组，低危组比例为18.8%（88/469），中危组比例为48.2%（226/469），高危组比例为33.0%（155/469）。基于NSABP B-20 RS分组，低危组比例为43.1%（202/469），中危组比例为37.5%（176/469），高危组比例为19.4%（91/469）。无论使用TAILORx RS分组还是NSABP B-20 RS分组，21-Gene RS与患者的组织学分级、Luminal分型、Ki-67表达以及是否接受化疗和治疗方式的关联均有统计学意义（P<0.05）。Kaplan-Meier生存分析提示高危组患者预后较差（P<0.05，Log-rank检验）。多因素COX回归分析结果表明手术方式和21-Gene RS是影响患者预后的风险因素。 结论： 21-Gene RS与激素受体阳性、HER2阴性、未接受新辅助治疗的早期乳腺癌患者的预后以及患者的组织学分级、Luminal分型、Ki-67表达以及是否接受化疗和治疗方式等临床病理特征显著相关。以11与26分或18与31分作为21-Gene RS临界值标准均可用于早期乳腺癌患者预后的分级，未来需更深入研究此分级方式用于指导激素受体阳性、HER2阴性早期乳腺癌患者术后辅助治疗的选择。.

OBJECTIVE: HER3, a member of the EGFR receptor family, plays a central role in driving oncogenic cell proliferation in breast cancer. Novel HER3 therapeutics are showing promising results while recently developed HER3 PET imaging modalities aid in predicting and assessing early treatment response. However, baseline HER3 expression, as well as changes in expression while on neoadjuvant therapy, have not been well-characterized. We conducted a prospective clinical study, pre- and post-neoadjuvant/systemic therapy, in patients with newly diagnosed breast cancer to determine HER3 expression, and to identify possible resistance mechanisms maintained through the HER3 receptor.
METHODS: The study was conducted between May 25, 2018 and October 12, 2019. Thirty-four patients with newly diagnosed breast cancer of any subtype (ER ± , PR ± , HER2 ±) were enrolled in the study. Two core biopsy specimens were obtained from each patient at the time of diagnosis. Four patients underwent a second research biopsy following initiation of neoadjuvant/systemic therapy or systemic therapy which we define as neoadjuvant therapy. Molecular characterization of HER3 and downstream signaling nodes of the PI3K/AKT and MAPK pathways pre- and post-initiation of therapy was performed. Transcriptional validation of finings was performed in an external dataset (GSE122630).
RESULTS: Variable baseline HER3 expression was found in newly diagnosed breast cancer and correlated positively with pAKT across subtypes (r = 0.45). In patients receiving neoadjuvant/systemic therapy, changes in HER3 expression were variable. In a hormone receptor-positive (ER +/PR +/HER2-) patient, there was a statistically significant increase in HER3 expression post neoadjuvant therapy, while there was no significant change in HER3 expression in a ER +/PR +/HER2+ patient. However, both of these patients showed increased downstream signaling in the PI3K/AKT pathway. One subject with ER +/PR -/HER2- breast cancer and another subject with ER +/PR +/HER2 + breast cancer showed decreased HER3 expression. Transcriptomic findings, revealed an immune suppressive environment in patients with decreased HER3 expression post therapy.
CONCLUSIONS: This study demonstrates variable HER3 expression across breast cancer subtypes. HER3 expression can be assessed early, post-neoadjuvant therapy, providing valuable insight into cancer biology and potentially serving as a prognostic biomarker. Clinical translation of neoadjuvant therapy assessment can be achieved using HER3 PET imaging, offering real-time information on tumor biology and guiding personalized treatment for breast cancer patients.

OBJECTIVE: The causal relationship between breast cancer and its estrogen receptor (ER) subtypes and neutropenia and agranulocytosis is unclear.
METHODS: In two-sample Mendelian randomization (MR), we used inverse variance weighting (IVW), Bayesian weighted MR (BWMR), MR-Egger, weighted median, simple mode, and weighted mode methods to analyze causality for ER-positive breast cancer, ER-negative breast cancer, overall breast cancer, and drug-induced neutropenia and agranulocytosis. To validate the results, we performed the analysis again using GWAS data on neutropenia from different databases. In multivariable MR (MVMR), we assessed the independent effects of ER-positive and ER-negative breast cancer on causality.
RESULTS: Two-sample MR analysis showed a causal relationship between ER-positive breast cancer (IVW odds ratio (OR) = 1.319, P = 7.580 × 10-10), ER-negative breast cancer (OR = 1.285, P = 1.263 × 10-4), overall breast cancer (OR = 1.418, P = 2.123 × 10-13), and drug-induced neutropenia and a causal relationship between ER-positive breast cancer (OR = 1.349, P = 1.402 × 10-7), ER-negative breast cancer (OR = 1.235, P = 7.615 × 10-3), overall breast cancer (OR = 1.429, P = 9.111 × 10-10), and neutropenia. Similarly, ER-positive breast cancer (OR = 1.213, P = 5.350 × 10-8), ER-negative breast cancer (OR = 1.179, P = 1.300 × 10-3), and overall breast cancer (OR = 1.275, P = 8.642 × 10-11) also had a causal relationship with agranulocytosis. MVMR analysis showed that ER-positive breast cancer remained causally associated with drug-induced neutropenia (OR = 1.233, P = 4.188 × 10-4), neutropenia (OR = 1.283, P = 6.363 × 10-4), and agranulocytosis (OR = 1.142, P = 4.549 × 10-3). Heterogeneity analysis and pleiotropy test showed that our results were reliable.
CONCLUSIONS: Our study provides genetic evidence for a causal association between breast cancer and its estrogen receptor subtypes and neutropenia. In clinical practice, in addition to focusing on therapeutic factors, additional attention should be given to breast cancer patients to avoid severe neutropenia.

This study systematically reviewed the role of diffusion-weighted imaging (DWI) in the assessment of molecular prognostic biomarkers in breast cancer, focusing on the correlation of apparent diffusion coefficient (ADC) with hormone receptor status and prognostic biomarkers. Our meta-analysis includes data from 52 studies examining ADC values in relation to estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki-67 status. The results indicated significant differences in ADC values among different receptor statuses, with ER-positive, PgR-positive, HER2-negative, and Ki-67-positive tumors having lower ADC values compared to their negative counterparts. This study also highlights the potential of advanced DWI techniques such as intravoxel incoherent motion and non-Gaussian DWI to provide additional insights beyond ADC. Despite these promising findings, the high heterogeneity among the studies underscores the need for standardized DWI protocols to improve their clinical utility in breast cancer management.

Background and Objectives: Patients with human epidermal growth factor receptor 2 (HER2) -positive, hormone receptor-positive (HR-positive) metastatic breast cancer (MBC) usually undergo trastuzumab emtansine (T-DM1) therapy in subsequent lines. Combining endocrine therapy (ET) with T-DM1 can improve treatment outcomes in this subtype. Therefore, this study aimed to investigate the benefits of using T-DM1 with ET in HER2-positive and HR-positive MBC. This study was the first to investigate the benefits of combining ET with T-DM1. Material and Methods: This study analyzed the medical records of patients with HER2-positive and HR-positive MBC who were treated with T-DM1 from June 2010 to December 2021. The patients were divided into groups based on whether they received concomitant ET with T-DM1. The primary endpoint was to determine the progression-free survival (PFS), while the secondary endpoints were overall survival (OS), objective response rate, and safety of the treatment. Results: Our analysis examined 88 patients, of whom 32 (36.4%) were treated with T-DM1 in combination with ET. The combination therapy showed a significant improvement in median PFS (15.4 vs. 6.4 months; p = 0.00004) and median OS (35.0 vs. 23.1 months; p = 0.026) compared to T-DM1 alone. The ORR was also higher in the combination group (65.6% vs. 29.3%; p = 0.026). Patients treated with pertuzumab priorly had reduced median PFS on T-DM1 compared to those who were not treated with pertuzumab (11.7 vs. 5.4 months, respectively; p < 0.01). T-DM1 demonstrated better median PFS in HER2 3+ patients compared to HER2 2+ patients, with an amplification ratio of >2.0 (10.8 vs 5.8 months, respectively; p = 0.049). The safety profiles were consistent with previous T-DM1 studies. Conclusions: The combination of T-DM1 with ET can significantly improve PFS and OS in patients with HER2-positive and HR-positive MBC. Our study suggests that prior pertuzumab treatment plus trastuzumab treatment might decrease T-DM1 efficacy.

Breast cancer, known for its diverse subtypes, ranks as one of the leading causes of cancer-related deaths. Prostate-specific membrane antigen (PSMA), primarily associated with prostate cancer, has also been identified in breast cancer, though its role remains unclear. This study aimed to evaluate PSMA expression across different subtypes of early-stage breast cancer and investigate its correlation with clinicopathological factors. This retrospective study included 98 breast cancer cases. PSMA expression was examined in both tumor cells and tumor-associated blood vessels. The analysis revealed PSMA expression in tumor-associated blood vessels in 88 cases and in tumor cells in 75 cases. Ki67 expression correlated positively with PSMA expression in blood vessels (p < 0.0001, RSpearman 0.42) and tumor cells (p = 0.010, RSpearman 0.26). The estrogen and progesterone receptor expression correlated negatively with PSMA levels in blood vessels (p = 0.0053, R Spearman -0.26 and p = 0.00026, R Spearman -0.347, respectively). Human epidermal growth factor receptor 2 (HER2) status did not significantly impact PSMA expression. We did not detect any statistically significant differences between breast cancer subtypes. These findings provide evidence for a heterogenous PSMA expression in breast cancer tissue and suggest its correlation with tumor aggressiveness. Despite the limited sample size, the study provides valuable insights into the potential of PSMA as a prognostic, diagnostic, and therapeutic target in the management of breast cancer.

The G-protein-coupled estrogen receptor (GPER; G-protein-coupled estrogen receptor 30, also known as GPR30) is a novel estrogen receptor and has emerged as a promising target for ovarian cancer. GPER, a seven-transmembrane receptor, suppresses cellular viability and migration in studied ovarian cancer cells. However, its impact on the fallopian tube, which is the potential origin of high-grade serous (HGSC) ovarian cancer, has not been addressed. This study was conducted to evaluate the relationship of GPER, ovarian cancer subtypes, i.e., high-grade serous cell lines (OV90 and OVCAR420), as well as the cell type that is the potential origin of HGSC ovarian cancer (i.e., the fallopian tube cell line FT190). The selective ligand assessed here is the agonist G-1, which was utilized in an in vitro study to characterize its effects on cellular viability and migration. As a result, this study has addressed the effect of a specific GPER agonist on cell viability, providing a better understanding of the effects of this compound on our diverse group of studied cell lines. Strikingly, attenuated cell proliferation and migration behaviors were observed in the presence of G-1. Thus, our in vitro study reveals the impact of the origin of HGSC ovarian cancers and highlights the GPER agonist G-1 as a potential therapy for ovarian cancer.

Background: Breast cancer (BC) has the highest morbidity rate and the second-highest mortality rate of all cancers among women. Recently, multi-cancer genome profiling (multi-CGP) tests have become clinically available. In this study, we aimed to clarify the significance of multi-CGP testing of BC by using the large clinical dataset from The Center for Cancer Genomics and Advanced Therapeutics (C-CAT) profiling database in Japan. Materials and Methods: A total of 3744 BC cases were extracted from the C-CAT database, which enrolled 60,250 patients between June 2019 and October 2023. Of the 3744 BC cases, a total of 3326 cases for which the C-CAT included information on ER, PR, and HER2 status were classified into four subtypes, including TNBC, HR+/HER2-, HR+/HER2+, and HR-/HER2+. Comparisons between groups were performed by the χ2 test or Fisher\'s exact test using EZR. Kaplan-Meier curves were created using the log-rank test. Results: Of all 3326 cases analyzed, 1114 (33.5%) were TNBC cases, HR+/HER2- accounted for 1787 cases (53.7%), HR+/HER2+ for 260 cases (7.8%), and HR-/HER2+ for 165 cases (5.0%). Genetic abnormalities were most frequently detected in TP53 (58.0%), PIK3CA (35.5%), MYC (18.7%), FGF19 (15.5%), and GATA3 (15.1%) across all BCs. The rate of TMB-High was 12.3%, and the rate of MSI-High was 0.3%, in all BC cases. Therapeutic drugs were proposed for patients with mutations in six genes: PIK3CA, ERBB2, PTEN, FGFR1, ESR1, and AKT1. The prognoses of HR+/HER2- cases were significantly (p = 0.044) better in the treated group than in the untreated group. Conclusions: These findings suggest that cancer gene panel testing is useful for HR+/HER2- cases.

Biomarkers such as hormone receptors (HR) and human epidermal growth factor receptor2 (HER2) may change after neoadjuvant chemotherapy (NAC) in breast cancer patients. The aim of this study was to investigate the rates of receptor change after NAC and to evaluate the prognostic impact of change. Patients with breast cancer who received NAC were included in the study. Changes in pathological findings (ER, PR, HER-2, Ki-67, grade) before and after NAC were examined. In addition, the effect of receptor exchange on prognosis was evaluated. Kaplan Meier analysis was used for survival analyses. Study was approved by Ethics Board of Tepecik Training and Research Hospital (Decision number 2021/10-02). We confirm that all methods were performed in accordance with relevant named guidelines and regulations. The study included 203 female patients. When pathological findings before and after NAC were compared, significant regression was found in grade and Ki-67 values (p = 0.003, p < 0.001). ER change rate was 11.8%, PR change rate was 24.6% and HER-2 change rate was 12.5%. No significant correlation was found between ER, PR and HER-2 changes and prognosis. The pathological T stage after NAC being 1 or 2, no lymph nodes detected, and the tumor grade being 1 or 2 were independent variables related to survival (p: 0.002, p: 0.014, p < 0.001). In patients with breast cancer, it would be appropriate to re-evaluate the HER-2 and HR status of the surgical specimen following NAC, especially in initially negative patients. The correlation of receptor discordance with prognosis is not clear and more extensive studies are needed.