UNASSIGNED: Human epidermal growth factor receptor 2 (HER2) is a tumor biomarker with significant prognostic and therapeutic implications for invasive ductal breast carcinoma (IDC).
UNASSIGNED: This study aimed to explore the effectiveness of a multisequence magnetic resonance imaging (MRI)-based machine learning radiomics model in classifying the expression status of HER2, including HER2-positive, HER2-low, and HER2 completely negative (HER2-zero), among patients with IDC.
UNASSIGNED: A total of 402 female patients with IDC confirmed through surgical pathology were enrolled and subsequently divided into a training group (n = 250, center I) and a validation group (n = 152, center II). Radiomics features were extracted from the preoperative MRI. A simulated annealing algorithm was used for key feature selection. Two classification tasks were performed: task 1, the classification of HER2-positive vs. HER2-negative (HER2-low and HER2-zero), and task 2, the classification of HER2-low vs. HER2-zero. Logistic regression, random forest (RF), and support vector machine were conducted to establish radiomics models. The performance of the models was evaluated using the area under the curve (AUC) of the operating characteristics (ROC).
UNASSIGNED: In total, 4506 radiomics features were extracted from multisequence MRI. A radiomics model for prediction of expression state of HER2 was successfully developed. Among the three classification algorithms, RF achieved the highest performance in classifying HER2-positive from HER2-negative and HER2-low from HER2-zero, with AUC values of 0.777 and 0.731, respectively.
UNASSIGNED: Machine learning-based MRI radiomics may aid in the non-invasive prediction of the different expression status of HER2 in IDC.

OBJECTIVE: This study aimed to develop predictive models based on conventional magnetic resonance imaging (cMRI) and radiomics features for predicting human epidermal growth factor receptor 2 (HER2) status of breast cancer (BC) and compare their performance.
METHODS: A total of 287 patients with invasive BC in our hospital were retrospectively analyzed. All patients underwent preoperative breast MRI consisting of fat-suppressed T2-weighted imaging, axial dynamic contrast-enhanced MRI, and diffusion-weighted imaging sequences. From these sequences, radiomics features were derived. Three distinct models were established utilizing cMRI features, radiomics features, and a comprehensive model that amalgamated both. The predictive capabilities of these models were assessed using the receiver operating characteristic curve analysis. The comparative performance was then determined through the DeLong test and net reclassification improvement (NRI).
RESULTS: In a randomized split, the 287 patients with BC were allotted to either training (234; 46 HER2-zero, 107 HER2-low, 81 HER2-positive) or test (53; 8 HER2-zero, 27 HER2-low, 18 HER2-positive) at an 8:2 ratio. The mean area under the curve (AUCs) for cMRI, radiomics, and comprehensive models predicting HER2 status were 0.705, 0.819, and 0.859 in training set and 0.639, 0.797, and 0.842 in test set, respectively. DeLong\'s test indicated that the combined model\'s AUC surpassed the radiomics model significantly (p < 0.05). NRI analysis verified superiority of the combined model over the radiomics for BC HER2 prediction (NRI 25.0) in the test set.
CONCLUSIONS: The comprehensive model based on the combination of cMRI and radiomics features outperformed the single radiomics model in noninvasively predicting the three-tiered HER2 status in patients with BC.

Human epidermal growth factor receptor 2 has been a pivotal biomarker for gastric cancer treatment strategies for many years. However, more than a decade after the ToGA trial demonstrated the efficacy of trastuzumab in improving survival, the development of treatments targeting human epidermal growth factor receptor 2 remains challenging. Several large-scale clinical trials of tyrosine kinase inhibitors, non-trastuzumab anti-human epidermal growth factor receptor 2 antibodies, and antibody-drug conjugates have failed to meet the primary endpoints. The concept of trastuzumab beyond progression and the complexity of resistance mechanisms to anti-human epidermal growth factor receptor 2 therapy after trastuzumab treatment presented significant obstacles, leading to trastuzumab being the sole therapy for human epidermal growth factor receptor 2-positive gastric cancer for some time. Nevertheless, the landscape has shifted in recent years, especially since the introduction of the antibody-drug conjugate trastuzumab deruxtecan in 2020. This has rekindled the interest in developing treatments targeting human epidermal growth factor receptor 2 in gastric cancer.

Antibody-drug conjugates (ADCs) consist of monoclonal antibodies that target tumor cells and cytotoxic drugs linked through linkers. By leveraging antibodies\' targeting properties, ADCs deliver cytotoxic drugs into tumor cells via endocytosis after identifying the tumor antigen. This precise method aims to kill tumor cells selectively while minimizing harm to normal cells, offering safe and effective therapeutic benefits. Recent years have seen significant progress in antitumor treatment with ADC development, providing patients with new and potent treatment options. With over 300 ADCs explored for various tumor indications and some already approved for clinical use, challenges such as resistance due to factors like antigen expression, ADC processing, and payload have emerged. This review aims to outline the history of ADC development, their structure, mechanism of action, recent composition advancements, target selection, completed and ongoing clinical trials, resistance mechanisms, and intervention strategies. Additionally, it will delve into the potential of ADCs with novel markers, linkers, payloads, and innovative action mechanisms to enhance cancer treatment options. The evolution of ADCs has also led to the emergence of combination therapy as a new therapeutic approach to improve drug efficacy.

BACKGROUND: Due to cardiotoxicity concerns, the concurrent use of epirubicin and trastuzumab has not been fully studied. This study aimed to examine the cardiotoxicity and pathological complete response (pCR) rate associated with the concurrent regimens in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC).
METHODS: We conducted a systematic search for relevant literature in the NCBI/PubMed, the Cochrane database, and international conference abstracts for phase II or III randomized controlled trials between January 1, 2000, and February 28, 2021, focusing on the concurrent regimens in patients with HER2-positive EBC. To compare the risk of cardiotoxicity and the odds of the pCR rate, we performed linear meta-regression analyses to investigate the effects of multiple covariates.
RESULTS: We analyzed 7 neoadjuvant trials involving the concurrent use of epirubicin and trastuzumab with 1797 patients. The median cumulative dose of epirubicin used was 300 mg/m2, with a total of 96 reported adverse cardiac events. The concurrent regimens did not result in a significant increase in cardiotoxicity compared to nonconcurrent regimens (risk ratio [RR] = 1.18, 95% confidence interval [CI] = 0.68-2.05). Compared with nonconcurrent or non-anthracycline-containing regimens, concurrent regimens were associated with a significant increase in the pCR rate (odds ratio = 1.48, 95% CI = 1.04-2.12). The linear fixed-effects meta-regression analysis indicated that in trials including more patients with hormone receptor-positive EBC, the RR of cardiotoxicity significantly increased with concurrent regimens, and the pCR rate became less significant.
CONCLUSIONS: The combination of trastuzumab and a low dose of epirubicin positively impacted the pCR rate without a significant increase in cardiotoxicity. We recommend exploring concurrent regimens for HR-negative, HER2-positive tumors to enhance pCR rates, with caution advised for HR-positive tumors due to potential cardiotoxicity.

Extramammary Paget disease (EMPD) is a rare cutaneous intraepithelial adenocarcinoma, which is mostly distributed in areas with sweat gland cells and mainly occurs in the anogenital skin of women. The male genital tract involvement is extremely rare and often occurs with other malignant tumors. Paget\'s disease in the scrotum with sweat gland carcinoma is even rarer. In the first report of scrotal endocrine sweat gland carcinoma associated with Paget disease by Saidi et al. in 1997, no more than 50 cases have been reported in the relevant research worldwide. Early EMPD combined with sweat gland carcinoma is mainly surgical treatment, and there is no standard treatment plan for advanced EMPD with sweat gland carcinoma. Previous article has reported that chemotherapy such as paclitaxel, fluorouracil, platinum, and vinblastine and molecular targeted therapy based on the genetic test results of patients have certain efficacy. Here, we report a 79-year-old male case diagnosed with human epidermal growth factor receptor 2 (HER-2) overexpression, which was effectively controlled by chemotherapy and anti-HER-2 treatment such as pyrotinib.

Lung cancer is the most common malignant tumor and the second most common malignant tumor in terms of mortality in the world. Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. Currently, the first-line standard treatment for advanced NSCLC is immunotherapy and targeted therapy. Although these treatments prolong the survival of patients, acquired drug resistance is still inevitable. Antibody-drug conjugates (ADCs) are a new type of anti-tumor drug made by coupling cytotoxic payloads to specific monoclonal antibodies via linkers. Compared with chemotherapy drugs, ADCs have the advantages of accurate recognition, local release, and high patient tolerance. In recent years, they have shown good clinical benefits in the treatment of NSCLC. This article provides an overview of the mechanism of action of ADCs, clinical studies progress in advanced NSCLC, and existing problems and challenges.
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【中文题目：抗体偶联药物在非小细胞肺癌中的研究进展】 【中文摘要：肺癌是全球发病率第一位、病死率第二位的恶性肿瘤。非小细胞肺癌（non-small cell lung cancer, NSCLC）是最主要的肺癌病理分型。目前晚期NSCLC的一线标准治疗方案为免疫治疗、靶向治疗，虽然延长了患者的生存期，但获得性耐药仍是不可避免的。抗体偶联药物（antibody-drug conjugates, ADCs）是一类经由连接子将细胞毒性载荷与特异性单克隆抗体偶联制成的新型抗肿瘤药物，与化疗药物相比，ADCs具有精准识别、局部释放、患者耐受性高等优点，近年在NSCLC治疗方面显示出良好的临床获益。本文针对ADCs的作用机制、在晚期NSCLC中的临床研究进展以及存在的问题和挑战等方面进行概述。
】 【中文关键词：肺肿瘤；抗体偶联药物；人表皮生长因子受体2；人表皮生长因子受体3；滋养层细胞表面抗原2】.

Pyrotinib is a novel irreversible tyrosine kinase inhibitor that has shown efficacy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). This study explored the efficacy and safety of pyrotinib in the treatment of HER2-positive MBC patients in the real world.
From September 2018 to February 2022, 137 female patients with HER2-positive MBC treated in this center were enrolled in this study. The follow-up period ended on January 12, 2023. The primary endpoint of this study was progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), central nervous system (CNS)-PFS, CNS-ORR, CNS-CBR, CNS-DCR, and adverse event (AE) were the secondary endpoints.
The ORR, DCR and CBR were 41.98 % (55/131), 87.79 % (115/131) and 44.27 % (58/131) in this cohort, respectively. The median PFS for this cohort was 10.37 months [95 % confidence interval (CI): 9.205-11.535] and the median OS was 37.53 months (not reached). Univariate and multivariate analyses showed that trastuzumab sensitivity was an independent predictor of improved PFS [hazard ratio (HR): 0.579 (0.371-0.904, p=0.016)] and improved OS [0.410 (0.213-0.790, p=0.008)]. Patients treated with a pyrotinib-based regimen as second-line and third-or-post-line therapy had poorer PFS [second-line: 3.315 (1.832-6.000, p<0.001); third-or-post-line: 3.304 (1.749-6.243, p<0.001)] and OS [second-line: 4.631 (1.033-20.771, p=0.045); third-or-post-line: 5.738 (1.212-27.174, p=0.028)]. There were 38 brain metastases (BM) patients in this study, the CNS-mPFS [14.37 months (7.815-20.925) vs. 7.83 months (7.047-8.613), p=0.375] and mOS [not reached vs. 36.40 months (18.551-54.249), p=0.034] were better in brain radiotherapy (BRT) group than NBRT group. 18.98 % (26/137) of patients experienced grade 3 or higher diarrhea. No AE-related death was reported.
This study confirms the promising antitumor activity and acceptable safety of real-world pyrotinib-based regimens for the treatment of HER2-positive MBC patients, particularly those who are trastuzumab-sensitive and who are receiving pyrotinib-based regimens as advanced first-line therapy. It has also been demonstrated that these regimens combined with BRT, provide better intracranial responses and long-term survival benefits for these patients with BM.

BACKGROUND: Li-Fraumeni syndrome (LFS), a hereditary condition attributed to TP53 pathogenic variants,(PV), is associated with high risks for various malignant tumors, including breast cancer. Notably, individuals harboring TP53 PVs are more likely (67-83%) to develop HER2 + breast cancer than noncarriers (16-25%). In this retrospective study, we evaluated the associations between TP53 variants and breast cancer phenotype.
METHODS: We conducted a retrospective review of the medical records of patients with LFS treated at a single institution and reviewed the literature on TP53 functions and the mechanisms underlying HER2 + breast cancer development in LFS.
RESULTS: We analyzed data for 10 patients with LFS from 8 families. The median age at the onset of the first tumor was 35.5 years. Only case 2 met the classic criteria; this patient harbored a nonsense variant, whereas the other patients carried missense variants. We observed that 9 of 10 patients developed breast cancer. Immunohistochemical analyses revealed that 40% of breast cancers in patients with LFS were HR - /HER2 + . The median age at the onset of breast cancer was slightly younger in HR - /HER2 + tumors than in HR + /HER2 -  tumors (31 years and 35.5 years, respectively).
CONCLUSIONS: The occurrence of HER2 + breast cancer subtype was 40% in our LFS case series, which is greater than that in the general population (16-25%). Some TP53 PVs may facilitate HER2-derived oncogenesis in breast cancer. However, further studies with larger sample sizes are warranted to clarify the oncogenic mechanisms underlying each subtype of breast cancer in TP53 PV carriers.

OBJECTIVE: Over 50% of breast cancer cases are \"Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)\", characterized by HER2 immunohistochemistry (IHC) scores of 1+ or 2+ alongside no amplification on fluorescence in situ hybridization (FISH) testing. The development of new anti-HER2 antibody-drug conjugates (ADCs) for treating HER2-low breast cancers illustrates the importance of accurately assessing HER2 status, particularly HER2-low breast cancer. In this study we evaluated the performance of a deep-learning (DL) model for the assessment of HER2, including an assessment of the causes of discordances of HER2-Null between a pathologist and the DL model. We specifically focussed on aligning the DL model rules with the ASCO/CAP guidelines, including stained cells\' staining intensity and completeness of membrane staining.
RESULTS: We trained a DL model on a multicentric cohort of breast cancer cases with HER2-IHC scores (n = 299). The model was validated on two independent multicentric validation cohorts (n = 369 and n = 92), with all cases reviewed by three senior breast pathologists. All cases underwent a thorough review by three senior breast pathologists, with the ground truth determined by a majority consensus on the final HER2 score among the pathologists. In total, 760 breast cancer cases were utilized throughout the training and validation phases of the study. The model\'s concordance with the ground truth (ICC = 0.77 [0.68-0.83]; Fisher P = 1.32e-10) is higher than the average agreement among the three senior pathologists (ICC = 0.45 [0.17-0.65]; Fisher P = 2e-3). In the two validation cohorts, the DL model identifies 95% [93% - 98%] and 97% [91% - 100%] of HER2-low and HER2-positive tumours, respectively. Discordant results were characterized by morphological features such as extended fibrosis, a high number of tumour-infiltrating lymphocytes, and necrosis, whilst some artefacts such as nonspecific background cytoplasmic stain in the cytoplasm of tumour cells also cause discrepancy.
CONCLUSIONS: Deep learning can support pathologists\' interpretation of difficult HER2-low cases. Morphological variables and some specific artefacts can cause discrepant HER2-scores between the pathologist and the DL model.