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Background: Patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer with residual invasive disease after neoadjuvant systemic therapy have a high risk of recurrence and death. The primary analysis of KATHERINE, a phase 3, open-label trial, showed that the risk of invasive breast cancer or death was 50% lower with adjuvant trastuzumab emtansine (T-DM1) than with trastuzumab alone., Methods: We randomly assigned patients with HER2-positive early breast cancer with residual invasive disease in the breast or axilla after neoadjuvant systemic treatment with taxane-based chemotherapy and trastuzumab to receive T-DM1 or trastuzumab for 14 cycles. Here, we report the prespecified final analysis of invasive disease-free survival and the second interim analysis of overall survival., Results: With a median follow-up of 8.4 years, T-DM1 sustained the improvement in invasive disease-free survival over trastuzumab (unstratified hazard ratio for invasive disease or death, 0.54; 95% confidence interval [CI], 0.44 to 0.66). Seven-year invasive disease-free survival was 80.8% with T-DM1 and 67.1% with trastuzumab (difference, 13.7 percentage points). T-DM1 also led to a significantly lower risk of death than trastuzumab (unstratified hazard ratio, 0.66; 95% CI, 0.51 to 0.87; P = 0.003). Seven-year overall survival was 89.1% with T-DM1 and 84.4% with trastuzumab (difference, 4.7 percentage points). Adverse events of grade 3 or higher were noted in 26.1% of the patients in the T-DM1 group and 15.7% of those in the trastuzumab group., Conclusions: As compared with trastuzumab, T-DM1 improved overall survival with sustained improvement in invasive disease-free survival among patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy. (Funded by F. Hoffmann-La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472.)., (Copyright © 2025 Massachusetts Medical Society.)

Purpose: To investigate whether hormone receptor-positive, human epidermal growth factor receptor 2-low (HR+HER2-low) versus HR+HER2-zero early breast cancers have distinct genomic and clinical characteristics., Methods: This study included HR+, HER2-negative early breast cancers from patients enrolled in the phase III, randomized BIG 1-98 and SOFT clinical trials that had undergone tumor genomic sequencing. Tumors were classified HR+HER2-low if they had a centrally reviewed HER2 immunohistochemistry (IHC) score of 1+ or 2+ with negative in situ hybridization and HR+HER2-zero if they had an HER2 IHC score of 0., Results: A total of 1,795 tumors were evaluable for this study (BIG 1-98 n = 520, SOFT n = 1,275). The frequency of HER2-low tumors was 37% and 21% in the postmenopausal BIG 1-98 and premenopausal SOFT cohorts, respectively. There were no significant differences in clinicopathologic variables between HER2-low and HER2-zero groups which was consistent across both trials. There was no significant difference in risk of distant recurrence for patients with HER2-low tumors versus HER2-zero tumors (5-year % distant recurrence-free 94.0% v 92.8%, P = .61, in BIG 1-98; 89.4% v 92.7%, P = .31, in SOFT, respectively). Somatic genomic profiles were similar with the exception of MAP3K1 mutations which were more frequent in HER2-zero tumors (BIG 1-98 19% v 5%, SOFT 11% v 6%). Both ERBB2 copy number and ERBB2 gene expression abundance were significantly higher in HER2-low tumors compared with HER2-zero tumors; however, the absolute difference was small. Correlation between ERBB2 copy number values and gene expression was modest ( r = 0.17)., Conclusion: In two large clinical trials with centrally reviewed HER2 IHC, our findings do not support HER2-low breast cancer as a distinct clinical or biologic entity among HR+HER2- early breast cancers. Absolute differences in median ERBB2 copy number levels or gene expression are small and of unclear biologic relevance.

Purpose: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have shown promise in treating HER2 -amplified metastatic colorectal cancer (mCRC). Identifying optimal biomarkers for treatment decisions remains challenging. This study explores the potential of artificial intelligence (AI) in predicting treatment responses to trastuzumab plus pertuzumab (TP) in patients with HER2 -amplified mCRC from the phase II TRIUMPH trial., Materials and Methods: AI-powered HER2 quantification continuous score (QCS) and tumor microenvironment (TME) analysis were applied to the prescreening cohort (n = 143) and the TRIUMPH cohort (n = 30). AI analyzers determined the proportions of tumor cells (TCs) with HER2 staining intensity and the densities of various cells in TME, examining their associations with clinical outcomes of TP., Results: The AI-powered HER2 QCS for HER2 immunohistochemistry (IHC) achieved an accuracy of 86.7% against pathologist evaluations, with a 100% accuracy for HER2 IHC 3+ patients. Patients with ≥50% of TCs showing HER2 3+ staining intensity (AI-H3-high) exhibited significantly prolonged progression-free survival (PFS; median PFS, 4.4 v 1.4 months; hazard ratio [HR], 0.12 [95% CI, 0.04 to 0.38]) and overall survival (OS; median OS, 16.5 v 4.1 months; HR, 0.13 [95% CI, 0.05 to 0.38]) compared with the AI-H3-low (<50% group). Stratification among patients with AI-H3-high included TME-high (all lymphocyte, fibroblast, and macrophage densities in the cancer stroma above the median) and TME-low (anything below the median), showing a median PFS of 1.3 and 5.6 months for TME-high and TME-low respectively, with an HR of 0.04 (95% CI, 0.01 to 0.19) for AI-H3-high with TME-low compared with AI-H3-low., Conclusion: AI-powered HER2 QCS and TME analysis demonstrated potential in enhancing treatment response predictions in patients with HER2 -amplified mCRC undergoing TP therapy.

Biomarkers play a crucial role in the diagnosis, treatment planning, and prognosis of premalignant and malignant lesions and are increasingly used in neoplasia of the lower female genital tract (LFGT) including the cervix, vagina, and vulva. This review will discuss key biomarkers routinely used in LFGT pathology, including programmed cell death ligand 1 (PD-L1), mismatch repair (MMR), and tumor mutational burden (TMB) testing, which are FDA-approved companion diagnostics for anti-PD-1 checkpoint inhibitors. Recent developments in HER2 testing as a marker for anti-HER2 therapies, and prognostic biomarkers such as p53 in HPV-independent vulvar intraepithelial lesions and carcinomas, are also reviewed., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Everolimus was the first orally targeted therapy for certain cancers. It was introduced before CDK4/6 inhibitors and is widely used to treat advanced hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. This study presents comprehensive findings including updated data and long-term survival analyses focusing on patients with HR+/HER2- metastatic breast cancer who received everolimus-based treatment. The objectives were to assess the impact of everolimus on overall survival (OS) and progression-free survival (PFS) by treatment line, and to evaluate its role in therapeutic strategies in a real-world setting., Methods: We included 299 women aged over 20 years with histologically confirmed HR+/HER2- breast cancer who received everolimus-based treatment from multiple medical centers in Taiwan. Survival curves were generated using the Kaplan-Meier method, with the log-rank test for comparisons. Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events version 5.0., Results: The median PFS was 5.6 months, and the median OS was 60.1 months. Patients receiving everolimus treatment in three or more lines and those who underwent chemotherapy before everolimus-based treatment had a significantly shorter PFS but longer OS. Patients with liver and central nervous system metastases had significantly shorter PFS and OS. The disease control rate was 51.5%, and the overall response rate was 8.0%., Conclusion: These findings support current guidelines and advocate for the inclusion of everolimus in treatment plans for patients with metastatic HR+/HER2- breast cancer, particularly in late-line treatment, with careful consideration of the benefit-risk profile for each patient., Competing Interests: Conflicts of interest: Dr. Chun-Yu Liu and Dr. Ling-Ming Tseng, editorial board member at the Journal of the Chinese Medical Association , had no role in the peer review process or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)