Long-term overall survival of patients who undergo breast-conserving therapy or mastectomy for early operable HER2-Positive breast cancer after preoperative systemic therapy: an observational cohort study.

Background: Understanding the survival outcomes associated with breast-conserving therapy (BCT) and mastectomy after preoperative systemic therapy (PST) enables clinicians to provide more personalized treatment recommendations. However, lack of firm survival benefit data limits the breast surgery choices of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who receive PST. We sought to determine whether BCT or mastectomy after PST for early operable HER2-positive breast cancer is associated with better long-term survival outcomes and determine the degree to which PST response affects this association. Methods: In this observational cohort study, we compared the long-term survival outcomes of BCT and mastectomy after PST for HER2-positive breast cancer and evaluated the impact of PST response on the relationship between breast surgery performed and survival outcomes. Our cohort included 625 patients with early operable HER2-positive breast cancer who received PST followed by BCT or mastectomy between January 1998 and October 2009. These patients also received standard postoperative radiation, trastuzumab, and endocrine therapy as indicated clinically. We used propensity score matching to assemble mastectomy and BCT cohorts with similar baseline characteristics and used Kaplan-Meier plots and Cox proportional hazards regression to detect associations between surgery types and outcomes. Furthermore, in this study, we analyzed the original data of 625 patients using the inverse probability of treatment weighting (IPTW) method to enhance the reliability of the comparison between the mastectomy and BCT cohorts by addressing potential confounding variables. Findings: Propensity score matching yielded cohorts of 221 patients who received BCT and 221 patients who underwent mastectomy. At the median follow-up time of 9.9 years, compared with BCT, mastectomy was associated with worse overall survival (hazard ratio, 1.66; 95% confidence interval [CI]: 1.08-2.57; P = 0.02). In patients who had axillary lymph node pathological complete response, mastectomy was associated with worse overall survival before matching (hazard ratio, 2.17; 95% CI: 1.22-3.86; P < 0.01) and after matching (hazard ratio, 2.12; 95% CI: 1.15-3.89; P = 0.02). Among patients with pathological complete response in the breast, the survival results did not differ significantly between BCT and mastectomy patients. IPTW method validated that BCT offers better overall survival in patients who had axillary lymph node pathological complete response. Interpretation: People with HER2-positive breast cancer who have already had PST are more likely to survive after BCT, especially if they get a pathological complete response in the axillary lymph nodes. These findings underscore the necessity for further investigation into how responses to PST can inform the choice of surgical intervention and the potential impact on overall survival. Such insights could lead to the development of innovative tools that support personalized surgical strategies in the management of breast cancer. Funding: This work was supported by grants from the Nantong Science and Technology Project (JCZ2022079), Nantong Health Commission Project (QA2021031, MSZ2023040) and National Natural Science Foundation of China (No. 82394430).

Tailoring Neoadjuvant Therapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Recent Advances and Strategies.

Neoadjuvant HER2 Therapy: Beyond one-size-fits-all.

Next-Generation HER2-Targeted Antibody-Drug Conjugates in Breast Cancer.

Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic payload, which is attached by a linker, forming the basic structure of an ADC. Novel combinations and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd. Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal dosing regimens, understanding resistance mechanisms, and identifying patient populations that would derive the most benefit from these treatments. These novel ADCs are at the forefront of a new era in targeted cancer therapy, holding the potential to improve outcomes for patients with HER2-positive and HER2-Low breast cancer.