Somatic mutations in a multigene panel and impact on prognosis based on TP53 status in Chinese HER2-positive patients undergoing neoadjuvant therapy: A single-institution retrospective cohort.

BACKGROUND: Gene mutations play a crucial role in the occurrence and development of tumors, particularly in breast cancer (BC). Neoadjuvant therapy (NAT) has shown greater clinical benefit in HER2-positive breast cancer. However, further clinical investigation is needed to fully understand the correlation between genetic mutations and NAT efficacy and the long-term prognosis in HER2-positive BC. METHODS: This was a retrospective cohort study of 222 patients receiving NAT between 2017 and 2021 in the Department of Breast Surgery of Fudan University Shanghai Cancer Center. Tumor samples from these patients were subjected to Next Generation Sequencing (NGS) to analyze mutations in 513 cancer-related genes. This study aimed to investigate the association between these genetic mutations and postoperative pathological complete response (pCR), as well as their impact on disease-free survival (DFS). RESULTS: In total, 48.65% patients reached pCR, ER-negative status (p < 0.001), PR-negative status (p < 0.001), Ki67 ≥ 20 (p = 0.011), and dual-targeted therapy (p < 0.001) were all associated with enhanced pCR rates. The frequency of somatic alterations in TP53 (60%), PIK3CA (15%), and ERBB2 (11%) was highest. In the HER2+/HR- cohort, patients who achieved pCR had a significant benefit in prognosis (HR = 3.049, p = 0.0498). KMT2C (p = 0.036) and TP53 (p = 0.037) mutations were significantly increased in patients with DFS events. Moreover, TP53 mutations had prognostic significance in HER2-positive BC patients with HR-negative (HR = 3.712, p = 0.027) and pCR (HR = 6.253, p = 0.027) status and who received herceptin-only targeted therapy (HR = 4.145, p = 0.011). CONCLUSIONS: The genetic mutation profiles of Chinese HER2+ patients who received NAT were discrepant with respect to HR status or DFS events. TP53 mutations have significant prognostic value in patients with NAT for HER2-positive BC and patients benefit differently depending on HR status, the neoadjuvant regimen and response, which highlights the significance of genetic factors in treatment customization based on individual genetic and clinical characteristics.

Invasive ductal carcinoma with coexisting ductal carcinoma in situ (IDC/DCIS) versus pure invasive ductal carcinoma (IDC): a comparison of clinicopathological characteristics, molecular subtypes, and clinical outcomes.

PURPOSE: Ductal carcinoma in situ (DCIS) is widely recognized as the precursor of invasive ductal carcinoma (IDC). We aimed to analyze the clinicopathological characteristics and clinical outcomes of coexisting DCIS component in IDC and its clinical significance according to molecular subtypes. METHODS: Data from 3001 patients with IDC (79.4%) and IDC/DCIS (20.6%) who underwent surgery from January 2009 to June 2016 were retrospectively assessed. The clinical outcomes of IDC with coexistent DCIS in different molecular subtypes were evaluated. RESULTS: IDC/DCIS patients were more likely to be younger (P < 0.001), had low tumor grade (P = 0.001), had less lymph node involvement (P = 0.038) and received more mastectomy (P = 0.002) than IDC patients. In the comparison of molecular subtype prevalence, IDC/DCIS patients were more frequently presented with luminal B/HER2 positive (12.5% vs 11.0%, P < 0.001) and HER2 positive subtypes (20.9% vs 9.8%, P < 0.001). The 5-year disease-free survival (DFS, 90.9% vs 87.5%, P = 0.021) and 5-year overall survival (OS 96.1% vs 94.0%, P = 0.018) were significantly improved in IDC/DCIS patients compared to IDC patients. In multivariate analysis, the presence of coexisting DCIS (P = 0.048), tumor size (P < 0.001), lymph node status (P < 0.001), lymphovascular invasion (P = 0.007) and molecular subtypes (P < 0.001) were independent prognostic factors for DFS. Furthermore, coexistence of DCIS component in IDC significantly improved DFS in HER2 positive (94.8% vs 78.5%, P = 0.003), but had no association in luminal and triple negative subtypes. CONCLUSIONS: IDC with coexisting DCIS was associated with improved prognosis. Patients with IDC/DCIS presented with more HER2 positive expression and might improve DFS in HER2 positive breast cancer.