PURPOSE: Data about the clinical impact of human epidermal growth factor receptor 2 (HER2)–low expression in BRCA1/2 -mutated breast cancer (BC) are limited. This study aimed to clarify the clinical relevance of HER2-low in operable BRCA1/2 -mutated BC. MATERIALS AND METHODS: A total of 495 HER2-negative operable BC with germline BRCA1/2 pathogenic variants treated at our institute between October 2003 and September 2020 were included. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+/fluorescence in situ hybridization–negative, while HER2-zero as IHC 0. Tumor DNA from 25 BRCA1/2 -mutated triple-negative BCs (TNBCs) was subjected to whole-exome sequencing. RESULTS: Among the 186 BRCA1 carriers, 38.8% of TNBC (n = 121) and 52.3% of hormone receptor–positive/HER2-negative BC (n = 65) exhibited HER2-low tumors in the BRCA1 subgroup; among 309 BRCA2 carriers, 44.9% of TNBC (n = 49) and 68.1% of hormone receptor–positive/HER2-negative BC (n = 260) exhibited HER2-low tumors in the BRCA2 subgroup. After a median follow-up of 10.9 years (range, 1.23-19.8 years), among BRCA1 -mutated TNBC, HER2-low tumors were significantly associated with better recurrence-free survival (RFS; 10-year RFS: 90.3% v 75.1%; P = .015), distant recurrence-free survival (DRFS; 10-year DRFS: 92.4% v 76.5%; P = .010), and overall survival (OS; 10-year OS: 94.6% v 77.4%; P = .007) than HER2-zero tumors. However, the impact of HER2-low in survival was not observed either in BRCA2 -mutated TNBC or in BRCA1- and BRCA2 -mutated hormone receptor–positive/HER2-negative BC. Notably, BRCA1- mutated TNBC with HER2-low tumors showed higher homologous recombination deficiency scores than those with HER2-zero tumors. CONCLUSION: BRCA1 -mutated TNBC patients with HER2-low tumors have a significantly favorable survival, highlighting the possibility of stratifying these patients into two subgroups on the basis of HER2-low status.

Background/Objectives: Osteosarcoma exhibits bimodal age distribution with distinct clinical behaviors between pediatric and adult patients. Despite genomic evidence supporting age-related molecular heterogeneity, systematic transcriptomic characterization remains lacking. This study aimed to delineate age-associated transcriptional differences and develop a pediatric-specific prognostic signature. Methods: Bulk RNA sequencing was performed on tumor specimens from 70 osteosarcoma patients stratified into pediatric (≤14 years, n = 37), adolescent (15–18 years, n = 22), and adult (≥19 years, n = 11) groups. Differential expression, functional enrichment, and immune infiltration analyses were conducted. A pediatric-specific signature was validated in the TARGET-OS cohort (n = 87). Results: Pediatric osteosarcoma exhibited a hyperproliferative phenotype, enriched in E2F targets, G2M checkpoint, and DNA replication pathways. Adolescent tumors showed heightened immune–inflammatory signatures, while adult tumors activated osteogenic differentiation programs. Regarding the immune microenvironment, only adolescent tumors demonstrated active immune infiltration; pediatric and adult groups exhibited immunologically “cold” features. We identified a 10-gene pediatric-specific transcriptomic signature that declined with increasing age. High signature scores were significantly associated with inferior overall survival (hazard ratio [HR] = 5.6, 95% confidence interval [CI]: 1.2–26.2, p = 0.01) and progression-free survival (HR = 2.1, 95% CI: 1.1–4.2, p = 0.03). These findings showed concordant trends in the independent TARGET-OS cohort. Conclusions: Pediatric, adolescent, and adult osteosarcoma harbor distinct transcriptional profiles representing biologically different disease entities. The pediatric-specific 10-gene signature may serve as a clinically actionable biomarker for risk stratification and guide age-adapted therapeutic strategies.

Background/Objectives: Bone and soft tissue sarcomas frequently affect children, adolescents, and young adults, yet data on chemotherapy-related ovarian reserve decline in this population remain limited. We aimed to characterize anti-Müllerian hormone (AMH) dynamics during treatment and identify factors associated with post-neoadjuvant chemotherapy (post-NACT) ovarian reserve. Methods: We conducted a retrospective, single-center, longitudinal cohort study of 85 female patients with bone and soft tissue sarcoma who underwent serial serum AMH testing during treatment. In the paired cohort with complete baseline and post-NACT AMH measurements (n = 75), post-NACT AMH was defined as the value obtained at the surgery/post-neoadjuvant time point after completion of NACT. Log-transformed multivariable linear modeling and left-censored Tobit regression sensitivity analysis were performed. Results: Median AMH declined from 3.46 ng/mL at baseline to 0.39 ng/mL after the first NACT cycle and to 0.15 ng/mL after the second cycle, corresponding to reductions of 88.7% and 95.7%, respectively. In the paired cohort, median AMH declined from 3.81 ng/mL to 0.19 ng/mL post NACT, with a median absolute decline of 2.75 ng/mL and a median percent decline of 94.4%. In the log-transformed multivariable linear model, log(baseline AMH) was the sole independent predictor of log(post-NACT AMH) (β = 0.735, 95% CI 0.357–1.114, p < 0.001). In Tobit sensitivity analysis, 4 post-NACT AMH values were treated as left-censored at 0.05 ng/mL, and the pattern remained consistent. Conclusions: Ovarian reserve depletion in female sarcoma patients occurred predominantly within the first one to two cycles of NACT. These findings support early, individualized fertility preservation counseling in this population.

PURPOSE: The atlas of immune microenvironment at single-cell level in BRCA1/2 -mutated breast cancer is largely unknown and whether an immune signature on the basis of single-cell atlas is associated with response to neoadjuvant chemotherapy remains to be investigated. MATERIALS AND METHODS: The immune microenvironment between BRCA1/2 -mutated and BRCA wild-type breast tumors was explored using single-cell RNA sequencing (scRNA-seq) assay and was validated in an independent cohort of 40 BRCA1/2 carriers and 56 noncarriers via immunohistochemistry assay (IHC). Bulk RNA-seq was performed using RNA extracted from fresh-frozen pretreatment core-needle tumor tissues in 80 BRCA1/2 carriers with operable primary human epidermal growth factor receptor 2–negative tumors who received neoadjuvant chemotherapy, and the associations between immune cell subtypes defined by scRNA-seq and pathologic complete response (pCR) were investigated. RESULTS: BRCA1/2 -mutated tumors exhibited an enriched immune microenvironment compared with the wild-type counterparts at single-cell level, particularly regulatory T cells and exhausted T cells, which were validated in the IHC cohort. Among the neoadjuvant chemotherapy cohort of 80 BRCA1/2 carriers, 36.2% achieved a pCR. We established an immune signature on the basis of the single-cell and bulk RNA-seq data, named BRCA-IM. The BRCA-IM model exhibited an excellent prediction of pCR in the neoadjuvant chemotherapy cohort, with AUC values of 0.81(95% CI, 0.69 to 0.92) in the training set and 0.91(95% CI, 0.79 to 1.00) in the test set, respectively; and the BRCA-IM model remained as an independent predictor for pCR after adjusting for other factors. Moreover, higher BRCA-IM scores were significantly associated with more favorable survival in the neoadjuvant chemotherapy cohort. CONCLUSION: BRCA1/2 -mutated breast cancer shows an enriched tumor immune microenvironment, and the BRCA-IM model exhibits a good performance in prediction of pCR in BRCA1/2 -mutated tumors.