This study aimed to examine the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and other clinicopathological features in HER2+ MBC patients who received first-line anti-HER2 therapy. A total of 129 patients were assigned to NLR-low and NLR-high groups based on a cutoff value of 3.0 at baseline. Peripheral blood lymphocyte subsets and gene mutations in circulating tumor DNA were analyzed by flow cytometry and Next-generation sequencing, respectively. Survival was evaluated by the Kaplan–Meier method and Cox regression analysis. Of the 129 patients, 77 and 52 were assigned to the NLR-low (≤3) and NLR-high (>3) groups, respectively. Compared with NLR-high patients, the NLR-low patients had significantly longer median progression-free survival (PFS) (11.7 vs. 7.7 months) (p = 0.001, HR = 2.703 95% CI 1.543–4.736 and overall survival (OS) (37.4 vs. 28.7 months) (p = 0.044, HR = 2.254 95% CI 1.024–4.924). Furthermore, this association was independent of metastatic sites or estrogen receptor status. Peripheral blood CD3+ (p = 0.034) and CD4+ (p = 0.010) T cell numbers were significantly higher in the NLR-low group than the NLR-high group. The mutational profile of MBC was generally similar between the two groups. Baseline NLR was a prognostic factor of PFS and OS for patients with HER2+ MBC in the first-line setting. These results may facilitate the selection of patients who will benefit most from anti-HER2 treatment.

Background: Janus kinase 2 (JAK2) mutation plays an important role in T cell immunity. However, the effect of JAK2 mutation on immunotherapy is largely uncharacterized. Methods: In this study, we analyzed the effect of JAK2 mutation on the efficacy and outcomes of immune checkpoint inhibitor (ICI) therapy in the discovery cohort (n = 662) and the verification cohort (n = 1423). Furthermore, we explored the association of JAK2 mutation with the tumor immune microenvironment in a multiomics cohort. Results: In the discovery cohort (n = 662), JAK2 mutant-type patients had a better objective response rate (58.8% vs. 26.7%, P = 0.010), durable clinical benefit (64.7% vs. 38.9%, P = 0.043), progression-free survival (hazard ratio [HR] = 0.431, P = 0.015), and overall survival (HR = 0.378, P = 0.025), relative to JAK2 wild-type patients. Moreover, we further verified the prognostic significance of JAK2 mutation in an independent ICI treatment cohort with a larger sample size (n = 1423). In addition, we discovered that the JAK2 mutation was remarkably related to increased immunogenicity, such as a higher TMB, higher expression of costimulatory molecules and stimulation of antigen processing mechanisms. In addition, JAK2 mutation was positively correlated with activated anticancer immunity, such as infiltration of various immune cells and higher expression of chemokines. Conclusion: Our study demonstrates that JAK2 mutation is a novel marker that can be used to effectively predict prognosis and response to ICI therapy.

We retrospectively analyzed consecutive patients with HER2-positive metastatic breast cancer who received T-DXd at a single Chinese cancer center between March 2023 and March 2026. Progression-free survival (PFS), overall survival (OS), systemic and intracranial response, safety, prognostic factors, and exploratory subsequent treatment strategies were assessed. Among 173 eligible patients, 80.3% had received prior HER2-directed TKIs and 41.6% had CNS metastases. After a median follow-up of 14.3 months, median PFS and OS were 14.1 and 31.1 months, respectively. The objective response rate was 54.5% among 154 patients with measurable systemic disease, while the CNS objective response rate was 46.3% among 67 patients with measurable CNS lesions. Among patients with measurable CNS lesions, the CNS-ORR was comparable between patients with and without peri-T-DXd local treatment (53.8% vs. 44.4%, p = 0.21). Greater prior treatment exposure was associated with shorter PFS, whereas HER2 IHC 3+ disease was independently associated with longer OS and showed a trend toward improved PFS compared with HER2 IHC 2+/FISH-positive disease. Interstitial lung disease occurred in 13 patients (7.5%), all grade 1–2. Among 148 patients included in the maintenance analysis, 23 switched to alternative maintenance regimens after initial benefit from T-DXd. In an exploratory analysis, no statistically significant differences in PFS or OS were observed between patients who continued T-DXd and those who switched to maintenance therapy. However, these findings require cautious interpretation because of immortal-time bias, selection bias, and limited sample size. T-DXd demonstrated clinically meaningful systemic and intracranial activity with manageable toxicity in this heavily pretreated real-world cohort.