Background Recent evidence shows that inducing ferroptosis may improve efficacy of tumor therapy. However, ferroptosis-related genes have been little studied in patients with breast cancer especially in the neoadjuvant setting. ACSL4 and GPX4 have been well established as the positive and negative regulator of ferroptosis, respectively. This study aimed to explore the predictive value of ACSL4 and GPX4 for patients with breast cancer administered neoadjuvant chemotherapy. Methods This study included patients treated with paclitaxel-cisplatin-based neoadjuvant chemotherapy. Immunohistochemistry staining of ACSL4 and GPX4 was carried out on the core needle biopsy specimens. Logistic regression was performed to explore the predictive biomarkers of pathological complete response (pCR). Survival analyses were examined by log-rank test and Cox proportional hazard regression. Findings A total of 199 patients were included for the analyses. Both ACSL4 expression and ACSL4/GPX4 combination status could serve as independent predictive factors for pCR. The interaction for pCR was observed between ACSL4 and clinical tumor stage. Besides, ACSL4 expression, GPX4 expression, and their combination status were independent prognostic factors for disease-free survival. Analyses of the Kaplan-Meier Plotter database suggested that higher ACSL4 expression is related to better overall survival, and higher GPX4 expression is related to better distant metastasis-free survival. Pathway analyses revealed that ACSL4 and GPX4 might function in crucial pathways including apoptosis, autophagy, cell adhesion, lipid metabolism, etc . Interpretation This study revealed the critical value of ACSL4 and GPX4 serving as novel predictive and prognostic biomarkers for patients with breast cancer receiving neoadjuvant chemotherapy. It might be a novel strategy to induce ferroptosis to promote chemosensitivity. Future studies are required to elucidate the potential mechanisms. Funding This work was supported by Shanghai Natural Science Foundation [grant number 19ZR1431100], Clinical Research Plan of Shanghai Hospital Development Center [grant numbers SHDC2020CR3003A, 16CR3065B, and 12016231], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Youth Medical Talents - Specialist Program [grant number 2018-15], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Outstanding Youth Medical Talents [grant number 2018-16], Shanghai Collaborative Innovation Center for Translational Medicine [grant number TM201908], Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University [grant numbers YG2017QN49, ZH2018QNA42, and YG2019QNA28], Nurturing Fund of Renji Hospital [grant numbers PYMDT-002, PY2018-IIC-01, PY2018-III-15, and PYIII20-09], Science and Technology Commission of Shanghai Municipality [grant numbers 20DZ2201600 and 15JC1402700], and Shangha...
Purpose: Despite accumulating evidence on dual blockade of HER2 for locally advanced HER2-positive breast cancer, no robust evidence supports the addition of pyrotinib to trastuzumab in the neoadjuvant setting. The NeoATP trial aimed to evaluate the efficacy and safety of pyrotinib with neoadjuvant trastuzumab and chemotherapy. Patients and Methods: The phase II NeoATP trial included female patients with histologically confirmed stage IIA to IIIC and HER2-positive primary invasive breast cancer. Eligible patients received pyrotinib and trastuzumab with weekly paclitaxel–cisplatin neoadjuvant chemotherapy for four cycles. The primary endpoint was pathologic complete response (pCR; ypT0 ypN0) rate. Key secondary endpoints included locoregional pCR (ypT0/is ypN0) rate, biomarker analysis, and safety. Results: Among 53 enrolled patients (median age, 47 years; 73.58% stage III), 52 completed the study treatment and surgery. Overall, 37 patients (69.81%) achieved pCR. For women with hormone receptor–negative and –positive tumors, the pCR rates were 85.71% and 59.38% (P = 0.041), while the corresponding rates were 69.23% and 70.00%, respectively, for those with and without PIK3CA mutation (P = 0.958). The most frequently reported Grade 3 to 4 adverse events were diarrhea (45.28%), leukopenia (39.62%), and neutropenia (32.08%). No deaths occurred, and no left ventricular ejection fraction <50% or >10 points drop from baseline to before surgery was reported. Conclusions: The addition of pyrotinib to trastuzumab plus chemotherapy is an efficacious and safe regimen for patients with HER2-positive locally advanced breast cancer in the neoadjuvant setting. The randomized controlled clinical trial is warranted to validate our results.
Success in curing breast cancer largely depends on the stage at diagnosis. Circulating microRNAs are becoming a promising noninvasive biomarker. We postulate that a postoperative decline in circulating microRNAs might have diagnostic and prognostic value. Applying high-throughput microarrays, we screened the dysregulated microRNAs in paired serum samples before and after surgery. The relative concentrations of putative markers between the early breast cancer and cancer-free groups were evaluated in the training set and verified in the validation set. Sensitivity, specificity, and receiver operating characteristic (ROC) curves were used to assess diagnostic value. Survival analysis was performed using Kaplan–Meier estimates and a Cox proportional hazards model. Five microRNAs significantly reduced after surgery were selected for the training set. We found that miR-130b-5p, miR-151a-5p, miR-206, and miR-222-3p were significantly higher in the breast cancer group. Each of the four microRNAs had potential diagnostic value. The combined four microRNAs (training set: area under the curve (AUC) 0.8457; validation set: AUC 0.9309) had better diagnostic value than each single microRNA. MiR-222-3p was an independent prognostic factor for disease-free survival (HR = 13.19; 95% CI, 1.06–163.59; P = 0.045). Patients with no fewer than three highly expressed miRNAs had shorter DFS than patients with 0–2 highly expressed miRNAs (HR = 2.293; 95% CI, 1.128–0.662; P = 0.022). Our findings indicate that postoperatively downregulated circulating miR-130b-5p, miR-151a-5p, miR-206, and miR-222-3p may be potential biomarkers for breast cancer diagnosis and prognosis.
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