Pathological response and metabolites’ prognostic role in HER2-positive breast cancer treated with neoadjuvant pyrotinib, trastuzumab, nab-paclitaxel, and carboplatin: a single-arm phase II trial

The trial aimed to evaluate the efficacy and safety of pyrotinib in combination with trastuzumab, nab-paclitaxel, and carboplatin (TCbHPy) in the neoadjuvant setting (ChiCTR2100043523), as well as the role of metabolites in predicting the efficacy of neoadjuvant therapy (NAT). In this study, treatment-naive women with HER2-positive early or locally advanced breast cancer (II–III) were enrolled and received six neoadjuvant cycles of pyrotinib (400 mg) once daily, plus trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg), nab-paclitaxel (260 mg/m2), and carboplatin (area under the curve [AUC] = 6) every 3 weeks. Plasma samples from 26 patients were collected at baseline, and serum metabolites were analyzed based on liquid chromatography–mass spectrometry data. The primary endpoint was the total pathological complete response (tpCR; ypT0/is and ypN0) rate. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), breast pCR (bpCR; ypT0/is) rate, safety, and the predictive effect of metabolites on NAT. Among the 35 patients enrolled, the tpCR rate was 55.9% (19/34). For women with hormone receptor–negative and–positive tumors, the tpCR rates were 64.7% and 47.1% (P = 0.5034). The bpCR, ORR, and DCR were 61.8%, 91.2%, and 100.0%, respectively. The most common grade 3–4 adverse events were diarrhea (17.6%), vomiting (17.6%), and alopecia (11.8%), with 2 patients experiencing neutropenic fever. There were significant differences in plasma metabolic profiles between tpCR patients and non-tpCR patients at baseline. These differentially expressed metabolites were markedly enriched in the ABC transporter pathway. The area under the curve values for discriminating the tpCR and non-tPCR groups from the NAT of the single potential metabolite [spermidine and l-isoleucine] or combined panel of the two metabolites were greater than 0.875, implying that spermidine and l-isoleucine could be useful biomarkers for distinguishing between non-sensitive and sensitive individuals. Neoadjuvant TCbHPy is an effective and safe treatment option for HER2-positive breast cancer. Serum-metabolomics could be a powerful tool for exploring informative biomarkers for predicting efficacy, and facilitate the development of new treatment targets for insensitive patients. A randomized controlled trial is necessary to validate our findings.