No abstract

This study aimed to analyze and discuss the biomarkers of PEGylated liposomal doxorubicin (PLD) injection-induced hypersensitivity reactions (HSRs) in advanced breast cancer patients. Fourteen patients from Sun Yat-sen Memorial Hospital were included in the study between April 15th, 2020 and April 14th, 2021. Patient plasma was collected 30 min before PLD injection. HSRs were found to occur in a total of 9 patients (64.3%). No association was found between HSRs and various patient characteristics such as age, body surface area, anthracycline treatment history, IgE, and complement 3 and 4 (p > 0.05). Non-targeted metabolomics analysis of patient plasma was performed, and several metabolites showed significant association with HSRs. In particular, l-histidine (fold change = 91.5, p = 0.01) showed significantly higher levels in the immediate HSR group, while myristicin (fold change = 0.218, p = 0.003), urocanic acid (fold change = 0.193, p = 0.007), and d-aldose (fold change = 0.343, p = 0.003) showed significantly lower levels in the same group. In vivo experiments showed that exogenous histidine aggravated HSRs and increased IgE plasma levels in rats following the injection of PLD. Histidine can be decarboxylated to histamine by histidine decarboxylase. Histidine decarboxylase inhibitor 4-bromo-3-hydroxybenzoic acid improved symptoms and IgE levels in vivo. These findings suggested that l-histidine can be a potential biomarker for PLD-induced HSR. Moreover, an antihistamine drug, histidine decarboxylase inhibitor, or dietary histidine management could be used as potential preventive measures. Furthermore, metabolomics research could serve as a powerful method to explore biomarkers or uncover mechanisms of drug side effects.

Background: Pyrotinib (an irreversible tyrosine kinase inhibitor targeting EGFR, HER2, and HER4) plus capecitabine previously demonstrated a statistically significant improvement in progression-free survival (PFS) over placebo plus capecitabine for HER2-positive local relapsed or metastatic breast cancer after prior trastuzumab and taxanes in the interim analysis of the PHENIX trial (NCT02973737; Jiang Z et al. Oral presentation at ASCO 2019, Abstract 1001). It is shown that patients also benefit from subsequent pyrotinib monotherapy after progressed on capecitabine alone. Here we present an updated OS from a follow-up period with a median of 42.1 months. Methods: This PHENIX trial enrolled patients with HER2-positive local relapsed or metastatic breast cancer who had received prior trastuzumab and taxanes and up to two prior lines of chemotherapy for relapsed or metastatic disease. Eligible patients were randomized 2:1 to receive pyrotinib (400 mg orally once daily) in combination with capecitabine (1000 mg/m2 orally twice daily on days 1-14 for 21-day cycles; P+C group) or placebo plus capecitabine followed by pyrotinib monotherapy upon disease progression (C-P group). Randomization was stratified by the presence of visceral disease (yes vs. no) and the hormone receptor status (estrogen receptor [ER]- and/or progesterone receptor [PR]-positive vs. ER- and PR-negative). The primary endpoint was the independent review committee-assessed PFS. The data cutoff for the updated OS analysis was January 15, 2021. Results: A total of 279 eligible patients were randomized, with 185 to P+C group and 94 to C-P group. As of data cutoff, the median duration of follow-up was 41.7 months (95% CI 40.2-42.4) in P+C group and 43.1 months (95% CI 38.8-44.5) in C-P group. 71 out of 94 patients who progressed on placebo plus capecitabine received pyrotinib monotherapy as the first subsequent anti-cancer therapy according to protocol. Excluding the protocol prespecified pyrotinib monotherapy, 129 (69.7%) patients in the P+C group and 74 (78.7%) patients in the C-P group received anti-cancer therapy after discontinuing study treatment, and 107 (57.8%) patients and 61 (64.9%) patients received post-discontinuation anti-HER2 drugs, respectively. 98 (53.0%) of the 185 patients in P+C group and 59 (62.8%) of the 94 patients in C-P group died by the time of data cutoff. Kaplan-Meier estimated median OS was 34.9 months (95% CI 28.4-42.1) in P+C group and 23.6 months (95% CI 19.3-34.4) in C-P group (HR 0.74, 95% CI 0.54-1.02; p=0.068). The 2-year OS rate was 65.2% (95% CI 57.6%-71.8%) versus 48.9% (95% CI 38.1%-58.7%), respectively. Subgroup analyses of OS were generally consistent with the overall result (Table 1). Conclusion: The updated OS analysis highlighted the long-term efficacy of pyrotinib plus capecitabine in pretreated HER2-positive local relapsed or metastatic breast cancer. We did not observe a statistically significant difference in OS between pyrotinib plus capecitabine group and capecitabine group followed by subsequent pyrotinib monotherapy upon disease progression. Table 1.Subgroup analysis of OS.Pyrotinib plus capecitabine (n=185)Placebo plus capecitabine (n=94)HR (95% CI) *Brain metastasesPresentEvents14/21 (66.7)8/10 (80.0)Median OS22.9 (19.7-35.0)17.3 (1.6-34.4)0.77 (0.32-1.84)AbsentEvents84/164 (51.2)51/84 (60.7)Median OS36.7 (30.7-43.0)23.6 (21.5-40.4)0.72 (0.51-1.02)Previous chemotherapyNoneEvents29/60 (48.3)12/22 (54.5)Median OS37.5 (34.2-NA)32.6 (18.9-NA)0.75 (0.38-1.47)1 lineEvents34/70 (48.6)27/47 (57.4)Median OS35.6 (25.9-NA)31.6 (18.0-NA)0.73 (0.44-1.21)2 linesEvents30/44 (68.2)13/18 (72.2)Median OS21.1 (13.6-33.4)15.9 (5.4-44.0)0.77 (0.40-1.49)Data are n/N (%) or median (95% CI). NA, not available. *HRs are from unstratified analyses. Citation Format: Zefei Jiang, Min Yan, Li Bian, Tao Wang, Xichun Hu, Qingyuan Zhang, Quchang Ouyang, Jifeng Feng, Yongmei Yin, Tao Sun, Zhongsheng Tong, Xiaojia Wang, Herui Yao, Shuping Jiang, Xiaoyu Zhu, Jianjun Zou. Overall survival (OS) results from the phase III PHENIX trial of HER2+ metastatic breast cancer treated with pyrotinib plus capecitabine [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-05.