BACKGROUND Chemo- and radiotherapy for breast cancer (BC) can lead to cardiotoxicity even years after the initial treatment. The pathophysiology behind these late cardiac effects is poorly understood. Therefore, we studied a large panel of biomarkers from different pathophysiological domains in long-term BC survivors, and compared these to matched controls. METHODS AND RESULTS In total 91 biomarkers were measured in 688 subjects: 342 BC survivors stratified either to treatment with chemotherapy ± radiotherapy (n = 170) or radiotherapy alone (n = 172) and matched controls. Mean age was 59 ± 9 years and 65 ± 8 years for women treated with chemotherapy ± radiotherapy and radiotherapy alone, respectively, with a mean time since treatment of 11 ± 5.5 years. No biomarkers were differentially expressed in survivors treated with radiotherapy alone vs. controls (P for all >0.1). In sharp contrast, a total of 19 biomarkers were elevated, relative to controls, in BC survivors treated with chemotherapy ± radiotherapy after correction for multiple comparisons (P <0.05 for all). Network analysis revealed upregulation of pathways relating to collagen degradation and activation of matrix metalloproteinases. Furthermore, several inflammatory biomarkers including growth differentiation factor 15, monocyte chemoattractant protein 1, chemokine (C-X-C motif) ligand 16, tumour necrosis factor super family member 13b and proprotein convertase subtilisin/kexin type 9, elevated in survivors treated with chemotherapy, showed an independent association with lower left ventricular ejection fraction. CONCLUSION Breast cancer survivors treated with chemotherapy ± radiotherapy show a distinct biomarker profile associated with mild cardiac dysfunction even 10 years after treatment. These results suggest that an ongoing pro-inflammatory state and activation of matrix metalloproteinases following initial treatment with chemotherapy might play a role in the observed cardiac dysfunction in late BC survivors.

中文翻译：

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与匹配的对照相比，经化学疗法治疗的早期乳腺癌的长期幸存者的特征在于促炎性生物标志物谱。

背景技术即使在最初治疗数年后，乳腺癌的化学疗法和放射疗法也可能导致心脏毒性。这些晚期心脏影响背后的病理生理学知之甚少。因此，我们研究了长期BC幸存者中来自不同病理生理学领域的大量生物标志物，并将其与匹配的对照进行了比较。方法和结果在688位受试者中总共测量了91个生物标志物：342名BC幸存者分层接受化学疗法±放射疗法（n = 170）或单独放射疗法（n = 172）和匹配的对照组。单独接受化疗±放疗和放疗的妇女的平均年龄分别为59±9岁和65±8岁，自治疗以来的平均时间为11±5.5岁。与单独放疗相比，在没有放疗的幸存者中没有生物标志物的差异表达。控件（对于所有> 0.1的控件均为P）。与之形成鲜明对比的是，经过多重校正校正后，接受化学疗法±放射疗法治疗的BC幸存者中，相对于对照，总共升高了19种生物标志物（全部P <0.05）。网络分析显示与胶原蛋白降解和基质金属蛋白酶激活有关的通路上调。此外，在用化学疗法治疗的幸存者中升高的几种炎症生物标记物（包括生长分化因子15，单核细胞趋化蛋白1，趋化因子（CXC基序）配体16，肿瘤坏死因子超家族成员13b和前蛋白酶转化酶枯草杆菌蛋白酶/ kexin 9型）升高。与左下室射血分数相关。结论化疗±放疗治疗的乳腺癌幸存者即使在治疗后10年也显示出与轻度心脏功能障碍相关的独特生物标志物特征。这些结果表明，化疗初期治疗后持续的促炎状态和基质金属蛋白酶的激活可能在晚期BC幸存者中观察到的心脏功能障碍中起作用。