Obesity and metabolic syndrome are associated with short-term endocrine therapy resistance in early ER plus breast cancer
Obesity and metabolic syndrome are associated with short-term endocrine therapy resistance in early ER plus breast cancer
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DOI：
10.1007/s10549-022-06794-y
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发表时间：
2022-11-17
影响因子：
3.8
通讯作者：
Rexer, Brent N.
中科院分区：
文献类型：
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作者：
Bergman, Riley;Berko, Yvonne A.;Rexer, Brent N.
体重指数（BMI）和代谢综合征（MS）升高与乳腺癌复发风险增加相关。这是由于固有的肿瘤生物学还是肥胖状态的可改变因素尚不完全清楚。方法采用BMI对751例患者的Oncotype DX复发评分进行分层，评估其与肿瘤内在复发风险的相关性。术前来曲唑治疗10-21天后，Ki67细胞增殖情况作为内分泌治疗反应的分层指标(sensitivity -ln(Ki67) < 1；intermediate-ln (Ki67) 1 - 2;resistance -ln(Ki67) > = 2)。回顾性收集143例患者手术时BMI和MS变量，分析治疗反应与BMI/MS的相关性。此外，通过磷酸化Akt和S6的免疫组织化学评估PI3K通路信号。结果BMI与复发评分无显著相关性（p = 0.99）， BMI组间风险评分分布相似。然而，BMI与短期内分泌治疗耐药相关，肥胖患者中中级和耐药肿瘤显著富集（55%,p = 0.0392）。同样，多发性硬化症患者发生内分泌治疗耐药肿瘤的相对风险高出1.4倍（p = 0.0197）。在评估PI3K通路介质时，我们发现具有3个或更多MS标准的患者有更多pAkt评分高于中位数的肿瘤（p = 0.0436）。S6的激活无显著性差异。结论肥胖/代谢综合征与乳腺癌复发之间的关系更能通过治疗反应来反映，而不是肿瘤的内在特性，表明干预逆转肥胖和/或MS可能改善乳腺癌复发的结果。
Purpose Increased body mass index (BMI) and metabolic syndrome (MS) are associated with increased breast cancer recurrence risk. Whether this is due to intrinsic tumor biology or modifiable factors of the obese state remains incompletely understood. Methods Oncotype DX Recurrence Scores of 751 patients were stratified by BMI to assess association with tumor-intrinsic recurrence risk. Cellular proliferation by Ki67 after 10-21 days of presurgical letrozole treatment was used to stratify endocrine therapy response (sensitive-ln(Ki67) < 1; intermediate-ln(Ki67)1-2; resistant-ln(Ki67) > = 2). BMI at the time of surgery and MS variables were collected retrospectively for 143 patients to analyze association between therapy response and BMI/MS. Additionally, PI3K pathway signaling was evaluated by immunohistochemistry of phosphorylated Akt and S6. Results There was no significant association between BMI and recurrence score (p = 0.99), and risk score distribution was similar across BMI groups. However, BMI was associated with short-term endocrine therapy resistance, with a significant enrichment of intermediate and resistant tumors in patients with obesity (55%, p = 0.0392). Similarly, the relative risk of an endocrine therapy-resistant tumor was 1.4-fold greater for patients with MS (p = 0.0197). In evaluating PI3K pathway mediators, we found patients with 3 or more MS criteria had more tumors with pAkt scores above the median (p = 0.0436). There were no significant differences in S6 activation. Conclusion Our findings suggest the association between obesity/metabolic syndrome and breast cancer recurrence is better reflected by response to treatment than tumor-intrinsic properties, suggesting interventions to reverse obesity and/or MS may improve outcomes for breast cancer recurrence.