向心型肥胖与双阴性乳腺癌相关

中国多中心大样本病例对照研究：

不同肥胖类型对乳腺癌的影响不同

　　肥胖是众所周知的乳腺癌风险因素，其风险可被某些方式部分减少，如改变生活方式、对高风险女性使用他莫昔芬等药物，然而长期用药会有副作用，而且他莫昔芬仅适用于乳腺癌细胞表面具有雌激素受体（雌激素受体阳性）的女性。雌激素受体阳性乳腺癌与雌激素受体阴性乳腺癌相比，肥胖的影响更大。对于激素受体阳性乳腺癌风险的药学干预，肥胖为考虑因素之一。肥胖通常采用体重指数（体重除以身高的平方）进行衡量，但是向心型肥胖（又称腹部型肥胖、中心型肥胖、内脏型肥胖）的体重指数可能正常，通常需要采用腰臀比（腰围与臀围的比值）进行衡量。体重指数和腰臀比对激素受体状态相关乳腺癌风险的影响不同，不过既往研究结果存在分歧。此外，中国女性的情况也不明确。根据既往研究，中国学者假设女性发生雌激素受体阳性型或雌激素受体阴性乳腺癌的风险可能随其身体脂肪分布情况而不同。

　　2017年9月14日，美国《肿瘤学家》在线发表山东大学第二医院、郑州大学河南省肿瘤医院、山西医科大学山西省肿瘤医院、吉林大学第一医院、河北医科大学第四医院、天津医科大学肿瘤医院、滨州医学院附属医院、中国医学科学院肿瘤医院、临沂市人民医院、北京大学人民医院、首都医科大学北京朝阳医院、北京大学第一医院、青岛大学附属医院、潍坊市中医院、青岛大学第二医院青岛市中心医院青岛市肿瘤医院、哈尔滨医科大学第二医院、中国医科大学第一医院、南京医科大学江苏省肿瘤医院、淄博市中心医院、烟台毓璜顶医院、山东大学山东省肿瘤医院、山东大学苏州研究院的研究报告，发现在肥胖女性中，向心型肥胖女性（脂肪主要堆积在腹部内脏）、全身型肥胖女性（脂肪分布在全身皮下）可能发展为不同亚型的乳腺癌，表明乳腺癌与肥胖之间的相关性可能比以前想象的更为复杂。

　　该多中心大样本病例对照研究于2012年6月～2013年6月从中国北方和东部地区11个省市21家医院共入组1439例确诊为乳腺癌的25～70岁汉族女性住院患者，其中1316例可知雌激素受体（ER）和孕激素受体（PR）状态。对照组从同一医院门诊定期体检的健康人群按1∶1随机抽取，要求年龄相似（±3岁）、随访时间相似（±2个月）、均确诊无乳腺癌（乳房体检、乳房超声扫描、乳房钼靶筛查结果均为阴性）。通过多元多重无条件逻辑回归分析，评定身材相关因素与受体状态相关乳腺癌风险之间的相关性。

　　结果发现：

• 体重指数、腰臀比与乳腺癌总风险成正比

• 体重指数与双阳性乳腺癌风险成正比，且有统计学意义

• 体重指数与双阴性乳腺癌风险成正比，但无统计学意义

• 腰臀比与双阴性乳腺癌风险成正比且不受体重指数影响

• 体重指数与绝经前女性双阳性乳腺癌风险成正比

• 体重指数与绝经前女性双阴性乳腺癌风险成正比

• 腰臀比与绝经前女性雌激素受体阳性乳腺癌风险成反比

• 腰臀比与绝经前女性双阴性乳腺癌风险成正比

• 腰臀比>0.85与绝经后女性双阴性乳腺癌风险增加有相关性

　　因此，虽然全身型和向心型肥胖均可增加乳腺癌风险，但是对特定亚型的影响不同：

• 反映全身型肥胖的体重指数，与双阳性亚型乳腺癌风险相关性更强，尤其绝经前女性（即体重指数高的女性，更有可能患雌激素受体阳性乳腺癌，尤其在绝经前）

• 反映向心型肥胖的腰臀比，对双阴性亚型乳腺癌风险更有特异性，尤其绝经后女性（即腰臀比较高的女性，更有可能患雌激素受体阴性乳腺癌，尤其在绝经后）

　　上述结果表明，全身型和向心型肥胖可能对不同的乳腺癌亚型发挥不同的作用，证实了该假说：肥胖除了通过雌激素，还通过复杂分子学相互作用影响乳腺癌发生的。上述结果还意味着对于不同肥胖类型女性，可能需要不同的化学预防策略，尤其需要注意体重指数正常但是腰臀比较高的向心型肥胖女性（即使体重指数不高，腰臀比较高的女性患雌激素受体阴性乳腺癌的风险也较高）。可能的原因是皮下脂肪参与雌激素生产，可能促进雌激素受体阳性乳腺癌，而内脏脂肪与胰岛素抵抗密切相关，因此更有可能促进雌激素受体阴性乳腺癌。因此，建议临床医生使用他莫昔芬防治乳腺癌之前，先对肥胖女性患雌激素受体阳性乳腺癌的风险进行评估。因为他莫昔芬无法防治雌激素受体阴性乳腺癌，所以腰臀比较高的女性可能无法获益。由于缺乏任何经过证实的雌激素受体阴性乳腺癌药学干预，对于这些个体可能建议采用更严格的体重控制措施。并且，建议对肥胖女性的其他乳腺癌风险因素（如胰岛素抵抗和炎症）的影响进行深入研究，开发预测高风险女性可能发生雌激素受体阳性还是雌激素受体阴性乳腺癌的工具。

　　此外，与黑人和白人女性相比，中国女性绝经前的体重指数高对乳腺癌并无预防作用，这可能有两个原因：首先，与西方女性相比，绝经前亚洲女性（包括中国女性）身体往往比较苗条，故脂肪量可能影响较大；其次，亚洲肥胖女性以内脏脂肪堆积居多，这与西方国家女性更容易有皮下脂肪堆积的情况大不相同。由此进一步确认了原来发现的亚裔、黑人、白人女性之间的差异。

相关阅读

Oncologist. 2017 Sep 14. [Epub ahead of print]

Distinct Effects of Body Mass Index and Waist/Hip Ratio on Risk of Breast Cancer by Joint Estrogen and Progestogen Receptor Status: Results from a Case-Control Study in Northern and Eastern China and Implications for Chemoprevention.

Fei Wang, Liyuan Liu, Shude Cui, Fuguo Tian, Zhimin Fan, Cuizhi Geng, Xuchen Cao, Zhenlin Yang, Xiang Wang, Hong Liang, Shu Wang, Hongchuan Jiang, Xuening Duan, Haibo Wang, Guolou Li, Qitang Wang, Jianguo Zhang, Feng Jin, Jinhai Tang, Liang Li, Shiguang Zhu, Wenshu Zuo, Zhongbing Ma, Fei Zhou, Lixiang Yu, Yujuan Xiang, Liang Li, Shuohao Shen, Zhigang Yu.

Second Hospital of Shandong University, Jinan, Shandong, China; Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, Henan, China; Shanxi Cancer Hospital, Taiyuan, Shanxi, China; First Hospital of Jilin University, Changchun, Jilin, China; Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China; Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; First Affiliated Hospital of Binzhou Medical University, Binzhou, Shandong, China; Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Linyi People's Hospital, Linyi, Shandong, China; Peking University People's Hospital, Beijing, China; Beijing Chaoyang Hospital, Beijing, China; Peking University First Hospital, Beijing, China; Qingdao University Affiliated Hospital, Qingdao, Shandong, China; Weifang Traditional Chinese Hospital, Weifang, Shandong, China; Second Affiliated Hospital of Qingdao Medical College, Qingdao Central Hospital, Qingdao, Shandong, China; Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu, Nanjing, Jiangsu, China; Zibo Central Hospital, Zibo, Shandong, China; Yantai Yuhuangding Hospital, Yantai, Shandong, China; Shandong Cancer Hospital, Jinan, Shandong, China; Suzhou Institute of Shandong University, Suzhou, Jiangsu, China.

BACKGROUND: Obesity is a consideration in the pharmacologic intervention for estrogen receptor (ER) positive (ER+) breast cancer risk. Body mass index (BMI) and waist/hip ratio (WHR) have demonstrated different effects on breast cancer risk in relation to estrogen receptor (ER) status, but the results have been inconsistent. Furthermore, the situation in Chinese women remains unclear.

MATERIALS AND METHODS: We conducted a case-control study including 1,439 breast cancer cases in Northern and Eastern China. Both ER and progesterone receptor (PR) statuses were available for 1,316 cases. Associations between body size-related factors and breast cancer risk defined by receptor status were assessed by multiple polytomous unconditional logistic regression analysis.

RESULTS: Body mass index and WHR were positively associated with overall breast cancer risk. Body mass index was positively associated with both ER+/PR positive (PR+) and ER negative (ER-)/PR negative(PR-) subtype risks, although only significantly for ER+/PR+ subtype. Waist-hip ratio was only positively correlated with ER-/PR- subtype risk, although independent of BMI. Body mass index was positively associated with risk of ER+/PR+ and ER-/PR- subtypes in premenopausal women, whereas WHR was inversely correlated with ER+/PR- and positively with ER-/PR- subtype risks. Among postmenopausal women, WHR >0.85 was associated with increased risk of ER-/PR- subtype.

CONCLUSIONS: Both general and central obesity contribute to breast cancer risk, with different effects on specific subtypes. General obesity, indicated by BMI, is more strongly associated with ER+/PR+ subtype, especially among premenopausal women, whereas central obesity, indicated by WHR, is more specific for ER-/PR- subtype, independent of menopausal status. These results suggest that different chemoprevention strategies may be appropriate in selected individuals.

IMPLICATIONS FOR PRACTICE: The results of this study suggest that general and central obesity may play different roles in different breast cancer subtypes, supporting the hypothesis that obesity affects breast carcinogenesis via complex molecular interconnections, beyond the impact of estrogens. The results also imply that different chemoprevention strategies may be appropriate for selected individuals, highlighting the need to be particularly aware of women with a high waist/hip ratio but normal body mass index. Given the lack of any proven pharmacologic intervention for estrogen receptor negative breast cancer, stricter weight-control measures may be advised in these individuals.

DOI: 10.1634/theoncologist.2017-0148