DataSheet_2_Relationship between metastasis and second primary cancers in women with breast cancer.xlsx

BackgroundBreast cancer (BC) survivors have an increased risk of developing second primary cancers (SPCs); however, it is still unclear if metastasis is a risk factor for developing SPCs. Usually, long-term cancer survivors face an increased risk of developing SPCs; however, less attention has been paid to SPCs in patients with metastatic cancer as the survival outcomes of the patients are greatly reduced.
MethodsA total of 17,077 American women diagnosed with breast cancer between 2010 and 2018 were identified from Surveillance, Epidemiology, and End Results (SEER) database and were included in the study. The clinical characteristics, standardized incidence ratio (SIR), standardized mortality ratio (SMR), and patterns of SPCs in BC patients with no metastasis, regional lymph node metastasis, and distant metastasis were investigated. Kaplan-Meier method was used to compare the prognosis of BC patients after developing SPCs with different metastatic status. XGBoost, a high-precision machine learning algorithm, was used to create a prediction model to estimate the prognosis of metastatic breast cancer (MBC) patients with SPCs.
ResultsThe results reveal that the SIR (1.01; 95% CI, 0.99–1.03, p>0.05) of SPCs in non-metastasis breast cancer (NMBC) patients was similar to the general population. Further, patients with regional lymph node metastasis showed an 8% increased risk of SPCs (SIR=1.08, 95%CI, 1.05–1.11, p<0.05), and patients with distant metastasis had a 26% increased risk of SPCs (SIR=1.26, 95%CI, 1.16–1.37, p<0.05). The SIR of SPCs in all patients below the age of 40 was the highest, which decreased with age. Patients with poorly differentiated cancers, large tumor size, and late N stage had an increased risk of SPCs. However, an increase in SIR of SPCs was observed in distant MBC patients, even at the early T1 (SIR=1.60, 95% CI, 1.22–1.98, p<0.05) and N1 (SIR=1.27, 95% CI, 1.10–1.44, p<0.05) stage. An increase in the SIR of SPCs was observed in patients with triple-negative BC, and the SIR of SPC increased with metastasis development in BC patients with luminal A subtype. The peak of SPCs risk occurrence was earlier in MBC patients (4-6 months and 10 months) compared to NMBC patients (12 months). The effect of metastasis on the prognosis of SPCs patients was dependent on the type of SPCs. Meanwhile, the XGBoost model was created to predict the 3-year (AUC=0.873) and 5-year survival (AUC=0.918) of SPCs in MBC patients.
ConclusionsOur study provides novel insight into the impact of metastasis on SPCs in BC patients. Metastasis could promote the second primary tumorigenesis which further increased cancer-related deaths. Therefore, more attention should be paid to the occurrence of SPCs in MBC patients.

背景：乳腺癌（Breast cancer, BC）幸存者罹患第二原发癌（second primary cancers, SPCs）的风险升高，但目前仍不明确转移是否为罹患SPCs的危险因素。通常而言，长期癌症幸存者罹患SPCs的风险会升高，但由于转移性癌症患者的生存结局大幅下降，学界对这类患者的SPCs关注较少。
方法：本研究从监测、流行病学与最终结果（Surveillance, Epidemiology, and End Results, SEER）数据库中筛选出2010年至2018年间确诊的17077名美国女性乳腺癌患者作为研究对象。研究针对无转移、区域淋巴结转移及远处转移的乳腺癌患者，分别分析其临床特征、标准化发病率（standardized incidence ratio, SIR）、标准化死亡率（standardized mortality ratio, SMR）以及SPCs的发病模式。采用Kaplan-Meier法对比不同转移状态的乳腺癌患者罹患SPCs后的预后差异。此外，本研究采用高精度机器学习算法XGBoost构建预测模型，以评估伴SPCs的转移性乳腺癌（metastatic breast cancer, MBC）患者的预后情况。
结果：研究结果显示，非转移性乳腺癌（non-metastasis breast cancer, NMBC）患者的SPCs标准化发病率为1.01（95%置信区间：0.99~1.03，p>0.05），与普通人群无显著差异。区域淋巴结转移患者的SPCs发病风险升高8%（SIR=1.08，95%CI：1.05~1.11，p<0.05），而远处转移患者的SPCs发病风险升高26%（SIR=1.26，95%CI：1.16~1.37，p<0.05）。40岁以下所有患者的SPCs标准化发病率均为最高，且随年龄增长逐渐降低。肿瘤分化程度差、肿瘤体积大以及N分期较晚的患者，其SPCs发病风险均有所升高。值得注意的是，即使在早期T1（SIR=1.60，95%CI：1.22~1.98，p<0.05）和N1（SIR=1.27，95%CI：1.10~1.44，p<0.05）分期的远处转移性乳腺癌患者中，SPCs的标准化发病率仍出现升高。三阴性乳腺癌患者的SPCs标准化发病率同样升高，而管腔A型（Luminal A）亚型乳腺癌患者的SPCs发病风险随转移进展逐步升高。与非转移性乳腺癌患者（发病峰值出现在确诊后12个月）相比，转移性乳腺癌患者的SPCs发病峰值出现更早，分别为确诊后4~6个月及10个月。转移对SPCs患者预后的影响取决于SPCs的类型。同时，本研究构建的XGBoost模型可预测转移性乳腺癌伴SPCs患者的3年生存率（曲线下面积AUC=0.873）与5年生存率（AUC=0.918）。
结论：本研究为转移对乳腺癌患者SPCs的影响提供了全新的视角。转移可促进第二原发肿瘤的发生，进而进一步增加癌症相关死亡风险。因此，临床应更加关注转移性乳腺癌患者的SPCs发生情况。