| 【Background and objective】Breast cancer is one of the biggest threats to women’s health in the world.In China,it has become the second most common cancer after lung cancer,accounting for 16.72 percent of malignancies in women.Although great progress has been made in diagnosis and treatment,patient outcomes have not met our expectations due to individual differences.Because of differences in molecular genetics,breast cancer patients who respond differently to treatment have significantly different outcomes.Currently,the recognized molecular types of breast cancer include Luminal A,Luminal B,HER2-positive,and triple-negative breast cancer subtypes.Among them,there is a special type of breast cancer in Luminal B,namely triple-positive breast cancer(TPBC),which is immunohistochemically expressed as ER+/ PR + / HER2 + and any status of Ki-67,accounting for about 10% of breast cancer cases.Combinatorial therapies have improved patient outcomes in recent years,but triple-positive breast cancer still has the worst prognosis among luminal breast cancers,which may be related to heterogeneity within the tumor.Therefore,this study collected clinical and prognostic information from breast cancer patients and analyzed the clinicopathological characteristics,treatment and prognosis of TPBC versus HR(+)and HER2(-)breast cancer patients,intending to reveal the clinicopathological characteristics and prognostic factors affecting triple-positive breast cancer(Part Ⅰ).The TNM prognostic staging system has long been used to evaluate the prognosis of breast cancer patients.In the 8th edition of the Prognostic Staging System,the U.S.Joint Committee on Cancer incorporated estrogen and progesterone receptors,human epidermal growth factor 2 expression status,and histological grading based on TNM staging,whose prognostic value and availability has been validated in breast cancer patients.However,the controversial nature of the new staging system,which may be due to an overabundance of groupings or interactions between factors,does not facilitate clinical application,and patient outcomes are frequently affected by a plethora of factors due to the heterogeneity of breast cancer.Therefore,a suitable predictive model for different molecular stages of breast cancer can benefit clinical practice.Nomogram is a common survival prediction method that combines intuition,accuracy,reliability,and utility,and such models have been successfully used for prognostic prediction of numerous malignancies,including breast cancer.Therefore,based on data from a single center in Northwest China and the SEER database in the United States,this study developed a Nomogram model to predict the overall survival of TPBC patients,aiming to provide clinicians with a decision support tool to optimize individualized treatment(Part Ⅱ).Part Ⅰ:1.To compare and analyze the differences in clinicopathological characteristics and treatments between the TPBC and control groups.2.To explore and analyze the factors affecting postoperative recurrence in domestic TPBC patients.Part Ⅱ:1.To comparatively analyze the differences in the clinical characteristics of domestic and foreign TPBC patients.2.To explore and identify independent risk factors for postoperative OS in TPBC.3.To construct an individualized prognostic nomogram model applicable to TPBC,and validate its predictive performance through internal and external validation.【Methods】Part Ⅰ:1.We retrospectively analyzed the clinicopathological characteristics,treatment and prognosis of TPBC and control groups admitted to Xijing Hospital for surgery between January 2013 and December 2017.2.Multivariate logistic regression was used to analyze the independent risk factors for lymph node metastasis in the TPBC group.3.The Kaplan-Meier method was used to analyze the overall survival of TPBC patients in the targeted and non-targeted treatment groups and the survival curves were plotted.4.The Cox risk ratio model was used to analyze the prognostic factors of TPBC patients by univariate and multivariate analysis.Part Ⅱ:1.Data for TPBC patients from January 2013 to December 2017 were extracted and screened from the SEER database and included in the training cohort,and TPBC patient data from Xijing Hospital for the same period were collected and included in the validation cohort.2.We retrospectively analyzed the clinicopathological characteristics,treatment,and prognosis of the training and validation cohort.3.The Cox risk ratio model was used to analyze the prognostic factors for OS in TPBC patients.4.Based on the independent prognostic factors of TPBC,we constructed the nomogram using the Rms and Survival packages in the R software.To confirm the predictive accuracy of the nomogram,we perform internal(Bootstrap=200 replicate sampling based on training cohort)and external validation.5.The decision curve analysis of the model was performed to test the clinical benefits and application value of the model.【Results】Part Ⅰ:1.Baseline analysis showed statistically significant differences(P<0.05)in the distribution of variables such as age,menopausal status,histological grade,tumor diameter,lymph node metastasis,whether chemotherapy was administered,Ki-67,and ER expression between the TPBC and control groups.2.Multivariate logistic regression analysis showed that tumor diameter(T>2 VS T≤2,OR=3.059,95% CI=1.662-5.632)and vascular invasion(OR=4.615,95% CI=1.509-14.111)were independent risk factors for lymph node metastasis in TPBC patients.3.The results of the Kaplan-Meier survival analysis showed that there was no statistically significant difference in the recurrence and survival rates of breast cancer between the two groups(P=0.52,P=0.5).Chemotherapy had a smaller effect on survival for breast cancer patients in both groups;endocrine therapy could significantly improve the survival rate of breast cancer patients in both groups(TPBC group: 59.0%-92.3%;control group: 72.1%-88.4%),but endocrine therapy had a higher degree of effect on the survival rate of the TPBC group.Targeted therapy has been shown to improve the prognosis of TPBC patients with high PR expression.4.Multivariate Cox analysis showed that lymph node metastasis(HR=3.425,95%CI=1.456-8.053),tumor diameter(2<T≤5 VS T≤2,HR=2.787,95% CI=1.226-6.335;T>5VS T≤2,HR=2.978,95% CI=0.845-10.492),endocrine therapy(HR=0.256,95%CI=0.111-0.590)were independent influencing factors of postoperative recurrence in TPBC patients.Part Ⅱ:1.Baseline analysis showed that patients in the validation cohort were statistically different in terms of age,histological grade,tumor size,lymph node metastasis,distant metastasis,and choice of treatment compared to the training cohort(P<0.05).2.The Kaplan-Meier survival analysis revealed that there was no statistical difference in the overall survival rate between the two groups of TPBC patients(P=0.53).3.Multivariate Cox analysis showed that age,radiotherapy,chemotherapy,tumor size,lymph node metastasis,distant metastasis,and surgical proximity were independent influences on postoperative OS in TPBC(See Figure 2-2 for details).4.The nomogram prediction model was constructed based on the seven variables screened,and the AUC was greater than 0.8 in both the training and validation sets,indicating that our model had excellent predictive performance in both internal validation and external validation.In addition,the calibration curve of the model was close to the ideal curve(the actual curve was always within the 95% CI of the calibration curve),indicating that there was an excellent agreement between the actual survival rate and the survival rate predicted by the nomogram.5.The predictive performance of the model was analyzed using decision curves and its net clinical benefit in predicting 3-year OS and 5-year OS improved within appropriate thresholds,indicating the superior clinical efficacy of the model.【Conclusion】1.The TPBC patients are younger,with obvious lymph node metastasis,severe vascular invasion and excessive expression of Ki67;compared with the United States,the age of onset of TPBC in China is younger and the tumor is more aggressive.2.Axillary lymph node metastasis and tumor diameter are independent risk factors for postoperative recurrence in TPBC patients,while endocrine therapy is a protective factor.3.This study is the first to incorporate an external validation cohort based on the construction of the TPBC nomogram prediction model.4.The constructed nomogram prognosis model is practically proven to have good predictive performance,which will help clinicians to make accurate evaluation and judgment of TPBC prognosis. |
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