Clinical Research Of Anthracyclines In Combination With Taxanes For Neoadjuvant Treatment In Patients With Breast Cancer

Objective Neoadjuvant therapy(NAT) has became a standard intervention for patients with conformed locally advanced breast cancer(LABC) and inflammatory breast cancer(IBC), In addition,this approach was introduced in operable BC with the initial aim to downstage the tumor for better loco-regional control and increased conservative surgery rate. Other very important advantages of NAT include the assessment of response to standard therapies and the ability to rapidly test novel agents that require in-vivo validation. Another important advantage of using NAC was an early identification of unresponsive tumors; that gives an opportunity to terminate the ineffective therapy and/or to switch to an alternative regimen. However, several important clinical questions remain unanswered, especially for the neoadjuvant chemotherapy platform,such as the chemotherapy protocol,the number of NCT cycles,timing of surgical treatment; meanwhile, it is not sure that if pathologic complete response(p CR) can be used as a surrogate marker of survival after neoadjuvant therapy for BC.In this paper, patients with confirmed BC received NCT,we aim to assess the efficacy and safety of Anthracyclines in combination with Taxanes(AT) regimen for neoadjuvant treatment of patients with BC; To analyze the predict values of p CR rates for paitent outcome, according to BC subtypes(luminal,Triple Negative and HER2-positive).Methods In this study, 416 patients with confirmed BC received neoadjuvant chemotherapy,the clinical and pathological characteristics of patients were collected. The primary endpoint was pathologic complete response(p CR) rates, the secondary endpoints were disease free survival(DFS),the objective response rates(ORR), adverse events(AE),overall survival(OS). Response Evaluation Criteria in Solid Tumors(RECIST1.1) was used to evaluate the clinical efficacy, Miller and Payne system was used to evaluate the pathologic response efficacy. Common Terminology Criteria for Adverse Events version(CTCAE)4.01 was used to evaluate the adverse reactions. NCT was given according to c NCCN guidelines. Statistical analysis All assigned patients were included in efficacy analyses,Categorical measures were compared by Fisher exact test or chi-square test,t test for measurement data. Univariate and logistic regression analyses of factors associated with p CR were performed. We calculated Kaplan-Meier curves and used these to estimate 3-year event-free survival rates and 95% CIs. Cox proportional hazards regression analysis was used to estimate HR sand 95% CIs. We also planned analysis of event-free survival(EFS) in key subsets of patients(according to hormone receptor status, clinical T status, clinical lymph nodal status, and achievement or not of pathological complete response in breast and lymph nodes tissue). Safety data were monitored throughout the study. All statistical analyses were done with the software SPSS(version 19.0).Results1.A total of 416 consecutive breast cancer patients confirmed by pathology were enrolled in this study. All of the enrolled patients received treatment and accessement.The median age was 46(22-73) year-old. According to molecular type, there’s 204 paitents in HR+/HER2- subtypes,55 paitents in HR+/HER2+ subtypes,65 paitents in HR-/HER2+ subtypes,91 paitents in HR-/HER2- subtypes. All patients were followed up, the follow up were 3 to 115 months, the median follow up was 40 months, 30 patients were lost to follow-up,and the dropout rate was 7.2%.2.In total,192 patients received AT regimen chemotherapy,the overall pathologic complete response(p CR) rate was 20.3%(39/192).The p CR rate was 8.5%(10/118)in patients of HR+/HER2- Subtype; 42.8%(6/8)in patients of HR-/HER2+Subtype;25%(5/20)in patents of HR+/HER2+ Subtype; 45%(18/40)in patients of HR-/HER2- Subtype. The logistic Regression revealed that ER status affected the p CR rates after neoadjuvant chemotherapy of the breast cancer.The dose limiting toxicities included: grade 3/4 neutropenia, grade 3/4 anemia, grade 3/4thrombocytopenia, and other grade 3 nonhematologic toxicity including bone pain,neuropathy, mucocitis etc. There were 182(94.7%) episodes of grade 3/4 neutropenia,2(1.4%) episodes of grade 3/4 anemia, and 1(1.9%) episodes of grade 3/4thrombocytopenia,12(29.8%) episodes of grade 2/3 emesis and there were 11(5.7%)episodes of cardiotoxicity.3.The p CR rates according to different breast cancer subgroups were analyzed. The overall pathologic complete response(p CR) rate was 23.1%(96/416). The p CR rate was 6.9%(14/204)in patients of HR+/HER2- Subtype; 41.5%(27/65)in patients of HR-/HER2+ Subtype;30.9%(17/55)in patents of HR+/HER2+ Subtype; 41.1%(37/91)in patients of HR-/HER2- Subtype. The correlation of the pathological status and the paitent outcome was analyzed.in total,compared with no p CR group, p CR group had significant higher disease free survival(DFS) rates(83.7% VS 93.8%,p=0.004);in HR+/HER2- Subtype,paitents who achievced p CR had a higher disease free survival(DFS) rates than that didn’t achievced p CR(88.6% VS 94.5%,p=0.287),but without significant difference. In HER2+ Subtype,paitents who achievced p CR had a higher disease free survival(DFS) rates than that didn’t achievced p CR(96.7% VS 81.6%,p=0.009),in HR-/HER2- Subtype,paitents who achievced p CR had a higher disease free survival(DFS) rates than that didn’t achievced p CR(89.7% VS 78.7%,log-rank p=0.055;Breslow p=0.045).4.The correlation of the characteristics, the clinical and pathological status of the tumor, and the outcome of the 416 paitents was analyzed. Univariate analysis revealed that: compared with T3/4 stage group, T1/2 stage group had a lower disease free survival(DFS) rates(71.9% VS 93.8%,p<0.001); compared with ER negative group,ER positive patients had significant higher disease free survival(DFS) rates(83.7%VS 93.8%,p=0.004);compared with Pg R negative group, Pg R positive patients had significant higher disease free survival(DFS) rates(85.5% VS 94.4%,p=0.018);paitents who didn’t achievced p CR had a lower disease free survival(DFS) rates than that achievced p CR(88.6% VS 94.5%,p=0.019); patients with HER2 positive(87.2%VS 90.9%,p=0.316)and N3 stage showed lower disease free survival(DFS) rates, but without significant difference. Multivariate analysis revealed that the risk of disease progression for patients with ER negative was more than the risk for patients with ER positive(HR=0.303, 95% CI, 0.167-0.551, P <0.001); the risk of disease progression for patients who didn’t achievced p CR after NCT was more than the risk for patients with p CR(HR=2.87, 95% CI, 1.32–6.25, P = 0.008); the risk of disease progression for patients with higher T stage(T3-4) was higher than the risk for patients with lower T stage(T0-2)(HR=0.250, 95% CI, 0.093-0.670, P =0.006). As a consequence, those results mean that ER status, p CR status,T stage were three independent prognostic factors for the outcome of BC.Conclusion1.Taxanes and Anthracyclines chemotherapy regimen for the treament of the patients with confirmed breast cancer show a better efficacy and safety, the demonstrated results justify the further use of this combination treatment in this patient population.2.The published results till now show that pCR rate varies significantly among different BC molecular sub-groups and greatly depends on pre-treatment tumor biological profile. So far, p CR was an established prognostic factor:reaching a p CR predicted improved survival in TNBC and HER2-enriched BC subgroup, while data remain controversial for the luminal subtypes. The results of this paper do not support the use of p CR as a surrogate end point of treatment efficacy in unselected patients with breast cancer submitted to neoadjuvant systemic therapy as the increase in p CR rate has not been clearly demonstrated to be associated with improved DFS and OS.3.Neoadjuvant therapy(NAT) is still a standard intervention for patients with locally advanced breast cancer(LABC) and operable BC. Through it is still no evidence that p CR be used as a ‘surrogate marker’ of treatment benefit,We believe that it can be a predictive factor of paitent outcome. Meanwhile, it may be considered as “surrogate marker” for accelerated drug registration in aggressive BC subtypes such as TN and HER2+ and exclusively in the neoadjuvant setting.Taken together, these data indicate that NAT may offer a valuable platform to advance personalized cancer medicine.