| Background and aim:Anemia is a syndrome prevalent in patients with cancer. Previous findings indicated that anemia might be predictive of worse treatment outcomes of chemotherapy in breast cancer. However, most studies were performed in the adjuvant setting, where a direct evaluation of tumor responsiveness to chemotherapy was lacking. Neoadjuvant chemotherapy (NCT) administered prior to definitive surgical resection has become new paradigm for the clinical management of breast cancer. NCT presents itself as an optimal model of assessing treatment efficacy in vivo and identifying potential response-related clinical or biological factors. Whether or not baseline anemia could contribute to poor treatment outcomes in the neoadjuvant setting has yet to be elucidated. The present population-based study was to investigate the correlation of pretreatment anemia with pathological response and long-term prognosis of breast cancer patients receiving NCT.Methods:From January 1999 to December 2011, a total of 655 patients with operable or locally advanced breast cancer who underwent NCT at our institution before definitive surgery were reviewed. The patients were subdivided into anemic (baseline hemoglobin (Hb)<12.0g/dL) and non-anemic (Hb≥12.0g/dL) groups. Comparison was made between anemic and non-anemic groups concerning the rate of pathological complete response (pCR), relapse-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS). Logistic and Cox regression models were utilized to determine the predictive value of pretreatment anemia in outcomes of patients undergoing NCT.Results:166 women (25.3%) were anemic before treatment. A markedly lower pCR rate was observed in the anemic group (5.4% vs.11.7%; p=0.024). Patients in the anemic group were less likely to achieve pCR after NCT than their non-anemic counterparts (odds ratio (OR) 0.428,95% confidence interval (CI) 0.198-0.927, p=0.031). Age and estrogen receptor (ER) status were also predictive of response to NCT. Baseline Hb level as a continuous variable however, was not significantly associated with pathological response. Patients with baseline anemia displayed inferior 10-year RFS (59.1% vs 66.0%, p=0.022 by log-rank), OS (75.3% vs 90.9%, p<0.001) and CSS (82.4% vs 94.4%, p<0.001) compared with those without. After adjustment for confounders, pretreatment anemia was demonstrated to correlate with elevated risk of relapse (hazard ratio (HR) 1.453,95% CI 1.077-1.962, p=0.015), cancer-specific mortality (HR 2.961,95% CI 1.679-5.222, p<0.001) and all-cause mortality (HR 2.873,95% CI 1.757-4.699, p<0.001). When evaluated as a continuous variable, pretreatment Hb level was again proved to be a prognostic factor, with lower Hb concentrations related to inferior CSS (HR 0.979,95% CI 0.961-0.997, p=0.021) and OS (HR 0.977,95% CI 0.962-0.992, p=0.003).Conclusions:Pretreatment anemia was associated with compromised pathological response to NCT as well as survival status in breast cancer, presenting itself as both a predictive and a prognostic factor in breast cancer patients treated with NCT. Further studies are warranted to identify optimal interventions and improve the prognosis of this subgroup.Background and aim:Neoadjuvant chemotherapy (NCT) is the standard of care for locally advanced breast cancer and in recent years expanded use of NCT has been seen in operable early stage cases. It is well established that responders who achieve pathological complete remission after NCT have significantly improved outcomes compared with those whose diseases fail to respond or worse still progress on therapy, which provides rationale for identification of predictive biomarkers capable of distinguishing chemo-sensitive cases from insensitive ones. Circulating microRNAs (miRNAs) refer to miRNAs that are stably present in the body fluid such as serum/plasma, and research into circulating miRNAs as diagnostic, predictive, disease-monitoring and prognostic markers is on steady rise. The present study was aimed to specify the dynamic change in the levels of plasma miRNAs during NCT and explore the association of miRNA dynamics with response to NCT, so as to identify potential biomarkers predictive of chemo-sensitivity early in the treatment.Methods:109 patients with operable or locally advanced breast cancer, who participated in a prospective randomized clinical trial exploring the optimal NCT regimens in different intrinsic subtypes, were enrolled in the current study. The patients were treated with four to six courses of ET regimen (epirubicin and paclitaxel) in the neoadjuvant setting before definitive surgery. According to the status of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) three subtypes were defined including HR+/HER2-, HER2+and triple-negative breast cancer (TNBC) groups, and research was conducted prospectively within these subtypes. As per predesigned schedule, blood samples were collected at baseline, after two cycles of chemotherapy (C2) and before surgery, all of which were assayed for levels of plasma miRNAs. Based on their clinical response the patients were defined as chemo-sensitive (with complete/partial remission) or insensitive (with stable/progressive disease). First, blood samples of selected cases from both groups were screened via TaqMan miRNA array for candidate miRNAs whose fluctuation might reflect response. Afterwards all of the biospecimens were tested for the candidate miRNAs by quantitative real-time PCR. Finally logistic regression model was utilized to determine the predictive value of baseline/C2 expression status of these miRNAs.Results:31.2% of the study cohort was insensitive to NCT by our definition. TaqMan miRNA array revealed two major patterns of change in plasma miRNAs which might relate to response. One pattern is that obvious discrepancy was present between sensitive and insensitive groups at baseline which further expanded along with cycles adding, and the other is that no apparent inter-group difference was observed pre-treatment yet the two groups exhibited chemo-induced contrary trends of change in the plasma miRNAs. In the HR+/HER2-subtype four miRNAs were validated including miR-222, miR-20a, miR-451 and miR-9. At baseline compared with the sensitive group, the insensitive group displayed a notably higher level of miR-222 (2.065-fold, p=0.047) which continued to increase after two courses of therapy (4.870-fold, p<0.001). For miR-20a, no significant inter-group difference was identified before chemotherapy (p=0.218), but up-regulation of miR-20a was detected in the C2 samples of insensitive group (C2 vs. baseline, 2.637-fold, p=0.008). Dynamics of plasma miR-451 demonstrated trends contrary to miR-20a, with down-regulation of miR-451 seen in the insensitive group (C2 vs. baseline, 0.762-fold, p=0.014). As for the sensitive group, the levels of candidate miRNAs remained relatively stable throughout treatment. Importantly, across all the three subtypes we consistently identified chemo-induced decrease in miR-34a levels in the insensitive patients. Finally, baseline miR-222 (OR=6.422, p=0.049), C2 miR-20a (OR=0.144, p=0.021) and C2 miR-451 (OR=8.213, p=0.012) expression were proved to be predictive of response to NCT in HR+/HER2- breast cancer.Conclusions:By dynamic evaluation of plasma miRNAs in breast cancer patients treated with NCT, we found that baseline miR-222 over-expression, C2 miR-20a up-regulation and C2 miR-451 down-regulation were predictors of chemo-sensitivity in HR+/HER2-breast cancer. Reduced expression of miR-34a was detected after chemotherapy in the insensitive patients, suggesting the association between C2 miR-34a and response to NCT.Background and aim:Research efforts have been dedicated to disclosing response predictors for neoadjuvant chemotherapy (NCT) in breast cancer for years only to result in inconsistent findings, which could be partially explained by the limited predictive capacity of single covariate. A valid solution might be to construct a multivariate model which takes into account multiple potential predictors. In addition to common clinico-pathological factors, pre-treatment anemia is also demonstrated to be predictive of response to NCT. Biomarkers such as dynamics of plasma miRNAs are also correlated to outcomes after NCT as previously proved. Nomogram is a statistical tool which is utilized to calculate the possibility or risk of specific clinical outcomes for individuals. The present study aims to identify response-related clinical and biological covariates and build a nomogram to provide early prediction of the ultimate response and assess the probability of benefiting from NCT for a given patient.Methods:The current study enrolled a total of 149 patients.109 patients were participants of a prospective randomized clinical trial and treated with four to six courses of ET regimen (epirubicin and paclitaxel) for NCT, all of whom make up the training set. The other 40 patients who did not take part in the clinical trial stated above were also given NCT with ET regimen at our institution, and they constitute the validation set. The patients were defined as chemo-sensitive (complete/partial remission) or insensitive (stable/progressive disease) according to their clinical response. In the training set (n=109) data on clinico-pathological variables and C2 miR-34a expression was collected and screened for potential predictors of response, based on which a multivariate logistic model was constructed and a predictive nomogram was generated. The performance of the predictive model was evaluated with respect to discrimination (quantified by area under curve, AUC) and calibration and internally validated within the training set. Finally external validation was conducted independently in the validation set (n=40) to test the accuracy of the nomogram.Results:In the training set, considering both the statistical and the clinical significance of the covariates, we included baseline Ki-67, pre-treatment anemia, C2 miR-34a expression, HER2 status and clinical node stage in the final predictive model, and depicted a nomogram accordingly. The predictive accuracy of the nomogram was quantified in the training set. The model showed an AUC of 0.765. We performed internal validation with bootstrap sampling and the corrected AUC remained high (0.726) after bootstrapping. The calibration of the nomogram was good without apparent over- or under-prediction compared with the observed rates (Hosmer-Lemeshow test, p=0.835). The performance of the nomogram was then independently examined in the validation set. The AUC was 0.751. The predicted and observed proportions were largely concordant, indicating good calibration of the nomogram (p value for U statistics>0.99).Conclusions:In the current study we developed a nomogram based upon multiple clinical and biological covariates, which could provide early prediction of response to NCT. The nomogram can facilitate rapid assessment of individual benefit from NCT with ET regimen. Large multi-center studies are warranted to further confirm the validity of the nomogram in other series of patients. In the future the nomogram could be modified and optimized for therapy other than ET regimen. |
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