neoadjuvant chemotherapy ( nct ) has emerged as the preferred initial treatment for patients diagnosed with locally advanced breast cancer . nct is administered to those with locally advanced breast cancer to make tumors more operable , to improve outcomes , and to predict treatment outcomes based on patient responses . the indications for nct have expanded to include patients with early breast cancer and prospective trials showing no survival disadvantage associated with the use of nct . the rate of the overall response to nct is high , which allows more patients to undergo breast conservation surgery ( bcs ) with better cosmetic outcomes . furthermore , bcs after nct does not increase ipsilateral breast tumor recurrence . in a significant number of patients , the relative ineffectiveness of nct in these patients may be associated with poor chemosensitivity of the tumor and to their clinicopathologic characteristics . accurate prediction of each patient s likelihood of achieving breast conservation after nct is important in establishing a treatment plan for patients with operable breast cancers . although many models and nomograms have been developed to predict the response of nct , these models were designed to predict the ability of nct in achieving a pathologic complete response ( pcr ) and not the ability of nct to achieve bcs [ 6 - 8 ] . we hypothesized that the efficacy of the current models could be improved by including clinical , imaging , and pathologic factors . we , therefore , formulated models that increased the accuracy in predicting the likelihood of achieving successful breast conservation and residual tumor size  3 cm in patients who receive nct . we reviewed the database of the seoul national university hospital breast care center ( snuhbcc ) to identify patients with stage ii / iii breast cancer who received nct followed by surgery from january 2001 to december 2010 . patients with inflammatory breast cancer , distant metastases at the time of diagnosis , and bilateral breast cancer were excluded . all patients were treated preoperatively with  anthracycline- and/or taxane - based regimen chemotherapy ( ac 6.2% , ac - t 2.5% , cyclophosphamide doxorubicin fluorouracil 1.8% , docetaxel doxorubicin 86.5% , paclitaxel gemcitabine trastuzumab 2.9% ) . tumor size before treatment and the distance between the nipple and the lesion were determined by breast magnetic resonance imaging ( mri ) . patients were considered estrogen receptor ( er) or progesterone receptor  positive if more than 10% of the cells were stained as positive by immunohistochemistry ( ihc ) . human epidermal growth factor receptor 2 ( her2 ) positivity was defined as either her2 gene amplification by fluorescent in situ hybridization or scored as 3 + by ihc . suspicious microcalcifications ( birads categorized into over c4a ) in the area of the lesion on mammography were considered positive for calcification . clinical and pathologic stages were assessed in accordance to the 7th edition of the american joint committee on cancer ( ajcc ) cancer staging system . we considered negative margin when there was no invasive ductal carcinoma and ductal carcinoma in situ ( dcis ) at the inked margin microscopically . nipple sacrifice was not considered as breast conservation and central lumpectomy cases were excluded for classifying the surgery type . a multivariate logistic regression analysis was used to test the associations between clinicopathologic characteristics ( including patient age , initial tumor size , er status , her2 overexpression , ki-67 level , p53 expression , breast volume , multifocality , multicentricity , distance from the nipple , presence of calcification , dcis component , size difference between mri and sonography , and histologic type ) and the ability to perform bcs and residual tumor size  3 cm after nct . these models were used to develop nomograms , which were built in a training cohort and validated in an independent validation cohort . discrimination was quantified with the concordance index ( c - index ) , which is identical to the area under the receiver operating characteristics ( roc ) curve . calibration was estimated by graphic representations of the relationships between observed outcome frequencies and predicted probabilities ( calibration curves ) for the groups of patients defined by quartiles ( each quartile included at least 35 patients ) . all statistical analyses were performed using spss ver . 19.0 software ( spss inc . , all p - values were two sided , and p < 0.05 was considered significant . we reviewed the database of the seoul national university hospital breast care center ( snuhbcc ) to identify patients with stage ii / iii breast cancer who received nct followed by surgery from january 2001 to december 2010 . patients with inflammatory breast cancer , distant metastases at the time of diagnosis , and bilateral breast cancer were excluded . all patients were treated preoperatively with  anthracycline- and/or taxane - based regimen chemotherapy ( ac 6.2% , ac - t 2.5% , cyclophosphamide doxorubicin fluorouracil 1.8% , docetaxel doxorubicin 86.5% , paclitaxel gemcitabine trastuzumab 2.9% ) . tumor size before treatment and the distance between the nipple and the lesion were determined by breast magnetic resonance imaging ( mri ) . patients were considered estrogen receptor ( er) or progesterone receptor  positive if more than 10% of the cells were stained as positive by immunohistochemistry ( ihc ) . human epidermal growth factor receptor 2 ( her2 ) positivity was defined as either her2 gene amplification by fluorescent in situ hybridization or scored as 3 + by ihc . suspicious microcalcifications ( birads categorized into over c4a ) in the area of the lesion on mammography were considered positive for calcification . clinical and pathologic stages were assessed in accordance to the 7th edition of the american joint committee on cancer ( ajcc ) cancer staging system . we considered negative margin when there was no invasive ductal carcinoma and ductal carcinoma in situ ( dcis ) at the inked margin microscopically . nipple sacrifice was not considered as breast conservation and central lumpectomy cases were excluded for classifying the surgery type . a multivariate logistic regression analysis was used to test the associations between clinicopathologic characteristics ( including patient age , initial tumor size , er status , her2 overexpression , ki-67 level , p53 expression , breast volume , multifocality , multicentricity , distance from the nipple , presence of calcification , dcis component , size difference between mri and sonography , and histologic type ) and the ability to perform bcs and residual tumor size  3 cm after nct . these models were used to develop nomograms , which were built in a training cohort and validated in an independent validation cohort . discrimination was quantified with the concordance index ( c - index ) , which is identical to the area under the receiver operating characteristics ( roc ) curve . calibration was estimated by graphic representations of the relationships between observed outcome frequencies and predicted probabilities ( calibration curves ) for the groups of patients defined by quartiles ( each quartile included at least 35 patients ) . all statistical analyses were performed using spss ver . 19.0 software ( spss inc . , all p - values were two sided , and p < 0.05 was considered significant . the median age was 42.4 years ( range , 24 to 67 years ) , and 54 patients ( 10.5% ) achieved pcr in response to nct . nct consisted of a mean 4.8 cycles of taxane and anthracycline - based preoperative chemotherapy . thirtyseven out of 513 patients ( 7.21% ) were observed to have a positive resection margin initially . smaller initial tumor size ( p < 0.001 ) , longer distance between the lesion and the nipple ( p < 0.001 ) , absence of suspicious calcifications on mammography ( p=0.013 ) , and absence of multicentric tumor ( p=0.015 ) were independently associated with bcs rather than mastectomy . tumor size after nct is an important and objective factor for considering breast conservation . in this cohort , the mastectomy rate in patients with tumors > 3 cm was 72.7% ; whereas the bcs rate in patients with tumors  3 cm was 63.2% ( p < 0.001 ) . before developing a predictive model , we excluded 94 patients with initial radiologic tumor size  3 cm . we analyzed the remaining 419 patients to determine the probability of residual tumor size  3 cm after nct . tables 3 shows the results from a multivariate logistic regression analysis ( appendix 2 ) . multivariate analysis showed that smaller initial tumor size ( p < 0.001 ) , absence of dcis component ( p < 0.001 ) , negative er status ( p=0.0023 ) , and higher ki-67 level ( > 15% ) ( p=0.0148 ) were independently associated with residual tumor size  3 cm . 2 ) . our nomograms predicting bcs and residual tumor size  3 cm were validated in an independent cohort of 149 breast cancer patients who underwent nct . patients were grouped into quartiles of predicted probabilities . to calibrate the nomogram , the actual proportions of patients who achieved bcs and residual tumor size the nomograms resulted in calibration plots , showing good agreement between the predicted and observed outcomes in most areas ( appendix 3 ) . the areas under the roc curves of the multivariate model predicting bcs and residual tumor size  3 cm were 0.800 ( 95% confidence interval [ ci ] , 0.769 to 0.844 ) and 0.777 ( 95% ci , 0.689 to 0.865 ) , respectively . the calibration plots showed a relatively good agreement between the predicted and actual probabilities ; however , the predictive probabilities of the third and fourth groups were a little higher and a little lower , respectively , than the actual probabilities of those groups ( appendix 4 ) . in comparing our nomograms with the previously developed mdacc nomograms , we found that our nomograms showed better performance in predicting bcs and tumor size  3 cm ( appendix 5 ) . however , it should be noted that we do not have information on the histologic grade of the core needle biopsy specimens . tables 2 shows the results of multivariate logistic regression analyses ( appendix 1 ) . smaller initial tumor size ( p < 0.001 ) , longer distance between the lesion and the nipple ( p < 0.001 ) , absence of suspicious calcifications on mammography ( p=0.013 ) , and absence of multicentric tumor ( p=0.015 ) were independently associated with bcs rather than mastectomy . tumor size after nct is an important and objective factor for considering breast conservation . in this cohort , the mastectomy rate in patients with tumors > 3 cm was 72.7% ; whereas the bcs rate in patients with tumors  3 cm was 63.2% ( p < 0.001 ) . before developing a predictive model , we excluded 94 patients with initial radiologic tumor size  3 cm . we analyzed the remaining 419 patients to determine the probability of residual tumor size  3 cm after nct . tables 3 shows the results from a multivariate logistic regression analysis ( appendix 2 ) . multivariate analysis showed that smaller initial tumor size ( p < 0.001 ) , absence of dcis component ( p < 0.001 ) , negative er status ( p=0.0023 ) , and higher ki-67 level ( > 15% ) ( p=0.0148 ) were independently associated with residual tumor size  3 cm . our nomograms predicting bcs and residual tumor size  3 cm were validated in an independent cohort of 149 breast cancer patients who underwent nct . patients were grouped into quartiles of predicted probabilities . to calibrate the nomogram , the actual proportions of patients who achieved bcs and residual tumor size the nomograms resulted in calibration plots , showing good agreement between the predicted and observed outcomes in most areas ( appendix 3 ) . the areas under the roc curves of the multivariate model predicting bcs and residual tumor size  3 cm were 0.800 ( 95% confidence interval [ ci ] , 0.769 to 0.844 ) and 0.777 ( 95% ci , 0.689 to 0.865 ) , respectively . the calibration plots showed a relatively good agreement between the predicted and actual probabilities ; however , the predictive probabilities of the third and fourth groups were a little higher and a little lower , respectively , than the actual probabilities of those groups ( appendix 4 ) . in comparing our nomograms with the previously developed mdacc nomograms , we found that our nomograms showed better performance in predicting bcs and tumor size  3 cm ( appendix 5 ) . however , it should be noted that we do not have information on the histologic grade of the core needle biopsy specimens . we have described here the development of nomograms predicting bcs and residual tumor size  3 cm in breast cancer patients receiving nct . after matching each factor to the appropriate point , the probability which responds to the total points is figured out . these models were validated in an independent patient set , and showed good performance in terms of discrimination and calibration , with some new factors predicting surgery and tumor response . these nomograms provided probability estimates that may be useful for individual patients , predicting tumor response to nct and bcs after nct . neoadjuvant therapy is administered to increase the likelihood of performing successful bcs on patients who are not or are borderline eligible for bcs prior to nct . our finding , in which 50.1% of patients underwent bcs after nct , was in agreement with the rates of 38%-68% reported in earlier studies , suggesting that predictive tools are necessary to assess the likelihood of bcs for patients treated with nct . furthermore , as management of breast cancer patients become more multidisciplinary , objective models in clinical settings are going to be necessary for both surgeons and oncologists , when predicting treatment outcomes . prior to the administration of nct for breast conservation , it is important to determine whether a patient has a low probability of becoming eligible for bcs . alternatively , nct could be offered after a patient is informed about the low probability of achieving bcs and provides informed consent . the mdacc nomograms were developed to determine the eligibility for bcs and to predict small residual tumor (  3 cm ) for patients receiving nct . clinicopathologic factors predicting bcs included the following : er status , tumor size and grade , multicentricity , and histological type ; whereas factors predicting tumor size  3 cm included er status , initial tumor diameter , histologic grade and type , and number of chemotherapy cycles . these nomograms were validated in an independent test set of 109 patients , with a c - index of 0.71 for predicting bcs eligibility , although decisions regarding mastectomy versus bcs were reported to be influenced more by subjective factors , such as regional and cultural attitudes than by clinical factors . therefore , new tools are needed that can predict which patient in clinical practice are eligible for nct for breast conserving purposes . we did not include a histologic grade as a predictive marker for nct , since the histologic grade in the core biopsy tends to underestimate the grade in the surgical specimen , due in part to the underestimation of the mitotic count . the agreement between core needle biopsy and surgical biopsy specimens for grade , mitosis , tubules , and pleomorphism was reported to be 61% . in practice , histologic grade of a presurgical biopsy specimen as a determinant for histologic grade of a surgical specimen may be subjective , dependent on individual pathologists , and our pathologist did not report information from needle biopsy specimens . the predictive factors of our two nomograms differed , which suggest that any decision of the type of surgery should depend on the surgeon 's judgment , not only on objective tumor size after nct . indeed , the nomogram for residual tumor size  3 cm includes greater biologic factors , including er status , ki-67 level , dcis component , and initial size , in agreement with previous models . furthermore , we found that achieving breast conservation and tumor size  3 cm were independent of the number of cycles of chemotherapy ( > 6 cycles vs.  6 cycles ) or regimen of chemotherapy ( including taxane or not ) . although we thought that the initial breast volume would be a predictive factor for breast conservation , we discovered that it was not significant . rather , the ability to conserve the nipple areola complex was more important for surgical decision making , since the distance between the nipple and the lesion was a significant factor for bcs . recently , mathieu et al .   reported that breast cancer index , which is a combination of the two - gene ratio hoxb13 : il17br(h:1 ) and the five - gene molecular grade index , was found to be clinically useful in identifying patients who are not candidates for bcs . in addition , they showed it was the only biologic predictor of bcs in their study . in the near future , some genetic factors predicting chemotherapeutic response or these risk stratifying genes will help our decision making in addition to our model combining clinical , pathological , and imaging variables . the study subjects did not receive homogeneous nct , and most of her2 positive patients did not received her2 targeted therapy ; thus , chemotherapy may be a confounding factor . we also did not consider whether bcs was possible before nct , and we did not distinguish between nct designed to reduce tumor size or preserve the breast . moreover , the retrospective nature of the study design made it difficult to obtain information concerning those subjective factors . in conclusion , we have established a new model to predict bcs and residual tumor size  3 cm after nct . this model had a better predictive accuracy than the previously similar models , including novel factors that can affect surgical decision making and tumor response . use of our nomograms can assist in surgical decision making for patients who are candidates for nct .
purposethe ability to accurately predict the likelihood of achieving breast conservation surgery ( bcs ) after neoadjuvant chemotherapy ( nct ) is important in deciding whether nct or surgery should be the first - line treatment in patients with operable breast cancers.materials and methodswe reviewed the data of 513 women , who had stage ii or iii breast cancer and received nct and surgery from a single institution . the ability of various clinicopathologic factors to predict the achievement of bcs and tumor size reduction to  3 cm was assessed . 
 nomograms were built and validated in an independent cohort.resultsbcs was performed in 50.1% of patients , with 42.2% of tumors reduced to  3 cm after nct . 
 a multivariate logistic regression analysis showed that smaller initial tumor size , longer distance between the lesion and the nipple , absence of suspicious calcifications on mammography , and a single tumor were associated with bcs rather than mastectomy ( p < 0.05 ) . 
 negative estrogen receptor , smaller initial tumor size , higher ki-67 level , and absence of in situ component were associated with residual tumor size  3 cm ( p < 0.05 ) . 
 two nomograms were developed using these factors . 
 the areas under the receiver operating characteristic curves for nomograms predicting bcs and residual tumor  3 cm were 0.800 and 0.777 , respectively . 
 the calibration plots showed good agreement between the predicted and actual probabilities.conclusionwe have established a model with novel factors that predicts bcs and residual tumor size after nct . 
 this model can help in making treatment decisions for patients who are candidates for nct .