Ey Cho

Abstract P6-10-03: Does participation in clinical trials influence on survival in patients with metastatic breast cancer?

Background Recently, many clinical trials (TRIAL) especially incorporated with molecular-targeted agents are being conducted in treatment for breast cancer worldwide. However, the relation of participating clinical trials with survival has not been actively studied. This study was designed to evaluate whether participation in clinical trials could improve overall survival (OS) or not in patients with metastatic breast cancer (MBC), compared with conventional treatment. Method Korean Cancer Study Group (KCSG) has successfully established Nationwide Cohort in KOREA to conduct diachronic analysis (KCSG BR 14-07). Clinical data for patients with MBC were collected from this Cohort. OS was defined as the time duration from first diagnosis of metastasis to any cause of death. This work is supported by National Strategic Coordinating Center for Clinical Research (H110C2020). Results A total of 575 patients with metastatic breast from 26 institutes in KOREA cancer MBC were consequently enrolled between September 2014 and May 2015. 156 (27.1%) of patients were enrolled to at least one or more clinical trials and 419 patients received only conventional treatment (CONV). Age, hormone status, HER2 status, initial pathologic stage, metastasis versus recurrence, adjuvant treatment, ECOG performance status (PS) (0, 1 vs 2 or more) were similar between TRIAL and CONV. 30% of trials were associated with HER2-targeted agents. As initial treatment, chemotherapy was more frequently used in TRIAL (85.9%) than in CONV (79.0%) (P=0.038). Number of regimens of chemotherapy was greater in TRIAL (2.9+/-1.8) than CONV (2.1+/-1.6) (P Conclusion Participating in clinical trials could be associated with prolongation of survival. This results constantly maintained in HER2-positive and triple-negative MBC. These findings suggested that clinical trials are useful for the patients with MBC, even if the patients do not complete the standard treatment. Citation Format: Kim T-Y, Sohn JH, Kim S-B, Yoon JH, Kim GM, Lee KH, Koh S-J, Park YH, Lee SE, Chae Y, Lee KS, Lee KE, Won HS, Kim JH, Jeong J, Park KH, Cho EK, Im Y-H, Im S-A, Jung KH. Does participation in clinical trials influence on survival in patients with metastatic breast cancer?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-03.

Abstract P1-09-09: Role of endocrine therapy in premenopausal patients with hormone receptor-positive metastatic breast cancer, compared with postmenopausal patients: Diachronic analyses from nationwide cohort in Korea (KCSG BR 14-07)

Background Endocrine therapy (E) has a major role in treatment of hormone receptor (HR)-positive metastatic breast cancer (MBC). However, in contrast to western countries, premenopausal patients (PRE) more prevalent (50% of all breast cancer patients) and have less options of E than postmenopausal patients (POST) in Korea where the use of LHRH agonist in combination aromatase inhibitors (AIs) in PRE is restricted. Recently we have been successfully established nationwide cohort for the patients MBC (575 patients from 26 institutes). This study was designed to evaluate the role of E especially in PRE. Methods The patients with MBC were prospectively or retrospectively enrolled between September 2014 and May 2015. Only menopausal status-confirmed patients (296) were analyzed. Postmenopause was defined, based on NCCN guideline. Total duration of treatment was defined as the time from start day of any first treatment to end of any last treatment. Total duration of E was defined as the sum of time duration of each E. Overall survival was calculated from the start day of any treatment for MBC to any causes of death. This work is supported by National Strategic Coordinating Center for Clinical Research (H110C2020). Results A total of 296 patients with HR-positive MBC were analyzed [PRE, 169 (57.1%) and POST, 127 (42.9%)]. Except age (mean 44 and 60 years), baseline characteristics including in pathology, HER2 status, initial pathologic stage, de novo metastasis versus recurrence, surgery and adjuvant treatment (chemotherapy, endocrine therapy and radiotherapy) were well balanced. 92 (54.4%) of PRE and 77 (60.6%) of POST received at least one or more E through all treatment course. 41 (24.2%) of PRE and 44 (34.6%) received E as 1st-line treatment (p=0.034). Among PRE who received 1st-line of E, 30 (71.4%) and 9 (21.4%) of PRE received 2nd- and 3rd-line E. 20 (45.4%) and 10 (22.7%) of POST received 2nd- and 3rd- or more line of E. Most of PRE (54%) received tamoxifen+/-goserelin and 32% of PRE received AIs along with ovarian suppression. 71% of POST received AIs. As initial treatment, E was more frequently used in POST than in PRE (34.6% and 24.3%, p=0.053). Overall survival (OS) of all patients was 18.2 months (95% CI, 14.8-21.5). There was no difference in OS between PRE (17.8 months, 10.9-24.8) and POST (18.5 months, 95% CI, 13.2-23.9) (P=0.337). No difference of OS was observed (E, 18.1 moths, 95% CI, 13.0-23.3; chemotherapy 21.2 moths, 95% CI, 16.8-25.5), regardless of initial treatment. Total duration of treatment of PRE and POST were 15.2 and 13.6 months, respectively with no significant difference (p=0.389). PRE (8.3 moths, 95% CI,5.7-10.8) showed the trend toward longer duration of E in comparison with POST (5.5 moths, 95% CI,4.4-6.7), however the difference did not reach statistical significance (p=0.051). Conclusion E was more commonly used as 1st-line therapy in POST than in PRE. Although PRE had limited options of E, E was used in long duration of treatment especially in PRE. These findings suggested that E had a role in treatment for PRE with HR-positive MBC and could be used in treatment for PRE with good efficacy. Citation Format: Kim T-Y, Ahn J-H, Yoon JH, Sohn JH, Kim GM, Lee KH, Park YH, Koh S-J, Lee SE, Chae Y, Lee KS, Lee KE, Won HS, Kim JH, Jeong J, Park KH, Cho EK, Im Y-H, Im S-A, Jung KH. Role of endocrine therapy in premenopausal patients with hormone receptor-positive metastatic breast cancer, compared with postmenopausal patients: Diachronic analyses from nationwide cohort in Korea (KCSG BR 14-07). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-09-09.

Abstract P2-05-20: Validation and comparison of CS-IHC4 score with a nomogram based on Ki67 index, Adjuvant! Online, and St. Gallen risk stratification to predict recurrence in early Hormone Receptor (HR)-positive breast cancers

Background: Recently, the information in the IHC score was reported to be similar to that in the 21-gene Genomic Health recurrence score (GHI-RS). The aim of this study is to develop a nomogram based on Ki67 index to predict recurrence and to validate the nomogram by comparison with CS-IHC4 as well as Adjuvant! Online and St. Galen risk stratification. In addition, we validated our nomogram with external cohort. Methods: We retrospectively analyzed the clinicopathologic characteristics and outcomes of 1,070 postoperative HR-positive breast cancer patients between 2004 and 2007 at the Samsung Medical Center to determine recurrence-free survival (RFS). We constructed nomogram using Cox proportional hazard model and validated externally in a cohort of 1,028 at Seoul National University Hospital. A prognostic model that used classical variables, Adjuvant! Online, St. Gallen risk stratification, and the four IHC markers (IHC4 score) were created and assessed in our cohort by LR-χ2 test using the bootstrapping method. Results: Nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.70 (95% CI, 0.62–0.75) in the training set. The validation set showed a good discrimination with an AUC of 0.65 (95% CI, 0.58–0.72). In LR-χ2 test, the nomogram score was found to be more informative than the IHC4 with CS (LR-χ2 4.0539 [df1], 95% CI; 0.1038–8.004 for CS-IHC4 + nomogram score vs. CS-IHC4). Prognostic significance was more prominent in N1 diseases than in the others (LR-χ2 4.199, 95% CI; 1.496–6.902 for CS-IHC4 + nomogram score vs. CS-IHC4). However, Adjuvant! Online and St. Galen risk stratification did not show any definitive additional prognostic value. Conclusions: We developed and validated a nomogram based on Ki67 index in external patients9 cohort. It was compared with CS-IHC4 in our patients9 cohort in early HR-positive breast cancers. This study implicates the amount of prognostic information contained in the nomogram is superior to that in the CS-IHC4 score. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-20.

P1-12-15: Adjuvant Trastuzumab Effect on HER2−Positive Breast Cancers According to Hormonal Receptor (HR) Status: Crosstalk between ER and EGFR/HER2 Pathway May Prevent Trastuzumab from Improving Outcomes in HER2−Positive and HR-Positive Breast Cancers.

Background: Crosstalk between growth factor receptor, especially the EGFR/HER2 pathway, and ER pathways has been associated with endocrine resistance. Thus, combination therapy targeting both ER and EGFR/HER2 signaling to block the crosstalk between these pathways and eliminate escape routes have been proven effective in both preclinical and clinical models. Anti-HER2 directed therapy has been reported to restore hormone sensitivity in HER2−positive breast cancers. Adding trastuzumab to conventional treatment has been a standard treatment of choice in HER2−positive breast cancer irrespective of hormonal receptor (HR) status. The purpose of the study is to evaluate adding effect of 1 year of trastuzumab to conventional adjuvant treatment in patients with HER2−positive breast cancer who received surgery according to HR status. Patients and Methods: We retrospectively analyzed the clinicopathologic characteristics and outcomes of 618 postoperative HER2−positive breast cancer patients between 2001 and 2008 at the Samsung Medical Center. Most of HER2−positive patients in our institute were treated with 1 year of trastuzumab as a part of adjuvant therapy since 2007 (post-trastuzumab era) compared with 2000–2006 (pre-trastuzumab era). Clinical outcomes including recurrence-free survival (RFS) were analyzed between pre-trastuzumab and post-trastuzumab era according to HR status. We performed Cox regression multivariate analysis for relapse using variables from univariate analysis by log-rank test for relapse. Clinical presentations and clinicopathologic characteristics were evaluated at the time of recurrence between both eras. Results: The median age at diagnosis was 46 years (range, 22–79). During the median 60.0 months of follow-up, the 5-year recurrence rate was 20.2%. The 618 patients were divided into two groups (patients who received (n=175) and did not receive (n=443) adjuvant trastuzumab). Recurrence rate was much lower in post-trastuzumab era than in pre-trastuzumab era (13.6% vs. 32.3%, p Conclusion: Cross-talk between ER and EGFR/HER2 pathways may mitigate trastuzumab effect in HER2+ve/ER+ve breast cancers. Further study is warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-15.

P5-01-11: Small Node-Negative (T1b-cN0) Invasive Hormone Receptor (HR)-Positive Breast Cancers: Is There a Population Which Might Have Benefit from Adjuvant Chemotherapy?

Background It has been widely accepted that small and node-negative breast cancers have an excellent prognosis and do not generally have clinical benefit from adjuvant chemotherapy. Recently, the role of adjuvant chemotherapy for small node negative breast cancers has been justified in some high-risk patients, which include HER2−positive and triple negative breast cancers. However, the question has been raised as to whether there are some patients who might have benefit from adjuvant chemotherapy in small node-negative HR-positive breast cancers. According to the current 2011 NCCN guideline, 21-gene RT-PCR assay can be considered for tumor size of more than 0.5 cm in HR-positive, HER2−negative cancers. In cases of high recurrence score (≥ 31), adjuvant chemotherapy in addition to endocrine therapy is recommended as category 2B. Because gene array cannot routinely be used in clinical practice and has not been validated in prospective randomized trials and the usefulness of it still needs to be defined, it would be better if there were valuable markers to determine risk for relapse in this setting. We hypothesized that there could be a population who might have clinical benefit from adjuvant chemotherapy in this small node-negative HR-positive tumors. Patients and Methods We retrospectively analyzed the clinicopathologic characteristics and outcomes of 538 postoperative HR-positive (ER-positive and/or PgR-positive) T1b-cN0 breast cancer patients between 2004 and 2007 at the Samsung Medical Center. We performed Cox regression multivariate analysis for relapse using variables from univariate analysis by log-rank test for relapse. Results : The median age at diagnosis was 46 years (range, 22–79). During the median 60.5 months of follow-up, the 5-year recurrence rate was 5.2%. Anthracycline-based adjuvant chemotherapy was administered to 44.8% of the patients. Adjuvant endocrine and radiation treatment were administered to 94.6% and 63.7% of the patients. There were significant differences according to histologic grade (HG), Ki67 index, and age of less than 35 years in univariate analyses regarding RFS (p=0.003, p Conclusion : A patients’ population may exist who have clinical benefit from adjuvant chemotherapy in T1b-cN0 HR-positive breast cancer patients. Ki67 index and age are useful as valuable surrogate markers to predict recurrence and to have benefit from adjuvant chemotherapy in this population. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-01-11.

P2-12-19: Nomogram To Predict Recurrence and To Avoid Unnecessary Adjuvant Chemotherapy Based on Ki67 Index and ER Status in Hormone Receptor (HR)-Positive Breast Cancers with Low Number of Nodal Metastases (≤3) (NCT01273415).

Background Hormone receptor (HR) positive breast cancers characterized with ER-associated genes are differentiated luminal B from luminal A tumors mainly by proliferation genes. According to NCCN guideline 2011, node positivity has been a main determinant to decide adjuvant chemotherapy with category 1. However, the experts’ panel at the St. Gallen Consensus in 2009 do not provides definite indications to give or withhold chemotherapy in patient group with intermediate criteria including low numbers (1-3, N1) of involved lymph nodes. Thus, in cases of limited number of nodal metastases, the role of biologic factors including Ki67 index needs to be defined. The aims of this study are to evaluate of Ki67 index as a useful surrogate marker to predict recurrence and to avoid unnecessary adjuvant chemotherapy and to develop nomogram based on Ki67 index to determine adjuvant therapeutic options in HR-positive in N0 and N1 breast cancers. Patients and Methods We retrospectively analyzed the clinicopathologic characteristics and outcomes of 953 postoperative HR-positive N0 and N1 breast cancer patients between 2004 and 2007 at the Samsung Medical Center. We constructed nomogram based on Cox regression model using independent factors demonstrated in multivariate analysis and validated externally in a cohort of 895 patients treated at Seoul National University Hospital. Results: In Cox regression multivariate analysis, ER-ve/PgR+ve and Ki67 index were identified as independent factors. Nomogram base on Cox-regression model showed an AUC of 0.75 (95% CI, 0.72−0.77) in the training set. The validation set showed a good discrimination with an AUC of 0.63 (95% CI, 0.60−0.66). We defined low nomogram score as less than 53, and high nomogram score as 53 or more from the cut-off value of the nomogrma ROC curve. Patients who received anthracycline-containing adjuvant chemotherapy with high nomogram scores showed better RFS with statistical significance than those who did not receive anthracycline-containing adjuvant chemotherapy with high nomogram scores (p Conclusion: Ki67 index is useful as a valuable surrogate marker to predict recurrence and to avoid unnecessary chemotherapy. Nomogram based on Ki67 index is constructed and validated to determine adjuvant therapeutic options in HR-positive N0 and N1 breast cancers. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-19.

Abstract P2-06-01: Ki67 Proliferative Index as an Invaluable Biomarker in Hormone Receptor (HR)-Positive Breast Cancer: Ki67 Labelling Index Can Reflect the Differences between Luminal A and B Subtypes Better Than HER2 Expression

Background: Differentiation by multigene signatures with excellent performance of hormone receptor (HR)-positive BC largely related to their proliferation genes. Despite questions about its usefulness, there is increasing evidence that Ki67 is a valuable prognostic marker. Standardization of Ki67 pathological assessment is the main problem to interpret reported trials. The aims of the study are to evaluate the role Ki67 as prognostic marker to predict relapse in HR-positive BC patients (luminal A and B) in adjuvant setting using prospective patients’ cohort. In addition, cut-off value and significant level of Ki67 were investigated comparing with other biomarkers including HER2 in luminal BCs. Method: We retrospectively analyzed the clinicopathologic characteristics of 1,070 postoperative breast cancer patients including Ki67 and clinical outcomes in terms of relapse free survival (RFS) between 2004 and 2007 at the Samsung Medical Center. Ki67 labelling index was measured in quantitative and semiquantitative method, independently. The percentage of positive nuclei stained for Ki67 was calculated each section based on the approximately 1,000 carcinoma cell nuclei. In addition, Ki67 was graded on a scale from 0 to 4, where 0 = staining of 0-4% of tumor cells, 1 = staining of 5-25% of tumor cells, 2 = 26-50% of tumor cells, 3 = staining of 51-75% of tumor cells, and 4 = staining of more than 76% of tumor cells. ROC curve was drawn to evaluate the usefulness of Ki67 index to get AUC then, find out the proper cut-off value of Ki67 to predict relapse. Multivariate analyses with Cox-regression model were performed. Results: Among 1,564 patients who received curative surgery for invasive breast cancer from January 2004 to June 2007, 1,070 patients with HR-positive were included in this analysis excluding 494 with HER2-enriched or triple negative breast cancer patients. Median follow-up duration was 56.9 months (range 36-77 months). Median age was 46 years (range 22-83 years). Ki67 threshold >19.5%, corresponding to a sensitivity 78.3%, a specificity 51.6% was chosen as cut-off value for relapse in adjuvant patients’ cohort. The AUC was 0.689 (P Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-06-01.

Abstract P6-13-04: Thymidylate Synthase (TS) and Thymidine Phosphorylase (TP) Expression as Predictive Markers of Capecitabine Mono-Chemotherapy for Patients with Anthracyclin-Taxane Pretreated Metastatic Breast Cancer (MBC)

Background: Capecitabine, one of the widely used cytotoxic agents for breast cancer, achieved high tumor control rate with low toxicity even in heavily-pretreated patients with metastatic breast cancer (MBC). Capecitabine (Xeloda®) is an oral fluoropyrimidine pro-drug that is transformed to fluorouracil (FU) in several steps, the last of which is conversion of 59-deoxy-5-fluorouridine to FU by TP. And TS is a target enzyme of 5-FU. The primary purpose of this study was to evaluate the role of TS and TP as biomarkers to predict clinical outcomes of capecitabine monotherapy for MBC. Method: Of Three hundreds fifty-three patients with MBC treated with capecitabine at Samsung Medical Center from 2000 to 2008, ninety patients who were previously treated with anthracycline and taxanes containing regimens and had available tissues for immunohistochemical stainings with estrogen (ER), progesterone (PgR), and human epidermal growth factor receptor-2 (HER2), TS, and TP were included in this analysis. All patients had received capecitabine 2000-2500mg/m2/day for 14days q 3 weeks. Results: The median age of these 90 patients was 49 (26-76) years. The response rate (RR) was 25.6% and the disease control rate (DCR) was 65.6%. The median progression-free survival (PFS) and overall survival (OS) from the 1 st day of capecitabine monotherapy were 4.8 (95% C.I.; 3.1-6.5) and 26.7 (95% C.I.; 17.1-36.3) months, respectively. High TS expression (TS score ≥100) was more common in patients with triple negative (TN) subtype than in those with other subtypes (16% for HR+, 22% for HER2+, 44% for TN, p=0.023). Median PFS was significantly lower in high TS expression (6.6 vs. 3.0 months; p=0.017) and low TP expression (TP Conclusion: Our data suggests that high TS score and low TP score correlated with shorter PFS for capecitabine monotherapy of patients with anthracycline and taxane pretreated MBC. Potential role of TS, TP expression as predictive markers of capecitabine monotherapy in patient with MBC should be confirmed by prospective studies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-04.

Evaluation of response to neoadjuvant chemotherapy in primary breast cancer using PET.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #4019 Purpose To estimate the usefulness of PET scan to assess the response of neoadjuvant chemotherapy, PET scan results were compared with conventional imaging modalities(US and MRI). Patients and Methods Fourty-one patients undergoing neoadjuvant chemotherapy between December 2004 and March 2008 were included. PET scan was performed before and after chemotherapy. Pathologic results were classified into two groups; pathological complete response(pCR) and non-pCR. Clinical responses were assessed with the results of imaging modalities such as post-chemotherapy size or pSUV(postTx), size difference between treatment(delta) and reduction rate(RR) of size or pSUV, and they are compared with postoperative pathologic results. Results 7 out of 41 patients (17.1%) had pCR. The results of US shows that postTx size (1.7±1.5cm) of pCR was not dfferent from those of non-pCR (3.6±3.0cm), and the delta (3.1±1.9cm) and RR (67.7±29.1%) of pCR were higher than those of non-pCR (1.3±1.3cm, 31.0±25.4%), respectively. As a result of MRI, postTx size, delta, RR of pCR was differ from those of non-pCR (1.0±1.7cm vs 2.8±1.7cm p<0.05; 4.5±1.0cm vs 2.3±1.8cm, p<0.05; 88.0±20.8% vs 44.6±24.7%, p<0.01). In PET scan, only postTx pSUV of pCR was differ from that of non-pCR (1.4±1.3 vs 5.3±8.3cm, p<0.05). As a result of receiver operating characteristic curve analyses for the prediction of pathological response of breast cancer, area under curve values (95% confidence interval) of US, MRI, PET for delta were 0.83(0.69∼0.98), 0.91(0.80∼1.01), 0.62(0.38∼0.86), and those of RR were 0.80(0.60∼0.99), 0.90(0.77∼1.02), 0.72(0.47∼0.96), respectively Conclusions We suggest that MRI is useful method to evaluate the response of neoadjuvant chemotherapy. Although PET scan shows less effective for evaluating the response of chemotherapy than MRI, PET scan with the ability to detect the distant metastatic lesions may be helpful to decide the proper management plans for advanced breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4019.