J-H Ahn

Tissue microarray-based study of patients with lymph node-negative breast cancer shows that HER2/neu overexpression is an important predictive marker of poor prognosis

BACKGROUND Despite good prognosis in most cases of lymph node (LN)-negative breast cancer, individual patients may have markedly different clinical outcomes. Here, we investigated the prognostic significance of HER2/neu overexpression in these tumors. MATERIALS AND METHODS We employed a tissue microarray to examine HER2/neu overexpression by immunohistochemical staining in 359 consecutive patients diagnosed with LN-negative breast cancer, who underwent surgery from January 1993 to December 1998. RESULTS HER2/neu overexpression was detected in 81 of 359 (23.1%) patients. The 10-year disease-free survival (DFS) values (81.2% versus 61.8%, P value 0.000) and overall survival (OS) rates (85.7% versus 63.9%, P value 0.000) were significantly different between cases with HER2/neu-negative or HER2/neu-positive tumors. After multivariate analysis, HER2/neu status and tumor size were identified as independent prognostic factors for 10-year OS. Moreover, HER2/neu overexpression was significantly associated with poorer clinical outcomes in an intermediate-risk group identified by the St Gallen classification (10-year DFS, 79.6% versus 61.8%, P value 0.000; 10-year OS, 84.7% versus 63.9%, P value 0.000). CONCLUSIONS Our results show that HER2/neu overexpression is an important independent prognostic factor for LN-negative breast cancer cases and support the theory that more intensive adjuvant chemotherapy is required in the population with HER2/neu overexpression.

Abstract P1-02-14: Circulating cell-free DNA (CFD) measured by a simple fluorescent assay to predict relapse in triple negative breast cancer patients receiving neoadjuvant chemotherapy: A biomarker substudy of prospective observational study (NCT02001519, NCT02001506)

Background: Prior technique to measure cell free DNA(CFD) is labor-intensive and expensive, while, recently developed fluorescent CFD assay is more simple and convenient.The aim of this study was to evaluate the role of CFD measured by a fluorescent assay as a biomarker of patients with triple negative breast cancer (TNBC) received neoadjuvant chemotherapy Methods: We prospectively enrolled patients with TNBC, clinical stage II or III (T>1.5cm or lymph node > 1.5cm), who were scheduled for neoadjuvant chemotherapy. Patients received 4 cycles of adriamycin 60 mg/m2 plus cyclophosphamide 600 mg/m2 (AC) followed by 4 cycles of cisplatin or docetaxel, and surgery. Plasma samples were obtained from patients before initial chemotherapy (baseline-CFD) and after 4 cycles of AC neoadjuvant chemotherapy (AC-CFD). Results: This study included 72 patients who met the inclusion criteria. The mean levels of baseline-CFD and AC-CFD were 239±68 ng/mL and 210±66 ng/mL, respectively, and the CFD level was significantly decreased after AC chemotherapy.( p=0.001) The baseline-CFD was not associated with initial tumor characteristics. (T stage 1-2 vs. 3, p=0.313; N stage 0 vs. 1-3, p=0.317) There was no statistically significant difference between patients with response (CR or PR) to AC chemotherapy and those without response in terms of baseline-CFD, AC-CFD, and change of CFD between two values. (p=0.814, p=0.839, p=0.927) With 33.6 months of median follow up, there were 18 cases of relapse. Relapsed group showed numerically higher level of baseline-CFD, although it was not statistically significant. (relapse, 259 ng/mL; non-relapse, 233 ng/mL; p=0.161) We performed a ROC curve analysis of baseline-CFD for relapse, and found an area under the curve of 0.62 (95% CI, 0.46-0.78) at 222 ng/mL. Patients with baseline-CFD above 222 showed higher relapses than those below 222. (HR, 2.75; 95% CI, 0.96-7.84; p = 0.059) Conclusions: The baseline-CFD obtained using a simple and convenient fluorescent assay could predict relapse, suggesting baseline-CFD as a potential biomarker for risk stratification of TNBC. Citation Format: Park K, Woo M, Kim JE, Ahn J-H, Jung KH, Kim S-B. Circulating cell-free DNA (CFD) measured by a simple fluorescent assay to predict relapse in triple negative breast cancer patients receiving neoadjuvant chemotherapy: A biomarker substudy of prospective observational study (NCT02001519, NCT02001506) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-14.

Abstract P3-07-34: Predictive role of stromal tumor infiltrating lymphocytes (TILs) in patients with metastatic HER2-positive breast cancer (BC) treated with trastuzumab

Background: Prognostic significance of stromal TILs in metastatic BC has been suggested in various BC subtypes. However, predictive role of stromal TILs for the efficacy of trastuzumab has not been established in patients with HER2-positive BC. This study was performed to evaluate whether the stromal TILs are associated with the efficacy of trastuzumab in patients with metastatic HER2-positve BC. Method: Between June 2006 and March 2013, a total of 60 women with recurrent or metastatic HER2-positive BC treated with trastuzumab were included in this retrospective analysis. In these patients, trastuzumab was administered either as single agent or combination with taxanes. Stromal TILs were assessed using immunohistochemistry in surgical specimen (n=39, 65%) and biopsy specimen of metastatic lesion (n=21, 35%) by the academic pathologist (HJL). Primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were response rate and overall survival (OS). Result: Median age was 54 year old (range, 36-76), and all patients had invasive ductal carcinoma. Hormone receptor was positive in 34 patients (57%) and 18 patients (30%) initially presented with metastatic disease. Nine patients (15%) received cytotoxic chemotherapy without trastuzumab before the administration of trastuzumab. Patients were grouped according to the TILs ( 10% [n=10]), and there was no significant difference in age (p=0.68), histologic grade (p=1.00), metastatic sites (p>0.05), and number of lines of chemotherapy before the administration of trastuzumab(p=0.33) among patients with low and high stromal TILs. High TILs were more common in hormone receptor (HR)-negative tumor compared with HR–positive tumor (31% vs 6%; p=0.02). In overall, median PFS and OS were 15.0 months (95% CI, 9.7-20.2) and 35.0 months (95% CI, 29.8-40.2), respectively. Median PFS in patients with high stromal TILs were numerically longer than that in those with low TILs (22.0 months [95% CI, 9.6-34.4] vs 14.0 months [95% CI, 9.6-18.4]; p=0.057). There was no difference in response rates (p=0.43) and OS (p=0.94) according to the stromal TILs. FcR genotype was not significantly correlated with objective response rate, PFS and OS. Conclusion: This study suggests that the stromal TILs might be associated with the clinical outcomes of HER2-targeted therapy in patients with metastatic HER2-positive BC. Our finding should be validated in future studies based on a large sample size. Keywords: Breast cancer, tumor infiltrating lymphocyte. Trastzumab, HER2. Citation Format: Yoon JA, Yoo C, Lee HJ, Kim K-P, Kim J, Ahn J-H, Jung KH, Gong G, Kim S-B. Predictive role of stromal tumor infiltrating lymphocytes (TILs) in patients with metastatic HER2-positive breast cancer (BC) treated with trastuzumab. [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 P3-07-34.

Abstract P3-07-56: Predictive value of tertiary lymphoid structure assessed by high endothelial venule count in neoadjuvant setting of triple-negative breast cancer

Background Tertiary lymphoid structure (TLS) is an ectopic lymph node-like structure characterized by lymphoid aggregation with high endothelial venules (HEVs), and is an important source of tumor-infiltrating lymphocytes (TILs). TILs have a strong prognostic and predictive significance, particularly in triple-negative breast cancer (TNBC). We previously analyzed expression of immune-related genes in pre-neoadjuvant chemotherapy (NAC) biopsy samples using NanoString assay and showed that gene expression of follicular helper T cell marker CXCL13 , which is closely associated with TLSs, was an independent predictive factor for pathologic complete remission (pCR) in TNBC. However, measuring gene expression of biopsy sample is not easy to perform in daily pathology practice. Therefore, we evaluated TLSs by assessing hematoxylin and eosin (HE San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-56.

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 OT3-1-08: The PROCEED trial KCSG BR11-01: Phase III multicenter randomized open label study of irinotecan plus capecitabine versus capecitabine in patients previously treated with anthracycline and taxane for HER2 negative metastatic breast cancer

Background: Most patients with metastatic breast cancer (MBC) experience disease progression after being treated with an anthracycline or taxane. Irinotecan, a semisynthetic agent derived from the natural alkaloid camptothecin is metabolized to the active metabolite SN-38 which targets topoisomerase I leading to single and double strand DNA breaks. Irinotecan as a single agent demonstrated tumor activity with an objective response rate ranging from 5 to 23% in patients with MBC refractory to taxane and anthracycline. Irinotecan increased the activity of 5-FU, the active metabolite of capecitabine, and overcomes the negative effect of thymidylate synthase overexpression, which is the main target of an active metabolite of 5-FU. A phase II study that evaluated the efficacy and safety of irinotecan and capecitabin combination (IX) showed that the median progression free survival (PFS) was 7.6 months (95% CI, 5.0-10.2months), and the median OS was 22.6 months (95% CI, 15.4 – 29.8 months) with good tolerability in anthracycline and taxane pretreated MBC patients. Based on these results, we planned to conduct a multicenter, randomized phase III study which assesses the efficacy of irinotecan and capecitabine combination therapy compared with capecitabine alone in patients with anthracycline and taxane resistant MBC. Methods: In this trial, patients with HER2 normal tumor who previously received anthracycline and taxane based chemotherapies are enrolled. Eligible patients are randomly assigned in a 1:1 ratio to receive irinotecan plus capecitabine or capecitabine alone. The primary end point of this trial is PFS and a total number of accrual patients will be 222. Randomization is done using a random block size permutation method and stratified by hormone receptor status (negative vs. positive), first line vs. ≥second lines, visceral metastasis (negative vs. positive). Patients receive irinotecan at 80 mg/m2 on day 1 and 8 every 3 weeks and capecitabine 1000mg/m2 bid from day 1 to day 14 every 3 weeks. In control arm, patients receive capecitabine 1250mg/m2 bid from day 1 to day 14 every 3 weeks. Response will be assessed using RECIST1.1 criteria and toxicity will be graded according to NCI-CTCAE 4.0 criteria. Study Status: A total of 107 patients consented for the study since June 2011, and accrual is ongoing. Clinical trial information: NCT01501669. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-08.

Abstract P2-02-02: Prognostic significance of the ratio of absolute neutrophil to lymphocyte counts for breast cancer patients in neoadjuvant setting

Background: The baseline absolute neutrophil count/absolute lymphocyte count ratio (NLR) has potential prognostic importance in solid tumors, including breast cancer. However, NLR as a predictive factor of the pathologic complete response (pCR) or as a prognostic factor has not been fully studied in breast cancer patients who have received neoadjuvant chemotherapy. Materials and Methods: Using receiver operating characteristic curve analyses, we retrospectively examined the predictive and prognostic impact of the NLR at the diagnosis in 401 patients with primary breast cancer who were treated with neoadjuvant chemotherapy, followed by definitive surgical resection. Of the 401 included patients, 72 (18%) received anthracycline-based, 285 (71%) received anthracycline- and taxane-based, 37 (9.2%) received herceptin-based, and 7 (1.7%) received fluorouracil-based regimens. The significance of NLR was analyzed according to clinicopathologic variables and clinical outcomes. Results: Forty-three (10.7%) patients achieved pCR. On univariate analysis, high NLR (> 2.2) correlated with poor recurrence-free survival (RFS; P = 0.001) and overall survival (OS; P = 0.003). Subgroup analysis of the non-pCR group showed that NLR was significant for RFS and OS ( P = 0.002 and P = 0.007, respectively). Multivariate analysis showed NLR to be an independent prognostic factor for RFS and OS ( P = 0.002 and P = 0.007, respectively). Subgroup analysis of the pCR group showed that patients with high NLR have a higher recurrent rate than low NLR (30.8% vs. 13.3%). The NLR was not related to pCR ( P = 0.098). Conclusion: Our results suggest that the NLR is an independent prognostic factor for RFS and OS in breast cancer patients receiving neoadjuvant chemotherapy and may provide additional prognostic information for patients not achieving a pCR to determine who might profit from further therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-02-02.

Abstract PD09-05: Single nucleotide polymorphism of XRCC1 which participates in DNA repair mechanism predicts clinical outcome in relapsed or metastatic breast cancer patients treated with S1 and oxaliplatin chemotherapy: Results from multicenter prospective study (TORCH_KCSG BR07-03)

Background: S1 and oxaliplatin (SOX) combination chemotherapy is an effective regimen in anthracycline and taxane pretreated metastatic breast cancer (MBC) patients with manageable toxicities (KCSG BR07-03, SABCS 2011 #Abst P3-16-06). The aim of this study was to investigate the association of the single nucleotide polymorphisms (SNPs) and clinical outcome in MBC treated with SOX chemotherapy. Patients and Methods: A total of 87 MBC patients previously treated with or resistant to anthracycline and taxane chemotherapy were enrolled in this prospective multicenter trial. The patients received S-1 80mg/m2/day (day 1–14) and oxaliplatin 130 mg/m2 (day 1) every 3 weeks till progression. Among the 87 patients, 77 patients were available for SNP analysis. Germline DNA from peripheral blood (PB) mononuclear cells was extracted. SNPs in 4 genes from pathways that may influence cellular sensitivity to S1 and oxaliplatin (TS, ERCC, XPD, and XRCC) were genotyped from PB sample using PCR-restriction fragment length polymorphism. Results: Overall response rate (RR) was 38.5% (95% CI: 27.7–49.3) and disease control rate was 67.9% (95% CI:57.5–78.3) to SOX. Median time-to-progression (TTP) and overall survival (OS) were 6.0 mo (95% CI: 5.1–6.9 mo) and 19.4 mo (95% CI: not estimated), respectively. XRCC1 Arg194Trp SNP which participates in DNA repair mechanism showed correlation with the clinical outcome. RR was tend to higher in XRCC1 Arg194Trp CC genotype compared with CT or TT genotype (50.0 % vs 35.1% or 12.5%, P = 0.121). TTP of patients with CC genotype in XRCC1 Arg194Trp was significantly longer than the TTP of patients with CT or TT genotype (median TTP: 6.4 mo in CC, 5.9 mo in CT, 3.0 mo in TT, P = 0.007) as well as overall survival (OS) (median OS: not reached in CC, 13.9 mo in CT, 7.1 mo in TT, P = 0.006). After adjusting for hormone receptor status, performance status, and visceral involvement, prognostic value of XRCC1 Arg194Trp SNP remained significant (Hazard Ratio=1.322 and 4.484, P = 0.016). Other SNPs were not significantly associated with survival or toxicities. Conclusion: XRCC1 Arg194Trp SNP is associated with clinical outcome of MBC patients treated with SOX chemotherapy. Further studies of the relationship between germline polymorphisms in XRCC1 and functional mechanism researches are warranted. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-05.

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.

Abstract P3-12-05: Clinical features and outcomes of leptomeningeal metastasis in patients with breast cancer: a single center experience

Background: Leptomeningeal metastasis (LM) is one of the major problems in managing metastatic breast cancer because of LM typically carries a devastating prognosis and often represents a terminal event. We analyzed the clinical features and outcomes of LM in patients with breast cancer. Methods: We retrospectively reviewed the medical records of patients who were diagnosed with LM from breast cancer between 2002 and 2012 at Asan Medical Center. Results: Of the 95 LM patients by cytologically proven (n = 81) or radiologically diagnosed (n = 14), 57 (60%) had an ECOG performance status (PS) ≥ 3, and the median age was 47 years (range, 26–72 years). The patients were diagnosed with LM after a median of 10.3 months (95% CI, 5.5–15.0 months) from the time of diagnosis of metastatic breast cancer. LM was present in 2 patients at the time of initial diagnosis. Twenty-three patients (24.2%) had isolated CNS metastasis, and 6 (6.3%) had only LM without any detectable metastasis sites. At the time of diagnosis of LM, 46 patients (48.4%) presented with coincidental failure of systemic disease control. Seventy-eight patients (82.1%) underwent intrathecal chemotherapy (methotrexate; n=78, thiotepa; n=11), resulting in one-third of cytologic negative conversion (n = 26), and 41 (43.2%) received systemic chemotherapy. The overall median survival time was 3.3 months (95% CI, 2.5–4.2 months) and 7.8% of the patients survived for more than 1 year. Overall survival tended to be better in patients who achieved cytologic negative conversion to intrathecal chemotherapy than those did not (median 4.5 months versus 3.2 months, P = 0.241). Overall survival was not different according to subtypes; hormone receptor (+), HER2 (+), and triple negative (median 3.6 months, 3.3 months, and 3.2 months, P = 0.937). Multivariate analysis demonstrated that ECOG PS ≥ 3 (HR = 2.09, 95% CI 1.21–3.58, P = 0.007), coincidental failure of systemic disease control at LM (HR = 3.01, 95% CI 1.76–5.15, P P = 0.001) were independent factors associated with survival. Conclusions: The prognosis for patients with LM from breast cancer was still poor. Systemic chemotherapy in addition to intrathecal chemotherapy might confer a survival benefit, even after the detection of LM. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-05.