S-W Han

Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer.

This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m−2 at week 1 and 250 mg m−2 weekly thereafter until disease progression. Oxaliplatin (100 mg m−2) and leucovorin (100 mg m−2) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m−2) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1–65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5–6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-α levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P<0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.

Efficacy of Prophylactic Ondansetron in a Patient-Controlled Analgesia Environment

We conducted a prospective, randomized, double-blind, placebo-controlled trial to examine the efficacy of prophylactic ondansetron on post-operative nausea and vomiting (PONV) during opioid patient-controlled analgesia (PCA). In total, 374 patients using opioid PCA, but otherwise considered to be low risk for PONV, were randomly allocated to ondansetron (4 mg given intravenously and 16 mg added into the PCA pump) or saline (control group). PONV was evaluated in terms of nausea graded on a visual analogue scale, and the number of patients who experienced emetic episodes or needed rescue anti-emetics in the 48-h post-operative period. Patient satisfaction for PCA was scored at the end of the evaluation period. The only difference between the two groups was the higher number of headaches in the ondansetron group. In patients using opioid PCA, but with no other high risk factors for PONV, prophylactic ondansetron does not have any clinical benefit.

Whole-exome sequencing study reveals common copy number variants in protocadherin genes associated with childhood obesity in Koreans

Recently, the prevalence of childhood obesity has significantly increased in industrialized countries, including Korea, and now controlling obesity is becoming an economic burden. However, knowledge of the risk factors associated with obesity is still limited. In this study, we aimed to discover additional obesity-associated loci in children. To achieve this, we conducted an exome-wide association analysis of copy number variation (CNV) using whole-exome sequencing (WES) data from a total of 102 cases and 86 controls. We newly identified a CNV locus that overlapped two protocadherin genes, PCDHB7 and PCDHB8, which are brain function-related genes (P-value=6.40 × 10−4, odds ratio=2.2189). A subsequent replication analysis using WES data from 203 obese and 291 normal weight children showed that this CNV region satisfied the genome-wide significance standard (Fisher’s combined P-value=3.76 × 10−5). Moreover, correlation test using 199 additional samples supported significant association between CNV and increased body mass index. This region also showed a meaningful association with 273 cases and 2596 controls in adult samples. Our findings suggest that differences in the common CNV region at 5q31.3 may have an impact on the pathophysiology of obesity.

Lapatinib can restore capecitabine sensitivity in HER2-positive breast cancer.

Abstract #3157 Background: Lapatinib in combination with capecitabine is an effective treatment option in HER2-positive metastatic breast cancer (MBC) that has progressed after trastuzumab-based therapy. However, the efficacy of lapaptinib plus capecitabine in capacitabine resistant MBC patients and mechanism of sensitivity in these patients is unclear.
 Methods: In the preclinical part of the study, the effect of lapatinib on 5-FU sensitivity was investigated in a HER2 amplified breast cancer cell line (SKBr3). In the clinical part, MBC patients who progressed after treatments with trastuzumab, anthracycline, and taxane were enrolled in an open-label expanded-access study of lapatinib plus capecitabine (GlaxoSmithKline, USA) at Seoul National University Hospital from Mar 2007 to Apr 2008. Patients received lapatinib (1,250mg/day, 1-21) and capecitabine (2,000mg/m 2 , D1-14) combination treatment every 3weeks. The clinical data were prospectively collected.
 Results: In SKBr3 cell line, genes related to 5-FU sensitivity [TS, thymidine kinase 1(TK1), dihydrofolate reductase (DHFR), and ribonucleotide reductase M2 (RRM2)] were downregulated after lapatinib treatment. These genes were more significantly reduced after lapatinib-treatment compared with gefitinib or trastuzumab. In addition, TS reporter gene expression was enhanced by EGFR/HER2. Nuclear translocation of EGFR/HER2 induced by EGF and its association with TS promoter was effectively abolished by lapatinib. In the clinical study, a total of 37 female patients with HER2-positive MBC were analyzed. Sixteen (43%) patients had previously been treated with capecitabine. Overall response rate (RR) was 27.0% (95% CI 12.7-41.3), and disease control rate (DCR) was 83.8% (95% CI 71.9-95.7). During the median follow-up duration of 9.1 months, median progression-free survival (PFS) was 5.6 months (95% CI 4.0-7.2), and median overall survival has not been reached yet. There was no significant difference in RR/DCR and PFS according to prior capecitabine use. Prior capecitabine treatment had been discontinued due to disease progression during treatment in 13 patients. Among these patients with resistance to capecitabine, lapatinib and capecitabine resulted in DCR/PFS comparable to that of patients without exposure to capecitabine. Biomarker analysis of tissue specimen is currently underway and will be presented at the meeting.
 Conclusion: Lapatinib plus capecitabine demonstrated clinical activity in capecitabine pretreated MBC. Our data suggests that lapatinib may resensitize capecitabine resistant tumors to capecitabine by downregulation of nuclear EGFR/HER2 and TS. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3157.

Abstract P1-02-05: Prognostic role of PIK3CA mutational status in circulating tumor DNA (ctDNA) from HER2-positive metastatic breast cancer patients

Phosphatidylinositol-4, 5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) is one of the most commonly mutated genes in breast cancer. But the prognostic and predictive role of PIK3CA mutations remains a matter of debate. It has been suggested that PIK3CA mutations are related to resistance to trastuzumab-based therapies, but they were also related to relatively indolent disease with better progression-free survival. Recently, circulating tumor DNA has been proposed to be a sensitive biomarker for detecting the presence of specific genetic aberrations in various cancer types, providing prognostic and predictive information. In this study, we evaluated prognostic and predictive role of PIK3CA mutations in patients with HER2-positive metastatic breast cancer treated with 1 st line trastuzumab and taxane combination chemotherapy. Thirty-four patients with blood samples obtained before 1 st line trastuzumab and taxane combination chemotherapy were included in the study. We analyzed two PIK3CA hotspot mutations (E545K, H1047R) in ctDNA by digital droplet PCR (Raindrop TM ). The samples were collected from April 2005 to December 2011, centrifuged and stored as plasma, and were analyzed in 2015, after 4-10 years of storage period. Median age was 47 years (range: 31 to 75 years), and histologic type of cancer was ductal carcinoma in all cases. PIK3CA mutations were detected in 21 (61.8%) of 34 patients. Patients with mutated PIK3CA in ctDNA had longer progression-free survival (PIK3CA wild type vs mutant, 11.0 months vs 22.0 months; P = 0.013). In hormone receptor positive group, patients with mutated PIK3CA had longer progression-free survival (PIK3CA wild type vs mutant, 12 months vs 18 months, P=0.17). Patients with PIK3CA mutations had a lower objective response rate than patients with wild-type, but there was no statistical significance (CR+PR; PIK3CA wild type vs mutant, 84.6% vs 66.7%, P=0.43). There was no significant difference in response rate (P = 0.48) or PIK3CA mutational status (P = 0.44) according to hormonal receptor status (estrogen receptor and/or progesterone receptor). In conclusion, PIK3CA mutations were frequently detected by digital PCR from ctDNA of patients with HER2-positive breast cancer and they were related to significantly better PFS. We plan to analyze the PIK3CA mutation status in matched tumor tissue. Citation Format: Lim J, Lee K-H, Min A, Kim S-G, Kim J-E, Kim T-Y, Han S-W, Oh D-Y, Kim T-Y, Lim S-A. Prognostic role of PIK3CA mutational status in circulating tumor DNA (ctDNA) from HER2-positive metastatic breast cancer patients [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 P1-02-05.

Abstract P4-07-08: The prognostic significance of ataxia-telangiectasia-mutated (ATM) and p53 expression in breast cancer

The purpose of this study was to investigate the correlation of ataxia-telangiectasia-mutated (ATM) protein and p53 expression with clinicopathological features and prognosis in patients with sporadic breast cancers. The expression of ATM and p53 was determined by immunohistochemistry in 420 surgically resected breast cancers. Loss of ATM was observed in 126 out of 407 evaluable cases (31.0%), and was significantly associated with aggressive features with large tumor size, lymph node metastasis, higher tumor grade, and negativity of ER and/or PR. ATM loss was associated with a significantly shorter disease-free survival (DFS) (p = 0.019). Abnormal p53 expression was found in 39.3% of tumors (157 out of 400), conferring a worse DFS as well (p = 0.002). When investigated together, combined ATM and p53 expression status were associated with a worse DFS (p = 0.002). On multivariate analysis, ATM loss and abnormal p53 expression status was an independent predictor of poorer DFS (intact ATM and normal p53 vs. ATM loss and abnormal p53, HR 3.350; 95% CI 1.496 - 7.502; p = 0.003). Furthermore, in patients treated with adjuvant anthracyclines, either p53 alone or p53 combined with ATM significantly influenced DFS (p = 0.004, p = 0.015, respectively). The present study demonstrates that expression of ATM and p53 is an independent prognostic marker in breast cancers, and might be a practical tool for predicting benefits from anthracycline-based adjuvant therapy. Citation Format: Suh KJ, Ryu HS, Lee K-H, Im S-A, Kim T-Y, Kim H, Yang Y, Moon H-G, Han S-W, Oh D-Y, Han W, Kim T-Y, Park IA, Noh D-Y, Bang Y-J. The prognostic significance of ataxia-telangiectasia-mutated (ATM) and p53 expression in 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 P4-07-08.

Abstract P4-13-19: Poziotinib, an oral, irreversible pan-HER inhibitor, demonstrates promising clinical activity in metastatic HER2 positive breast cancer patients

Background: Poziotinib is a novel, oral, irreversible pan-HER inhibitor that has been studied in two completed Phase 1 clinical trials in patients with advanced solid tumors (HM-PHI-101; HM-PHI-102) and is currently being studied in several Phase 2 clinical trials. Preclinical studies have shown poziotinib to be more potent in vitro than other EGFR- and HER2-directed tyrosine kinase inhibitors. This study collates the clinical experience of poziotinib in patients with advanced HER2 positive breast cancer from the two completed Phase 1 trials. Results: The maximum tolerated dose (MTD) and safety of poziotinib were evaluated in HM-PHI-101 (once daily, Day 1-14 q3 weeks) and in HM-PHI-102 (continuous dosing). The Dose Limiting Toxicity (DLT) was diarrhea in both studies. Anti-diarrheal medicine was allowed, but prophylactic anti-diarrheal therapy was not used. The most frequently reported Grade 3 AE was diarrhea (40%). The MTD for intermittent dosing of poziotinib was 24 mg and the MTD for continuous dosing was 16 mg. The Dose Limiting Toxicity (DLT) was diarrhea in both studies. Anti-diarrheal medicine was allowed, but prophylactic anti-diarrheal therapy was not used. In total, 10 patients with HER2 positive metastatic breast cancer were treated in the two trials (median age 56.5, range 30-69). These patients were heavily pretreated (median number of previous treatment regimens 5, range 3-9), and all patients had failed treatment with both trastuzumab and lapatinib. The Overall Response Rate (ORR) in these breast cancer patients was 60% and Clinical Benefit Rate (CBR) was 80%. The median duration of response was 32.5 weeks (range 18 - 56 weeks). Two patients in the early dose cohorts of 1 or 2mg had progressive disease. The median progression free survival (PFS) was 28 weeks (6, 6, 12, 17, 25, 31, 37, 49, 57, and 98 weeks). Conclusions: Poziotinib showed very promising clinical activity in Phase 1 patients with metastatic HER2 positive breast cancer, who had been heavily pretreated and failed two prior HER2-directed therapies. The ORR in this patient population was 60% and the CBR was 80% in these two early dose finding studies. The AEs observed in these studies was consistent with other pan-HER and EGFR inhibitors. While the majority of DLT cases involves diarrhea, toxicity of other adverse events was relatively tolerable. An intermittent dosing schedule seemed appropriate for poziotinib. Multiple Phase 2 studies with poziotinib are ongoing in patients with breast cancer and other solid tumors. Citation Format: Im S-A, Kim J-H, Lee K-H, Kim SH, Oh D-Y, Kim Y-J, Han S-W, Kim T-Y, Kim T-Y, Jung J, Bang Y-J. Poziotinib, an oral, irreversible pan-HER inhibitor, demonstrates promising clinical activity in metastatic HER2 positive breast cancer patients. [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 P4-13-19.

Abstract P1-10-11: Prognostic value of non-alcoholic fatty liver disease in stage II/III breast cancer patients who received neoadjuvant chemotherapy

Background Metabolic syndrome is associated with various malignancies, including breast cancer. Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. NAFLD is frequently observed during chemotherapy, but its clinical implication is unclear. The purpose of this study is to evaluate the prognostic value of NAFLD in patients with stage II/III breast cancer who received neoadjuvant chemotherapy (NAC Tx). Methods The patients with clinical stage II/III breast cancer who received NAC Tx with docetaxel and doxorubicin were enrolled. Treatment sequences were: 3 cycles of NAC Tx → surgery → 3 cycles of adjuvant chemotherapy (AC Tx), or 6 cycles of NAC Tx → surgery, allowing AC Tx at the physician9s discretion. NAFLD was determined by ultrasonography (radiologists9 decision), non-constrast computed tomography [CT] (the attenuation of liver is less than that of spleen or Results Between 2002 and 2008, 269 patients were enrolled. The median age was 45 (range 18-69), and 51.7% and 28.6% were with hormone receptor and HER2 positive tumors, respectively. The median number of NAC Tx was 3 cycles (range 1-6). NAFLD was observed in 33 (12.4%) patients at diagnosis, 52 (19.3%) after NAC Tx and 71 (26.4%) at the completion of AC Tx. The patients with NAFLD at diagnosis showed shorter overall survival than those without NAFLD (HR=2.688, 95% CI 1.259-5.747, P =0.011). The improvement of NAFLD during NAC Tx was observed in 28 (10.4%, group A) and persistence of NAFLD observed in 24 (8.9%, group B). Group A showed better prognosis in both PFS (HR 0.125, 95 % CI 0.016-0.962) and OS (no event), whereas group B showed worse PFS (HR 2.329, 95% CI 1.280-4.237) and OS (HR 3.721, 95% CI 1.727-8.015) compared to the patients without NAFLD at diagnosis. Conclusions NAFLD at diagnosis was a poor prognostic marker of OS in patients who received NAC Tx. Improvement of NAFLD during NAC TX was associated with good prognosis in terms of PFS and OS. Citation Format: Yang Y, Lee K-H, Kim T-Y, Han S-W, Oh D-Y, Kim T-Y, Han W, Moon H-G, Park IA, Noh D-Y, Im S-A. Prognostic value of non-alcoholic fatty liver disease in stage II/III breast cancer patients who received neoadjuvant chemotherapy. [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 P1-10-11.

345PCLINICAL USEFULNESS OF AJCC RESPONSE CRITERIA IN STAGE II/III BREAST CANCER PATIENTS WHO TREATED WITH LONG COURSE NEOADJUVANT CHEMOTHERAPY

ABSTRACT Aim: Neoadjuvant chemotherapy (NAC) is a standard therapy for American Joint Committee on Cancer (AJCC) stage II or III breast cancer. Response to NAC is a useful prognostic marker for relapse and overall survival in breast cancer patients. To improve the outcome of NAC, extended cycles of neoadjuvant chemotherapy was introduced. Recently, six to eight cycles of NAC has become the standard treatment in practice. The purpose of this study is to evaluate the clinical usefulness of AJCC response criteria in extended course (≥6 cycles) NAC. Methods: Clinical stage II or III breast cancer patients who received NAC of 6 cycles or more were enrolled. AJCC response after NAC and the clinicopathological factors of these patients were reviewed retrospectively. AJCC response criteria for NAC were adopted from the AJCC 7th edition: complete response (CR), absence of invasive carcinoma in both breast and lymph node; partial response (PR), decrease in either or both T or N stage; no response (NR), no change or increase in either or both T or N stage. Results: From January 2009 to December 2010, 183 patients were enrolled in the study with median follow up period of 38.0 months. Current gold standard for evaluating response to NAC is pathologic complete response (pCR) versus non-pCR. Twenty two patients (12.0%) and 161 patients (88%) belonged to pCR and non-pCR, respectively. On the other hand CR, PR, and NR by AJCC response criteria were consisted of 22 (12.0%), 123 (67.2%), and 38 (20.8%) patients respectively. The 3-year relapse free survival (RFS) rates were 90.9% in CR, 80.8% in PR, and 48.5% in NR. AJCC response was significantly associated with relapse free survival (RFS) (P Conclusions: AJCC response criteria is a useful clinical prognostic marker for RFS in 6 or more cycles of NAC in stage II/III breast cancer. AJCC criteria is a simple, eidetic and easily reproducible tool for response evaluation for the breast cancer patients in NAC setting compared with classically used various methods. Disclosure: All authors have declared no conflicts of interest.

664PPHASE IIA STUDY TO EVALUATE THE BIOLOGICAL ACTIVITY OF ASLAN001 IN HER-1/2 CO-EXPRESSING OR HER-2 AMPLIFIED ADVANCED GASTRIC CANCER

ABSTRACT Aim: ASLAN001 is a potent, specific inhibitor of the tyrosine kinase domains of human epidermal growth factor receptor (HER)-1, HER-2 and HER-4 (IC50 7, 2 & 0.195 nM). Approximately 30% of advanced gastric cancers (GCs) are known to co-express HER-1 and HER-2. Methods: This study was designed to evaluate the biological activity of ASLAN001 (formerly called ARRY-334543) in tumour biopsies from patients with relapsed or metastatic GC where there was either co-expression of HER-1 and HER-2, or amplification of HER-2. Pretreated patients with immunohistochemical evidence of HER-1 expression (at level from 1+ to 3+) and HER-2 expression (at level from 1+ to 3+) using standard criteria or with HER-2 gene-amplification by standard HER2 FISH were enrolled. Patients underwent endoscopic biopsy for screening on Day 0. Patients received ASLAN001 500 mg bid orally for 28 days. Post-treatment endoscopic biopsy was performed on D28. Activation of the downstream molecules involving signal transduction pathways was evaluated using antibodies to the total and phosphorylated forms of mitogen activated protein kinase (MAPK) and AKT using immunohistochemistry. Proliferation in the tumour was evaluated using Ki-67 and apoptosis by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results: Nineteen patients (12 HER-1/2 co-expressing and 7 HER-2 amplified) were enrolled between July 2012 and June 2013. Seven patients (58.3%) had activation of MAPK at the baseline in the HER1/2 co-expressing group. Of these, 6 (86%) had significant reduction in MAPK activity on D28. All of these patients also showed a marked reduction in Ki-67 staining. Two of these patients also showed reduction in phosphorylated AKT, and 5 patients showed an increase in TUNEL staining. The study demonstrated that ASLAN001 was biologically active in HER-1/2 co-expressing GC, and has the potential for future trial in this population. Conclusions: The pan-HER tyrosine kinase inhibitor ASLAN001 is a potent inhibitor of signal transduction in HER-1 and HER-2 co-expressing GC. Disclosure: M. Foster: not an employee of ASLAN, but an independent consultant histopathologist; M. McHale: co-founders and part owners of ASLAN Pharmaceuticals; A. Barge: co-founders and part owners of ASLAN Pharmaceuticals. All other authors have declared no conflicts of interest.