Y-J Bang

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.

FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study

Background:In preclinical gastric cancer (GC) models, FGFR2 amplification was associated with increased tumour cell proliferation and survival, and drugs targeting this pathway are now in clinical trials.Methods:FGFR2 FISH was performed on 961 GCs from the United Kingdom, China and Korea, and the relationship with clinicopathological data and overlap with HER2 amplification were analysed.Results:The prevalence of FGFR2 amplification was similar between the three cohorts (UK 7.4%, China 4.6% and Korea 4.2%), and intratumoral heterogeneity was observed in 24% of FGFR2 amplified cases. FGFR2 amplification was associated with lymph node metastases (P<0.0001). FGFR2 amplification and polysomy were associated with poor overall survival (OS) in the Korean (OS: 1.83 vs 6.17 years, P=0.0073) and UK (OS: 0.45 vs 1.9 years, P<0.0001) cohorts, and FGFR2 amplification was an independent marker of poor survival in the UK cohort (P=0.0002). Co-amplification of FGFR2 and HER2 was rare, and when high-level amplifications did co-occur these were detected in distinct areas of the tumour.Conclusion:A similar incidence of FGFR2 amplification was found in Asian and UK GCs and was associated with lymphatic invasion and poor prognosis. This study also shows that HER2 and FGFR2 amplifications are mostly exclusive.

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 P4-16-06: Histone deacetylases inhibitor SAHA enhances anti-tumor effects of poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in breast cancer cells

Background: The poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, has been found to have a therapeutic potential for treating cancers that have an impaired DNA repair ability. However, some cancer presents acquired resistance to PARP inhibitor or platinum. Histone deacetylases (HDACs) are important to enable functional homologous recombination (HR) by regulating the expression of HR-related genes and promoting the accurate assembly of HR-directed subnuclear foci. Thus, HDAC inhibitors have emerged recently as a class of therapeutic agents for the treatment of cancer by inhibiting DNA repair. For this mechanism, HDAC inhibition would enhance the anti-tumor effect of PARP inhibitor in cancer cells by blocking DNA repair pathway. Materials and Methods: We determined whether SAHA, a HDAC inhibitor could enhance the growth inhibition of olaparib on breast cancer cell lines using MTT assay. We examined whether exposure to SAHA affects the expression level of genes involved in HR. The accumulation of DNA double strand breaks (DSBs) induced by combination treatment was accessed by the comet assay. Cell cycle analysis and molecular changes induced by combination of olaparib plus SAHA were also performed. These in vitro data were validated in the in vivo xenograft model as well. Results: Triple-negative breast cancer cell lines showed heterogeneous response to dual inhibition of PARP and HDACs. SAHA enhanced olaparib-induced cell death of MDA-MB-157 and HCC1143 but not of HCC70 and MDA-MB-468. Combination of olaparib plus SAHA caused a greater decrease of pAKT, pERK, and pSTAT3 in MDA-MB-157 and HCC1143 cells compared with monotherapy either olaparib or SAHA. Furthermore, inhibition of PARP increased the accumulation of DNA DSBs induced by SAHA in these two cell lines, MDA-MB-157 and HCC1143. There was no change in proliferative pathway activation in HCC70 and MDA-MB-468 cells with combination of olaparib plus SAHA. Our findings showed that triple-negative breast cancer cells are differentially effective to combination of SAHA plus olaparib which increased levels of unrepaired DNA DSBs. Conclusion: HDAC inhibitor SAHA enhances growth inhibitory activity of PARP inhibitor olaparib in several triple-negative breast cancer cells with increased accumulation of DNA DSBs. Our results provide a rationale for the future clinical trials of olaparib combined with SAHA in the treatment of cancers that have an impaired DNA repair ability. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-16-06.

P3-14-03: ABCB1 Single Nucleotide Polymorphismas a Possible Prognostic Factor in Breast Cancer Patients Receiving Docetaxel and Doxorubicin Neoadjuvant Chemotherapy on Systemic Treatment.

Background Expression of the adenosine triphosphate-binding cassette B1 (ABCB1) transporter and P-glycoprotein are associated with resistance to anticancer drugs. The purpose of this thesis was to investigate the role of single nucleotide polymorphism (SNP) in the ABCB1 and CYP3A genes in breast cancer patients who were treated with neoadjuvant docetaxel and doxorubicin chemotherapy. Material and Methods : Patients with histologically confirmed breast cancer, Stage II or III, referred for neoadjuvant chemotherapy were enrolled. Patients were treated with 3 cycles of neoadjuvant and adjuvant chemotherapy with docetaxel and doxorubicin. The polymorphisms of ABCB1 (C3435T, G2677T/A, and C1236T) were genotyped by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assays. The genotyping of CYP3A was done by the GoldenGate assay (Illumina Inc). The correlation of genetic polymorphisms of ABCB1, CYP3A, and clinical outcomes was analyzed. Results : A total of 216 patients were enrolled, and the median age was 44 years (range 25–69 years). The overall radiological response rate (RR) was 76.8% while 8.3% of the patients achieved a pathologically complete response. After a follow-up duration of 48.8 months, the median relapse-free survival (RFS) and overall survival (OS) were not reached. ABCB1 3435TT genotype had a longer OS than CT/TT genotype ( p =0.045) and a trend toward a lower relapse rate (p=0.284) although it is statistically insignificant. With univariate analysis of the OS, good performance status (PS), invasive ductal carcinoma, initial operable stages, estrogen receptor (ER)-positive, non-triple negative, and the TT genotype of ABCB1 C3435T were associated with a lower risk of death. Multivariate analyses for the OS revealed that PS (HR 4.670, 95% CI=1.066−10.468; p =0.041), initial clinical stage (HR 3.198, CI=1.480−6.907; p =0.003), and triple negative phenotype (HR 3.091, 95% CI=1.245−6.570; p =0.004) were significantly associated with the OS. ABCB1 3435TT genotype was also associated with a lower risk of death with marginal significance not shown to be an independent prognostic factor (HR 0.295 95% CI=0.121−1.122; p =0.071). ABCB1 3435TT genotype had a higher AUC than CC/CT genotype for docetaxel with marginal significance ( p =0.054). These higher AUCs in the C3435TT genotype was associated with increased toxicities of neutropenia ( p =0.037) and diarrhea ( p =0.017). AA (*1/*1)/AG (*1/*3) genotypes of CYP3A5 had a higher AUC than GG (*3/*3) for docetaxel with statistical significance ( p =0.024). However, these higher AUCs of CYP3A5*1 allele carrier did not affect the survival and toxicities. Discussion : This study showed that the genetic polymorphism of ABCB1 C3435T might be associated with a longer OS and have predictive roles after the treatment with the neoadjuvant docetaxel/doxorubicin for stage II and III breast cancer. Our results also suggest that the prediction of docetaxel toxicity might be possible for ABCB1 C3435T polymorphism. Larger prospective studies as well as functional studies in human subjects are warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-03.

Abstract P2-09-36: Role of ABCB1 Polymorphisms as Predictive Markers in Patients with HER-2 FISH Positive Metastatic Breast Cancer Who Were Treated with Taxane Plus Trastuzumab First Line Chemotherapy

Background: ABCB1 polymorphisms could predict treatment results of taxane therapy in several malignancies. FCGR2A and FCGR3A polymorphisms were associated with clinical outcomes in several diseases after treatment with monoclonal antibody drugs which had antibody-dependent cell-mediated cytotoxicity activity. These polymorphisms could be possible predictive markers after taxane plus trastuzumab (TH) chemotherapy in patients with HER-2-positive metastatic breast cancer (MBC). Methods: Fifty-seven patients with HER-2 FISH positive MBC who received TH chemotherapy as the 1st-line treatment were enrolled. We analyzed 5 polymorphisms using DNA from peripheral blood mononuclear cells: ABCB1 1236C>T (rs1128503), ABCB1 2677G>T/A (rs2032582), ABCB1 3435C>T (rs1045642), FCGR2A 131H/R (rs1801274), and FCGR3A 158V/F (rs396991), then correlated them to treatment results of patients. Results: Among 57 patients, 22 patients (38.6%) received weekly paclitaxel plus trastuzumab, 26 patients (45.6%) tri-weekly paclitaxel plus trastuzumab, and 9 patients (15.8%) tri-weekly docetaxel plus trastuzumab. After a median follow-up of 30.6 (range, 0.6-75.9) months, median progression-free survival (PFS) was 15.1 (95% confidence interval (CI), 10.3-19.8) months. ABCB1 2677T allele carriers had longer PFS than the others (42.1 (95% CI, 12.7-71.4) months vs. 13.0 (95% CI, 10.6-15.4) months; p=0.037) along with a tendency toward higher response rate (RR) (86.4% vs. 76.0%; p=0.470) and longer overall survival (OS) (54.7 (95% CI, 43.0-66.4) months vs. 38.9 (95% CI, 18.1-59.7) months; p=0.057). In addition, ABCB1 3435CC genotype carriers had shorter PFS than the others (13.0 (95% CI, 10.8-15.2) months vs. 19.1 (95% CI, 0.0-38.5) months; p=0.039) along with a tendency toward lower RR (78.6% vs. 100%; p=0.567) and shorter OS (38.9 (95% CI, 19.7-58.1) months vs. 54.7 (95% CI, 43.0-66.4) months; p=0.093). ABCB1 1236C>T, FCGR2A 131H/R, and FCGR3A 158V/F were not significantly associated with RR, PFS, and OS. None of these polymorphisms were associated with any grades of hematologic or cardiac toxicities. Conclusions: Our results support that ABCB1 2677G>T/A and 3435C>T may have predictive roles after the 1st-line TH chemotherapy in patients with HER-2-positive MBC. In contrast, ABCB1 1236C>T, FCGR2A 131H/R, and FCGR3A 158V/F could not predict response after TH treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-36.