Min Hwan Kim

Impact of cigarette smoking on response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in lung adenocarcinoma with activating EGFR mutations.

OBJECTIVESnThe aim of this study is to evaluate the predictive impact of cigarette smoking on treatment outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma patients with activating EGFR mutations.nnnMETHODSnWe retrospectively analyzed 222 consecutive recurrent or unresectable lung adenocarcinoma patients who harbored activating EGFR mutations (exon 19 deletion or exon 21 L858R) and had received gefitinib or erlotinib. Detailed smoking histories were obtained from all patients according to a standard protocol.nnnRESULTSnOf 222 EGFR-mutated patients, 65.3% were never-smokers, 19.8% were smokers with < 30 pack-years, and 14.9% were smokers with ≥ 30 pack-years smoking dosage. The disease control rate (DCR) and objective response rate (ORR) of smokers with ≥ 30 pack-years were significantly lower than never-smokers and smokers with < 30 pack-years (DCR, 78.8% vs. 93.1%, p = 0.016; ORR, 45.5% vs. 62.4%, p = 0.020). Smokers with ≥ 30 pack-years showed significantly shorter PFS than never-smokers (6.4 vs. 11.8 months, p = 0.001) and smokers with < 30 pack-years (6.4 vs. 11.4 months, p = 0.033), as well as shorter overall survival from the time of metastatic diagnosis than never-smokers (33.6 vs. 46.2 months, p = 0.003). There was no survival difference between smokers with < 30 pack-year and never smokers. In the multivariate analysis adjusted for age, sex, performance status, initial stage, and line of EGFR-TKI, the presence of smoking dosage ≥ 30 pack-years was an independent predictive factor for the disease progression to EGFR-TKIs (hazard ratio, 1.87; 95% confidence interval, 1.15-3.05; p = 0.012).nnnCONCLUSIONSnCigarette smoking dosage of ≥ 30 pack-years is an independent negative predictive factor of EGFR-TKI treatment outcome in lung adenocarcinoma patients with activating EGFR mutations.

Clinical and prognostic implications of ALK and ROS1 rearrangements in never-smokers with surgically resected lung adenocarcinoma

OBJECTIVESnThe aim of this study is to evaluate the prevalence and prognostic significance of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement in never-smokers with surgically resected lung adenocarcinoma.nnnMETHODSnWe retrospectively analyzed 162 consecutive never-smokers who underwent curative resection for stage IB to IIIA lung adenocarcinoma at a single institution. We concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes, and investigated ALK rearrangements by fluorescence in situ hybridization assay. ROS1 rearrangement was also determined in all triple (EGFR/KRAS/ALK)-negative tumors.nnnRESULTSnOf 162 never smokers with lung adenocarcinoma, 14 (8.6%) and 5 (3.1%) had ALK and ROS1 rearrangements, respectively. Nineteen of the 74 (25.7%) EGFR and KRAS mutation-negative patients were fusion-positive (ALK or ROS1 fusion). Fusion-positive patients tended to have shorter median disease-free survival (DFS) than fusion-negative patients (28.0 vs. 33.9 months; p=0.128). In multivariate analysis, fusion-positive patients had significantly poorer DFS than fusion-negative patients after adjustment for age, sex, T stage, N stage, and adjuvant chemotherapy use (p=0.022; hazard ratio, 2.11; 95% confidence interval, 1.19-4.30). The first recurrence sites were not significantly different between fusion-positive and fusion-negative patients in this study.nnnCONCLUSIONnThis study shows significantly poorer DFS of ALK or ROS1 fusion-positive lung adenocarcinoma in never-smokers after curative surgery.

Anaplastic Lymphoma Kinase Gene Copy Number Gain in Inflammatory Breast Cancer (IBC): Prevalence, Clinicopathologic Features and Prognostic Implication

Background Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer, and its molecular pathogenesis still remains to be elucidated. This study aimed to evaluate the prevalence and implication of anaplastic lymphoma kinase (ALK) copy number change in IBC patients. Methods We retrospectively collected formalin-fixed, paraffin-embedded tumor tissues and medical records of IBC patients from several institutes in Korea. ALK gene copy number change and rearrangement were assessed by fluorescence in situ hybridization (FISH) assay, and ALK expression status was evaluated by immunohistochemical (IHC) staining. Results Thirty-six IBC patients including those with HER2 (+) breast cancer (16/36, 44.4%) and triple-negative breast cancer (13/36, 36.1%) were enrolled in this study. ALK copy number gain (CNG) was observed in 47.2% (17/36) of patients, including one patient who harbored ALK gene amplification. ALK CNG (+) patients showed significantly worse overall survival compared to ALK CNG (-) patients in univariate analysis (24.9 months vs. 38.1 months, p = 0.033). Recurrence free survival (RFS) after curative mastectomy was also significantly shorter in ALK CNG (+) patients than in ALK CNG (-) patients (n = 22, 12.7 months vs. 43.3 months, p = 0.016). Multivariate Cox regression analysis with adjustment for HER2 and ER statuses showed significantly poorer RFS for ALK CNG (+) patients (HR 5.63, 95% CI 1.11–28.44, p = 0.037). Conclusion This study shows a significant presence of ALK CNG in IBC patients, and ALK CNG was associated with significantly poorer RFS.

FOXP3 Expression Is Related to High Ki-67 Index and Poor Prognosis in Lymph Node-Positive Breast Cancer Patients

Background: Recent preclinical studies have shown that Forkhead box protein 3 (FOXP3) is an important tumor suppressor gene. The clinical and prognostic implication of FOXP3 expression in breast cancer cells still remains controversial. Methods: We evaluated the FOXP3 expression status of 183 patients who underwent curative surgery for breast cancer using the immunohistochemical assay of tissue microarray. Results: We found FOXP3 expression in 51 out of 183 (27.9%) surgically resected breast cancer tumors, and 33 patients were scored as weak positive and 18 as strong positive. FOXP3-positive tumors were associated with significantly higher nuclear grade, higher histologic grade and a more negative estrogen receptor status. The FOXP3 expression level was independently associated with high Ki-67 index in a logistic regression model. In the node-positive subgroup, strong FOXP3 positivity was related to poor disease-free survival and disease-specific survival compared to FOXP3-negative patients, whereas there was no survival difference between FOXP3-negative and FOXP3-weak-positive patients. Multivariate analysis with adjustment for patient age and human epidermal growth factor receptor 2 status demonstrated significantly poor survival of FOXP3-strong-positive patients in node-positive patients. Conclusion: Our results suggest that strong FOXP3 expression in breast cancer cells is associated with poor prognosis and high Ki-67 index.

EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E–Mutant NSCLC Cell Lines

Although treatment of BRAF V600E–mutant non–small cell lung cancer (NSCLCV600E) with GSK2118436 has shown an encouraging efficacy, most patients develop resistance. To investigate the mechanisms of acquired resistance to GSK2118436 in NSCLCV600E, we established GSK2118436-resistant (GSR) cells by exposing MV522 NSCLCV600E to increasing GSK2118436 concentrations. GSR cells displayed activated EGFR–RAS–CRAF signaling with upregulated EGFR ligands and sustained activation of ERK1/2, but not MEK1/2, in the presence of GSK2118436. Treatment of GSR cells with GSK2118436 enhanced EGFR-mediated RAS activity, leading to the formation of BRAF–CRAF dimers and transactivation of CRAF. Interestingly, sustained activation of ERK1/2 was partly dependent on receptor-interacting protein kinase-2 (RIP2) activity, but not on MEK1/2 activity. Combined BRAF and EGFR inhibition blocked reactivation of ERK signaling and improved efficacy in vitro and in vivo. Our findings support the evaluation of combined BRAF and EGFR inhibition in NSCLCV600E with acquired resistance to BRAF inhibitors. Mol Cancer Ther; 15(7); 1627–36. ©2016 AACR.

Abstract 1212: Anaplastic lymphoma kinase (ALK) gene copy number gain in inflammatory breast cancer (IBC): frequency, clinicopathologic features and prognostic implication .

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DCnnBACKGROUDnnThe aim of this study is to evaluate prevalence of ALK and MET copy number change and its relation to clinicopathologic characteristics and prognosis of patients with IBC.nnMETHODSnnThis study included 32 patients diagnosed as IBC between August 2000 and December 2011 from three cancer centers in Republic of Korea. ALK gene copy number change and rearrangement were assessed using FISH technique and ALK expression was assessed by IHC assay from biopsy or surgical pathology of IBC patients. FISH analysis of MET was also performed in same patient group. We determined disomy as ALK CNG (-); trisomy (3 fusion signals in ≥30% of cells) and polysomy (≥4 fusion signals in ≥ 10% of cells) as ALK CNG (+). Clinicopathologic characteristics, expression status of ER, PR, HER-2, progression-free survival (PFS) and overall survival (OS) were compared according to ALK gene copy number status.nnRESULTSnnThe median PFS and the median OS of IBC patients were 22.5 months and 37.2 months, and 50% and 34.4% of patients were HER-2 positive and triple negative breast cancer (TNBC), respectively. ALK CNG was observed in 17 patients (53%) out of 32 IBC patients and none had EML4-ALK rearrangement. IHC assay of ALK revealed moderate to strong cytoplasmic staining in majority of tumor cells in all IBC patients, but H-score was not correlated to ALK copy number status (p=0.417). The clinical characteristics of the patients were similar between ALK CNG (-) and ALK CNG (+) group, and proportion of TNBC is higher in ALK CNG (+) patients, but without statistical significance. (47.1% in ALK CNG (+) vs 20.0% in ALK CNG (-), p=0.147) All brain metastasis during follow up period occurred only in ALK CNG (+) patients. (4 patients) At a median follow-up of 17.6 months (range, 1.6-47.0), ALK CNG (+) patients showed worse PFS than patients with ALK CNG (-) patients (median PFS; 12.7months vs 34.3 months), but without statistical significance. (p = 0.274) Overall survival was worse in ALK CNG (+) patients compared to ALK CNG (-) patients (median OS; 24.9 months vs 60.6 months) with marginal statistical significance. (p= 0.074) Multivariate analysis of OS with adjustment for factors including cancer stage, mastectomy, HER2 positivity also revealed worse OS of ALK CNG (+) patients with marginal significance. (HR, 3.60; 95% CI, 0.962-13.463; p = 0.057). Increased MET copy number observed in 42.9% of IBC patients, but it was not related to PFS and OS of IBC patients (p=0.402, p=0.249), and there was no correlation between ALK and MET copy number change.nnCONCLUSIONnnThis study showed significant frequency of ALK CNG in IBC patients. ALK CNG was associated to poor overall survival in IBC patients in this study. Our finding suggests that ALK CNG may have a prognostic significance in IBC patients and their biological significance and relation to susceptibility to ALK inhibitor need to be elucidated.nnCitation Format: Min Hwan Kim, Joo Hyuk Sohn, Ja Seung Koo, In Hae Park, Kyung Hae Jung, Soohyeon Lee. Anaplastic lymphoma kinase (ALK) gene copy number gain in inflammatory breast cancer (IBC): frequency, clinicopathologic features and prognostic implication . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1212. doi:10.1158/1538-7445.AM2013-1212