H. Eugene Liu

NAT2 fast acetylator genotypes are associated with an increased risk for lung cancer with wildtype epidermal growth factor receptors in Taiwan

Identifying the risk factors responsible for lung cancer especially for nonsmokers is critical for both its prevention and treatment. Studies have linked the polymorphisms in N-acetyltransferases (NAT2), a key enzyme for metabolism of hydrocarbons, with lung cancer in Asian female nonsmokers. Since a high percentage of lung adenocarcinoma in Asian female nonsmokers contains activating hotspot mutations in epidermal growth factor receptors (EGFR), we hypothesized that NAT2 polymorphisms might represent a risk factor in lung cancer with EGFR mutations. We studied NAT polymorphisms in 117 nonsmall cell lung cancer (NSCLC) patients and in 119 healthy controls and EGFR hotspot mutations in exons 18-21 in 100 of the 117 patients using polymerase chain reactions. NAT2 fast acetylator genotypes were significantly associated with patients with lung cancer (P = 0.04, odds ratio (OR): 1.90, 95% confidence interval (CI): 1.02-3.57). Further analyses revealed that NAT2 fast acetylator genotypes were significantly associated with NSCLC with wildtype EGFR (P = 0.008, OR: 3.16, 95% CI: 1.31-7.63), but not with those with EGFR mutations (P = 0.40). Therefore, NAT2 fast acetylator genotypes are a potential risk factor especially for lung cancer with wildtype EGFR.

Human papillomavirus infections as a marker to predict overall survival in lung adenocarcinoma

Human papillomavirus (HPV) has been implicated in multiple cancers, but its significance in lung cancer has remained controversial. As the prevalence of HPV 16/18 infection was higher in lung adenocarcinoma among Taiwanese females, the aim of our study was to evaluate the clinical impact of HPV infections in lung adenocarcinoma. Two hundred and ten patients were enrolled to investigate the associations of HPV status in tumors with clinical characteristics as well as its impact on overall survival. The methods to assess HPV status were by immunohistochemistry for HPV L1 capsid protein and E6 protein and by nested polymerase chain reaction for HPV 16 and HPV 18. HPV infections were identified in 35.2% of patients, and associated with localized and smaller sized tumors (p = 0.022 and p = 0.002, respectively). Patients with HPV infections had a significantly better survival (p = 0.023, by log‐rank test) and a significantly reduced mortality risk after adjustments of age, tumor extent, epidermal growth factor receptor (EGFR) mutations status and treatments [adjusted hazard ratio = 0.68, 95% confidence interval (CI) = 0.49–0.96, p = 0.026, by multivariate Cox proportional hazards models]. Specifically, patients with both HPV infections and EGFR mutations had the best survival outcome [1‐year survival rate, 68.5% (95% CI = 52.2–4.8%)]. Our findings indicate that HPV infections represent an independent prognostic factor for overall survival in patients with lung adenocarcinoma.

Identification of subgroup patients with stage IIIB/IV non-small cell lung cancer at higher risk for brain metastases.

PURPOSE Brain metastases (BM), a common occurrence in non-small cell lung cancer (NSCLC), usually lead to a poor prognosis. Recently, the selection of treatment modalities for BM has modestly improved patient survival and quality of life. Treatment choice is largely based on the number of BM, the presence of BM-related symptoms, and performance status. Therefore, early BM detection is crucial. In this study, we aimed to elucidate the factors associated with BM and identify subgroups of patients at higher risk for BM. METHODS AND PATIENTS The medical records of 596 consecutive patients with stage I-IV NSCLC were reviewed between January 2006 and November 2011. A multivariate logistic regression (MLR) model was used to identify factors associated with BM. RESULTS Among 482 eligible stage IIIB/IV NSCLC patients, 173 (36%) experienced BM during their disease course. On MLR analysis, female gender, age < 60 years and adenocarcinoma were associated with BM (OR = 1.71, 95% CI = 1.06-2.75, P = 0.028; OR = 2.11, 95% CI = 1.38-3.22, P = 0.001; and OR = 2.39, 95% CI = 1.16-4.92, P = 0.018, respectively). The actuarial incidence of BM varied widely from 14% to 59% in different subgroups; younger patients with adenocarcinoma tended to experience BM more than older patients with squamous cell carcinoma (OR = 6.88, 95% CI = 2.97-15.94, P < 0.001). Furthermore, the incidence of BM correlated closely with survival after NSCLC diagnosis, and it was 42%, 54% and 64% in patients who survived more than 3, 12 and 24 months, respectively. Notably, the number of BM, the size of the largest BM and the proportion of multiple BM, defined as more than 4 metastatic tumors in brain, were significantly different in NSCLC patients with and without BM-related symptoms or signs (4.0 ± 2.1 vs 2.7 ± 1.9, P < 0.001; 2.6 ± 1.5 vs 1.3 ± 1.0 CM, P < 0.001, and 50% vs 21%, P < 0.001, respectively). CONCLUSION We found that subgroups of NSCLC patients characterized by younger age, female gender and adenocarcinoma are at higher risks for BM. These findings might be helpful to detect BM earlier and facilitate the design of clinical trials aiming at their prevention.

Multiple Analytical Approaches Demonstrate a Complex Relationship of Genetic and Nongenetic Factors with Cisplatin- and Carboplatin-Induced Nephrotoxicity in Lung Cancer Patients

Background. Cisplatin and carboplatin cause nephrotoxicity by forming platinum-DNA adducts and lead to cell death. Methods. One-hundred and sixteen Taiwanese lung cancer patients who received cisplatin or carboplatin more than twice were recruited, and their genotypes were determined. The risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease (RIFLE) criteria were used to evaluate the occurrence of nephrotoxicity. A logistic regression, multiple regression with a classification and regression tree (CART), and the Framingham study risk score were used to analyze interactions between genetic and nongenetic factors in producing platinum-induced nephrotoxicity. Results. ERCC1 118C and TP53 72Arg polymorphisms were associated with increased risks of platinum-induced nephrotoxicity. Other risk factors found included the platinum type, baseline serum creatinine (Scr), coadministration of vinorelbine, and the number of chemotherapy cycles. The overall prediction rate of the CART was 82.7%, with a sensitivity of 0.630 and specificity of 0.896. The Framingham study risk prediction model contained 7 factors. Its prediction rate was 84.5%, with a sensitivity of 0.643 and specificity of 0.909. Conclusions. Genetic polymorphisms of ERCC1 and TP53 are risk factors for nephrotoxicity. The CART analysis may provide a clinically applicable model to predict the risk of cisplatin- and carboplatin-induced nephrotoxicity.

Brain metastases in patients with non-small cell lung cancer: the role of mutated- EGFRs with an exon 19 deletion or L858R point mutation in cancer cell dissemination

Non-small cell lung cancer (NSCLC) patients tend to develop brain metastases (BM), but the link between BM occurrence and driver mutations in NSCLC is not very clear. We explored whether activating mutations of epidermal growth factor receptors (EGFRs) in exon 19 deletion or L858R predict BM in NSCLC. A retrospective multivariable logistic regression analysis of 384 patients demonstrated that the presence of mutated-EGFRs was associated with overall BM (OR=2.24, P=0.001) compared to that of wild-type EGFR (WT-EGFR). Moreover, the time-to-event analysis model considering death as a competing risk revealed that, irrespective of survival, mutated-EGFRs predicted subsequent BM (SBM) in stage IIIB-IV patients (37.1% vs. 10.6%, HR=2.98, P=0.002) after adjusting for age (HR=2.00, P=0.012), gender, histological subtype, and smoking history. Notably, the younger mutated-EGFR subgroup was at a higher risk for SBM compared to the older WT-EGFR one (58.1% vs.10.9%, HR=6.57, P<0.001). Additionally, EGFR exon 19 deletion, despite having a slightly longer overall survival (20.6 vs. 14.2 months, P=0.368), was comparable to L858R mutation in predicting SBM (39.5% vs. 34.5%, HR=0.91, P=0.770). In vitro, the overexpression of mutated-EGFRs induced morphological changes towards a mesenchymal-like phenotype and promoted mobility in lung cancer cells. Clinically, mutated-EGFR NSCLC displayed a higher proportion of vimentin-positive expression (75.3% vs. 51.2%; P=0.007) and a shorter median time to SBM (23.5 months vs. not reached, P=0.017) than WT-EGFR NSCLC. These results suggest that NSCLC patients carrying mutated-EGFRs may require a higher frequency of brain imaging assessments than those with WT-EGFR to facilitate earlier SBM detection during follow-up.Non-small cell lung cancer (NSCLC) patients tend to develop brain metastases (BM), but the link between BM occurrence and driver mutations in NSCLC is not very clear. We explored whether activating mutations of epidermal growth factor receptors (EGFRs) in exon 19 deletion or L858R predict BM in NSCLC. A retrospective multivariable logistic regression analysis of 384 patients demonstrated that the presence of mutated-EGFRs was associated with overall BM (OR=2.24, P=0.001) compared to that of wild-type EGFR (WT-EGFR). Moreover, the time-to-event analysis model considering death as a competing risk revealed that, irrespective of survival, mutated-EGFRs predicted subsequent BM (SBM) in stage IIIB-IV patients (37.1% vs. 10.6%, HR=2.98, P=0.002) after adjusting for age (HR=2.00, P=0.012), gender, histological subtype, and smoking history. Notably, the younger mutated-EGFR subgroup was at a higher risk for SBM compared to the older WT-EGFR one (58.1% vs.10.9%, HR=6.57, P<0.001). Additionally, EGFR exon 19 deletion, despite having a slightly longer overall survival (20.6 vs. 14.2 months, P=0.368), was comparable to L858R mutation in predicting SBM (39.5% vs. 34.5%, HR=0.91, P=0.770). In vitro, the overexpression of mutated-EGFRs induced morphological changes towards a mesenchymal-like phenotype and promoted mobility in lung cancer cells. Clinically, mutated-EGFR NSCLC displayed a higher proportion of vimentin-positive expression (75.3% vs. 51.2%; P=0.007) and a shorter median time to SBM (23.5 months vs. not reached, P=0.017) than WT-EGFR NSCLC. These results suggest that NSCLC patients carrying mutated-EGFRs may require a higher frequency of brain imaging assessments than those with WT-EGFR to facilitate earlier SBM detection during follow-up.

Primary Pulmonary Choriocarcinoma with Multiple Lung Metastases: A Case Report

Primary pulmonary choriocarcinoma (PPC) is an extremely rare malignant trophoblastic cancer unrelated to pregnancy, and is 1 of a subset of germ cell tumors. Only a few cases have been reported in the medical literature worldwide. We reported the case of a 43-year-old male patient who suffered from progressive dyspnea, dry cough and chest pain for about 2 weeks. A huge left lung mass associated with bilateral multiple pulmonary nodules was detected by chest radiography and computerized tomography. Bilateral gynecomastia associated with a high level of serum beta-human chorionic gonadotropin (β-HCG) was found during examination. Echo-guided biopsy showed a picture of carcinoma arranged in nests and in a decohesive pattern. Multinucleated syncytiotrophoblast-like tumor cells displayed nuclear hyperchromasia and pleomorphism. Immunohistochemical results showed positive responses to human leukocyte antigen G andβ-HCG. Choriocarcinoma was the definitive diagnosis. Because of the rarity of this malignancy, further studies and more reports of PPC worldwide may help clinicians become more knowledgeable about the clinicopathologic condition. The more understanding there is about the disease, the greater the improvement in the prognosis and survival rate that may be achieved.

Abstract 3867: EGFR genotype impacts expression of chemotherapeutic target biomarkers in NSCLC

BACKGROUND: Non small cell lung cancer EGFR mutations are prevalent in the East Asian population, especially in female non-smokers, the L858R and del 747-753 in exons 18-21 of the EGFR tyrosine kinase domains are activating mutations with increased sensitivity to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. EGFR gene amplification also increases susceptibility to EGFR TKIs as has been reported in the IDEAL / INTACT non small cell lung cancer (NSCLC) trials. Our study evaluated chemotherapeutic target biomarkers in Chinese NSCLC patients with varying EGFR genotypes. METHODS: Seventy NSCLC patients with known EGFR genotype received chemotherapy and EGFR TKI therapy with known response and survival, their pathology specimen were retrospectively retrieved for evaluation. EGFR and KRAS were sequenced for mutations and deletions. Fluorescent in situ hybridization (FISH) was performed for EGFR genes. Immunohistochemical analyses were performed for topoisomerase 1, c-myc, RRM-1, class III beta tubulin, topoisomerase IIα, p53, thymidylate synthase, and ERCC-1. The percentage of nuclear-stained malignant cells were recorded for T IIα, T1, p53, ERCC-1, c-myc, whereas for TS, tau, RRM-1, class III beta tubulin were cytoplasmic stains, only positive or negative was reported, eventually only 63 patients had complete data for evaluation. RESULTS: Significant increase in overall survival was found in females (p=0.002), non-smokers (p=0.005), younger age (p=0.001), less advanced staging (p=0.048), EGFR mutation (p=0.038); but not with KRAS genotype, or expression of any chemotherapeutic markers. Patients in this study were consecutive patients, 60-70% received treatment. When EGFR mutant tumors were compared to EGFR wildtype tumors, the mutant tumors had lower KRAS mutation (4% vs 19%, p=0.1238), more were ERCC1- (76% vs 63%, p=0.2925), more topoisomerase 1 + (28% vs 17%, p=0.3719), less RRM1+ (24% vs 35%, p=0.4142), more TS- (93% vs 86%, p=0.4478), lower class III beta tubulin (45% vs 57%, p=0.4515). CONCLUSIONS: A difference in expression of chemotherapeutic target markers has been detected in differing EGFR genotypes, although its significance has been dampened by our small patient population, and larger patients groups will be needed to evaluate the impact of different chemotherapies on survival of the different EGFR genotype tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3867. doi:10.1158/1538-7445.AM2011-3867

Favorable Response to Pemetrexed as a Salvage Agent for Patients with Advanced Lung Cancer Who Have Failed Conventional Platinum-Based Chemotherapy and EGFR Tyrosine Kinase Inhibitors

Background: For locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC), pemetrexed is currently recommended as first-line treatment in combination with platinum agents or second-line chemotherapy after the disease has become refractory to platinum-based doublet regimens, but few reports have addressed its role as salvage chemotherapy after failure of multiple therapies and the relationship between response rate and EGFR and K-ras mutations. Methods: We retrospectively evaluated the efficacy of pemetrexed in 11 patients with advanced NSCLC, who had failed at least platinum-based doublet combinations and erlotinib or gefitinib. The gender, performance status, number of cycles given, EGFR and K-ras mutation status, best response, adverse reactions, time to progression (TTP) and overall survival (OS) were used to assess the effects. Results: A median of 6.17 cycles of infusion was given. Six out of 11 patients experienced partial response, three stable disease and two disease progression. The TTP and OS of salvage pemetrexed therapy were 108 and 346 days, respectively. The EGFR mutation status did not affect its efficacy. It was well-tolerated and required no dose modification. Conclusions: Pemetrexed is a good option for patients with good performance status who have failed platinum-and taxane-containing regimens and EGFR tyrosine kinase inhibitors.