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405736 Background: There is an unmet need for novel targeted therapies that improve outcomes for pts with HER2− LA unresectable or mG/GEJ adenocarcinoma. CLDN18.2 is expressed in normal gastric mucosa cells and retained in most G/GEJ adenocarcinomas. In the phase 3 SPOTLIGHT study, zolbetuximab, a CLDN18.2-targeted chimeric monoclonal antibody, significantly prolonged PFS and OS in pts with CLDN18.2+/HER2− LA unresectable or mG/GEJ adenocarcinoma when combined with mFOLFOX6. GLOW (NCT03653507) is a phase 3 global, double-blind study comparing zolbetuximab or PBO with capecitabine and oxaliplatin (CAPOX) as 1L treatment for this pt population. Methods: Pts with CLDN18.2+ (moderate-to-strong membranous CLDN18 staining in ≥75% tumor cells by IHC)/HER2− LA unresectable or mG/GEJ adenocarcinoma were randomized 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (D1 in subsequent cycles) + CAPOX (oral capecitabine 1000 mg/m2 BID on D1−14 of each cycle; oxaliplatin IV 130 mg/m2 on D1 of each cycle) for eight 21-day cycles vs PBO + CAPOX; pts continued for >8 cycles with zolbetuximab or PBO, plus capecitabine (investigator decision), until PD or a discontinuation criterium was met. The primary endpoint (EP) was PFS per RECIST v1.1 by IRC. OS was a key secondary EP; other secondary EPs included ORR and safety. Differences between treatment arms in PFS and OS were tested by stratified log-rank tests; OS was tested if PFS was significant. Results: 507 pts were randomized 1:1 to zolbetuximab + CAPOX (N = 254) or PBO + CAPOX (N = 253). Both PFS (median 8.21 vs 6.80 mo, HR 0.687, P=0.0007) and OS (median 14.39 vs 12.16 mo, HR 0.771, P=0.0118) were significantly prolonged with zolbetuximab + CAPOX (Table); in pts with measurable disease, ORR (95% CI) was 53.8% (46.58−60.99) vs 48.8% (41.76−55.84) in zolbetuximab vs PBO arm. The most common TEAEs with zolbetuximab + CAPOX were nausea (68.5% vs 50.2% in zolbetuximab vs PBO arm), vomiting (66.1% vs 30.9%), and decreased appetite (41.3% vs 33.7%); serious TEAEs (47.2% vs 49.8%), grade ≥3 TEAEs (72.8% vs 69.9%), and drug-related TEAEs leading to death (2.4% vs 2.8%) were similar in both arms. Conclusions: Targeting CLDN18.2 with zolbetuximab combined with CAPOX significantly prolonged PFS and OS in 1L pts with CLDN18.2+/HER2− LA unresectable or mG/GEJ adenocarcinoma. These results align with those observed in SPOTLIGHT and establish zolbetuximab + chemotherapy as a potential new standard-of-care option for these pts. Clinical trial information: NCT03653507 . [Table: see text]

c-Myc regulates multiple genes involved in cell proliferation in various cancer types including non-small cell lung cancer (NSCLC). Copy number gains of cytoband 17q25.3, along with chromosome 17, have been reported in NSCLC patients, emphasizing the clinical significance as a potential molecular target for therapy. The upregulation of c-Myc has been found to accelerate tumor development associated with duplication of the syntenic human cytoband 17q25.3. This study aimed to explore and compare the correlations of chromosome 17 copy number and c-Myc expression in NSCLC with the paired-normal respiratory epithelium and to examine their role as potential molecular targets for NSCLC therapy.A total of 66 NSCLC tissue samples with paired-normal respiratory epithelium were examined. The copy number of chromosome 17 was determined by human epidermal growth factor receptor 2 (Copy number gains of chromosome 17 were identified in 8 of 60 (13.3%) available NSCLC specimens. No copy number gains of chromosome 17 were demonstrated in the paired-normal respiratory epithelium. The meanBoth biomarkers deserve further investigation to identify NSCLC patients with poorer survival outcomes requiring better therapeutic approaches.

Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer death worldwide, for which better knowledge in molecular prognostic factors is needed to improve clinical outcome. This study aimed to investigate the clinical significance of c-Myc, ALK, ROS1, BRAF, and PD-L1 in NSCLC patients. Methods: Formalin-fixed paraffin-embedded tissue specimens were obtained from 124 NSCLC patients. Of these, 66 matched specimens of normal respiratory epithelial and tumor tissue from patients with stages I-III, who underwent surgical resection, and 58 NSCLC specimens from stage IV patients were recruited into this analysis. Immunohistochemistry staining along with semiquantitative criteria were used to evaluate the expression of the interested proteins. Results: Of the 66 patients with stages I-III, positive expression of c-Myc was detected in 12 specimens (18.2%) of NSCLC tissue, whereas none of the normal respiratory epithelial tissue was found to have c-Myc expression ( P Conclusions: NSCLC tissue significantly expressed more c-Myc and PD-L1, compared with the matched normal respiratory epithelium, emphasizing the important role of these key drivers in tumorigenesis. Therapeutic approach to precisely inhibit the targetable molecular pathways should be considered on an individual patient basis to improve survival outcome.

241 Background: At interim analysis of the phase 3, randomized, double-blind KEYNOTE-590 (NCT03189719) study, 1L pembrolizumab (pembro) + chemotherapy (chemo) vs chemo alone provided superior OS, PFS, and ORR with a manageable safety profile in patients (pts) with untreated, advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric junction adenocarcinoma (EGJ). We report efficacy, safety, and health-related quality of life (HRQoL) results with an additional 12 months (mo) of follow-up. Methods: 749 eligible pts were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 2 yr + chemo. Randomization was stratified by geographic region, histology, and performance status. Treatment continued until progression, unacceptable toxicity, or withdrawal, or 2 yr. No crossover was permitted. Primary endpoints were OS in pts with ESCC PD-L1 combined positive score (CPS) ≥10 tumors, and OS and PFS (RECIST v1.1; by INV) in ESCC, PD-L1 CPS ≥10, and all pts. Secondary endpoints included ORR, DOR, safety, and HRQoL. HRQol was assessed in 711 treated pts with ≥1 HRQoL assessment (356 pembro + chemo; 355 chemo). Data cutoff was July 9, 2021. Results: At data cutoff, median follow-up (randomization to data cutoff) was 34.8 mo. Median OS was longer with pembro + chemo vs chemo in pts with ESCC CPS ≥10 (HR 0.59; 95% CI, 0.45-0.76), ESCC (HR 0.73; 95% CI, 0.61-0.88), CPS ≥10 (HR 0.64; 95% CI, 0.51-0.80), and all pts (HR 0.73, 95% CI, 0.63-0.86). In pts with adenocarcinoma OS HR was 0.73 (95% CI, 0.55-0.99). The 24-mo OS rate in all pts was 26.3% vs 16.1%. Median PFS was longer with pembro + chemo vs chemo in ESCC (HR 0.65; 95% CI, 0.54-0.78), CPS ≥10 (HR 0.51; 95% CI, 0.41-0.65), and all pts (HR 0.64; 95% CI, 0.55-0.75). The 24-mo PFS rate in all pts was 11.6% vs 3.3%. Confirmed ORR was 45.0% (25 CR [6.7%]) vs 29.3% (9 CR [2.4%]), with median DOR of 8.3 vs 6.0 mo. Approximately 20% vs 6% of pts had response duration ≥24 months. Grade 3-5 drug-related AE rates were 72% vs 68%. Discontinuation rates from drug-related AEs were 21% vs 12%. There was no significant difference in least square mean (LSM) change from baseline to wk 18 between arms in EORTC QLQ-C30 global health status/quality-of-life (LSM difference -0.10; 95% CI, -3.40-3.20). LSM change from baseline to wk 18 was better with pembro + chemo vs chemo for QLQ-OES 18 pain (-2.94; 95% CI, -5.86 to -0.02) and dysphagia (-5.54; 95% CI, -10.92 to -0.16). Conclusions: With an additional 12 months of follow-up, pembro + chemo continued to provide significant and clinically meaningful improvement in OS, PFS, and ORR vs chemo with a manageable safety profile, and stable quality-of-life for pts with untreated, advanced esophageal and EGJ cancer. These data continue to support 1L pembro + chemo as a new standard of care in these patients. Clinical trial information: NCT03189719.

Objective The Phase III, randomized, open-label IPASS study (NCT00322452) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) gefitinib versus carboplatin/paclitaxel for Asian patients with advanced non-small-cell lung cancer (NSCLC) showed that investigator-assessed progression-free survival (PFS) and objective response rate (ORR) were significantly prolonged in patients with EGFR mutation-positive NSCLC who received gefitinib versus patients with EGFR mutation-negative NSCLC. We report post-hoc analyses of IPASS data by blind independent central review (BICR), performed at the request of the US FDA, in a subset of patients with EGFR mutation-positive NSCLC. Patients and methods Eligible patients (aged ≥18 years; histologically/cytologically confirmed Stage IIB/IV adenocarcinoma NSCLC; non- or former light-smokers; treatment-naive) were randomly assigned 1:1 to gefitinib (250mg/day) or carboplatin (dose calculated to produce an area under the curve of 5 or 6 mg/mL/minute)/paclitaxel (200mg/m 2 ). Primary endpoint: PFS. BICR analyses included PFS, ORR, and duration of response (DoR). Results Scans from 186 IPASS patients (gefitinib n = 88, carboplatin/paclitaxel n = 98) with EGFR mutation-positive NSCLC were available for BICR. Consistent with investigator-assessed results, in patients with EGFR mutation-positive NSCLC: PFS (hazard ratio 0.54; 95% confidence interval [CI] 0.38, 0.79; p = 0.0012) and ORR (odds ratio 3.00; 95% CI 1.63, 5.54; p = 0.0004) were significantly longer with gefitinib versus carboplatin/paclitaxel. The median DoR by BICR was 9.6 months with gefitinib and 5.5 months with carboplatin/paclitaxel. Conclusion BICR analysis of IPASS data support the original, investigator-assessed results. EGFR mutation-positive status remains a significant predictor of response to first-line TKI therapy.

A multimodality approach using concurrent chemoradiotherapy (CRT) followed by esophagectomy has been the standard treatment in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Computed tomography (CT) is widely utilized to evaluate esophageal cancer before and after CRT. This study evaluated the utility of pretreatment maximal esophageal wall thickness on CT scans to predict treatment outcomes after CRT in patients with locally advanced ESCC. Eighty-one patients with T3 locally advanced ESCC, whom were treated completely with CRT with and without surgery, and had available CT scans before and after CRT at a university hospital between 2005 and 2015, were retrospectively reviewed. Twenty patients (24.7%) had esophagectomy after neoadjuvant CRT and sixty-one patients (75.3%) had definitive CRT. The maximal esophageal wall thicknesses were measured retrospectively and correlated with the response and survival after treatment. A total of 40% of neoadjuvant CRT patients achieved a pCR. There was a significant difference in pretreatment maximal esophageal wall thickness between the pCR and non-pCR groups (mean 11.9 ± 5.3 mm versus 16.9 ± 3 mm; p = 0.01). Pretreatment maximal esophageal wall thickness < 10 mm was significantly related to better overall survival than ≥ 10 mm (median survival 79 months versus 15 months; HR 3.21, 95%CI 1.14–9; p = 0.02). The neoadjuvant CRT group had significantly better survival than the definitive CRT group (median survival 51 months versus 14.5 months; HR 0.46; 95%CI 0.25–0.85; p = 0.01). In our study, pretreatment esophageal wall thickness of T3 locally advanced ESCC is a useful indicator for predicting survival and pCR after treatment.

Summary Background CLEOPATRA was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA. Methods This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators’ discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov , number NCT00567190 . Findings Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9–106·4) and 98·7 months (90·9–105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50–72) in the pertuzumab group and 40·8 months (36–48) in the placebo group (hazard ratio 0·69, 95% CI 0·58–0·82); 8-year landmark overall survival rates were 37% (95% CI 31–42) in the pertuzumab group and 23% (19–28) in the placebo group. The most common grade 3–4 adverse event was neutropenia (200 [49%] of 408 patients in the pertuzumab group, 183 [46%] of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis. Interpretation Our analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. Funding F Hoffmann-La Roche and Genentech.

Background The prognoses of head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC) are poor, especially when both tumors occur at the same time. We examined the clonal relatedness of HNSCCs with synchronous ESCCs to confirm whether the second tumors were metastasis or separate second primary malignancies (SPMs) using loss of heterozygosity (LOH) analysis. Methods Twenty-one pairs of formalin-fixed paraffin-embedded tissue from HNSCC patients with synchronous esophageal cancer were analyzed by single nucleotide polymorphism (SNP) array using the Illumina HumanCytoSNP FFPE-12 BeadChip (San Diego, CA), which contains approximately 300,000 probes. LOH was identified using Nexus Copy Number software (El Segundo, CA). Results Comparing the LOH pattern between HNSCC and paired ESCC, we found that 20 out of 21 paired tissues had a high number of discordant LOHs (LOH identified solely in the primary HNSCC but not in synchronous ESCC at the same genomic location) and a low number of concordant LOHs (LOH at the same genomic location in both HNSCC and ESCC). Only one case fell into the undetermined category. Therefore, these 20 ESCCs were classified as SPMs or second field tumors (SFTs). Moreover, the HNSCC patients with molecularly confirmed esophageal SPM had significantly poorer survival than the other patients. Conclusions We propose the use of a genome-wide SNP array as a tool to differentiate metastatic tumors from SPM/SFT. The SNP array offers genome-wide LOH information that earlier microsatellite analysis studies lack. The ability to accurately identify SPM should contribute to a better treatment plan and follow-up care of these patients.

168 Background: In the randomized, international, double-blind, placebo-controlled KEYNOTE-590 (NCT03189719) study, pembrolizumab (pembro) + chemotherapy (chemo) provided statistically significant and clinically meaningful improvement in OS, PFS, and ORR vs placebo + chemo as first-line therapy for patients (pts) with locally advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric junction adenocarcinoma (EGJ). Here we report HRQoL outcomes in KEYNOTE-590. Methods: 749 pts were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 2y + chemo (cisplatin 80 mg/m2 Q3W [d1; 6 doses] + 5-FU 800 mg/m2 on d1-5 Q3W). EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L questionnaires were administered at baseline, every 3 weeks (Q3W) up to week 24, and then Q9W up to 1 year or end of treatment, and at the 30-d safety follow-up visit. HRQoL was assessed in all treated patients who completed ≥1 HRQoL assessment (N = 711: 356 for pembro + chemo; 355 for chemo). Change from baseline to week 18 in EORTC-QLQ-C30 global health status (GHS)/QoL and physical functioning, and in QLQ-OES18 scores were prespecified secondary endpoints. Change from baseline to week 18 in EQ-5D scores was an exploratory endpoint. Time to deterioration (TTD) was evaluated for all endpoints. Least square mean (LSM) change from baseline (95% CI) was compared using a constrained longitudinal data analysis model. TTD was compared using a stratified log rank test and Cox proportional hazards model. P-values are nominal and two-sided. Results: QLQ-C30, QLQ-OES18 and EQ-5D-5L compliance was ≥90% in both arms at baseline and at week 18. There was no significant difference in least squares mean (LSM) change from baseline to week 18 in GHS/QoL status between arms (LSM difference [95% CI] -0.10 [-3.40-3.20]; P = 0.9530). Median TTD in GHS/QoL was similar between arms (HR, 0.86 [95% CI, 0.66-1.13]; P = 0.2864). Outcomes were similar in ESCC PD-L1 CPS ≥10, ESCC, and PD-L1 CPS ≥10 patient populations. LSM change from baseline to week 18 for QLQ-OES18 pain subscale was better for pembro + chemo (-4.78) vs chemo (-1.85 ) (-2.94, -5.86 to -0.02; P = 0.0487). There was no significant difference in LSM change from baseline to week 18 between arms for reflux (-1.19; -4.49-2.10; P = 0.4781) or dysphagia (-2.35; -7.78-3.07; P = 0.3945). VAS LSM change from baseline to week 18 was similar between arms (1.20, -1.61-4.01; P = 0.4016). Conclusions: HRQoL was stable and similar over 18 weeks in the pembro + chemo and chemo arms. Together with superior OS, PFS, and ORR and a manageable safety profile with pembro + chemo, these results support the clinically meaningful benefit of pembro + chemo in patients with advanced esophageal cancer including EGJ adenocarcinoma. Clinical trial information: NCT03189719.

e18560 Background: CN remains a frequent occurrence despite receiving standard fluid hydration, particularly for head and neck cancer patients undergoing CCRT. We aimed to investigate whether adding ORS to short hydration regimen can reduce CN. Methods: We conducted a randomized open-label controlled trial in patients with head and neck cancer receiving CCRT with 3-weekly cisplatin (≥ 60 mg/m²). Eligible patients were randomly assigned to receive short hydration regimen (2000 mL of normal saline on day 1) alone or in combination with 2000 mL of ORS on days -1, 2 and 3 of each cycle. All patients were instructed to drink at least 2000 mL of fluid. The primary end point was the incidence of ≥ gr 1 creatinine (Cr) elevation on day 8. The planned sample size was 160 (80 patients each arm). Results: Thirty-five patients in ORS group and 34 patients in control group (43% of planned sample size) were enrolled. Baseline characteristics were balanced between the two groups, except more patients in ORS group underwent surgery (35.3% vs. 22.9%), and had less feeding tube prophylaxis (76.5% vs. 88.6%), although there were not statistically significant. The mean dose of cisplatin on day 1 was significantly higher in ORS group (91.2 mg/m2 vs. 85.1 mg/m2, p=0.01). There was no difference of volume of total fluid intake and toxicities between the two groups. Less percentage of patients in ORS group developed ≥ gr 1 Cr elevation as shown in the Table, although there were not statistically significant. Conclusions: Although our interim analysis showed no significant difference of CN between the groups, there was a trend that addition of ORS might prevent acute and chronic kidney injury secondary to cisplatin. The completed enrollment is warranted to confirm this early findings. Clinical trial information: TCTR20200207005 . [Table: see text]

To identify potential biomarkers that may provide new therapeutic targets or prognostic indicators for non-small cell lung cancer (NSCLC), we investigated the three-dimensional (3D) organization of telomeres and cytoband 17q25.3 copy number in NSCLC tissues. NSCLC paraffin-embedded tissue specimens from 18 patients were assessed for 3D telomere organization by 3D nuclear telomere imaging followed by quantitative analysis. Patients were stratified by smoking, histology, and EGFR status. Cytoband 17q25.3 was examined by fluorescent in situ hybridization. Data from comparative genomic hybridization and/or single nucleotide polymorphism arrays for cytoband 17q25.3 were obtained and correlated with Q-FISH and 3D telomere results. 3D telomeric profiling demonstrated that the smokers, EGFR-negative, and squamous cell carcinoma subgroups tended to have higher numbers of lower-intensity telomeres, indicative of shorter telomeres, as well as higher numbers of telomeric aggregations compared to non-smokers, EGFR-positive, and adenocarcinomas, respectively. Gains of cytoband 17q25.3 in conjunction with an increase in the control region 17p11.2 were observed in 7 of 18 (38.9 %) patients, reflecting a gain of chromosome 17. Clonal gains of cytoband 17q25.3 were observed in 11 of 18 (61 %) patients, highlighting a potential biological significance for the genes in this region in NSCLC tumourigenesis. The 3D telomere profiles may differentiate NSCLC patients with different histologies, EGFR, and smoking statuses, rendering them a potential biomarker for distinguishing these clinically relevant histological and molecular subtypes of lung cancer. Highly frequent clonal gain of cytoband 17q25.3 was also demonstrated, suggesting an important biological role for the genes in this region.

Telomeres are repetitive nucleotide sequences (TTAGGG)n located at the ends of chromosomes that function to preserve chromosomal integrity and prevent terminal end-to-end fusions. Telomere loss or dysfunction results in breakage-bridge-fusion cycles, aneuploidy, gene amplification and chromosomal rearrangements, which can lead to genomic instability and promote carcinogenesis. Evaluating the hypothesis that changes in telomeres contribute to the development of esophageal squamous cell carcinoma (ESCC) and to determine whether there are differences between young and old patients, we compared the three-dimensional (3D) nuclear telomere architecture in ESCC tumor cells with that of normal epithelial cells obtained from the same patient. Patients were equally divided by age into two groups, one comprising those less than 45 years of age and the other consisting of those over 80 years of age. Tumor and normal epithelial cells located at least 10 cm from the border of the tumor were biopsied in ESCC patients. Hematoxylin and eosin staining was performed for each sample to confirm and identify the cancer and normal epithelial cells. This study was based on quantitative 3D fluorescence in situ hybridization (Q-FISH), 3D imaging and 3D analysis of paraffin-embedded slides. The 3D telomere architecture data were computer analyzed using 100 nuclei per slide. The following were the main parameters compared: the number of signals (number of telomeres), signal intensity (telomere length), number of telomere aggregates, and nuclear volume. Tumor and normal epithelial samples from 16 patients were compared. The normal epithelial cells had more telomere signals and higher intensities than the tumor cells, with P-values of P < 0.0001 and P = 0.0078, respectively. There were no statistically significant differences in the numbers of telomere aggregates or the nuclear volumes between the tumor and normal epithelial cells. Secondary analyses examined the effects of age on 3D telomere architecture and found no statistically significant differences in any parameter tested between the young and old patients in either the tumor or epithelial cells. The 3D nuclear telomeric signature was able to detect differences in telomere architecture between the ESCC and normal epithelial tissues. However, there were no differences observed between the young and old patients.

14 Background: “The South Thailand Insurgency” is burning violence in the deep south of Thailand. The insurgency which has been ongoing since 2004 has played out in the three southernmost districts of the country Pattani, Yala and Narathiwat and some area of Songkhla, so-called the “Red Zone”. The chronic terrorism had major affected on cancer service. Many cancer patients gave up on their lives due to struggle with the disease itself, financial constraints due to longstanding economic downturn and security concerns during travelling led to high loss to follow-up rate and treatment delay. We, an oncology service team working at Songklanagarind hospital, the only one cancer center served this area together with primary doctors and nurses in the Red Zone created a network and utilized an oncology-specific electronic consultation and referral system to make more efficient care. We reported its performance in 3 years period. Methods: Electronic consultation system (E-consult) was a web-based program developed to provide advice and facilitate the referral process in cancer care. Since October 2015, we prospectively surveyed the impact of this pilot project on the quality of service by counting waiting time, number of center visit until treatment, unnecessary referral avoidance, patient and potential cost saving compared to normal referral system. Results: E-consult reached out to 7 hospitals and 589 cancer patients successfully referred through E-consult. Among patients from the Red Zone, without E-consult, their average waiting time was 56.4 days, number of visit was 6.5 visits. The estimated financial burden was $758.8 per patient. After implementation of E-consult in 259 patients, average time to treatment was 41.5 days (p = 0.006) and a number of the counter visit was 2.3 visits (p < 0.001). Estimated financial burden could be reduced to $358.7(p < 0.001). Ultimately, we prevented 28 patients from unnecessary referral. Conclusions: In this special context the electronic referral system was helpful to improve medical access, timeliness to specialist care, saving the patients’ family time and resources. This model is widely applicable to oncology referral chain.

Background “The South Thailand Insurgency” is burning violence in the deep south of Thailand. The insurgency which has been ongoing since 2004 has played out in the three southern most districts of the country Pattani, Yala and Narathiwat and some area of Songkhla, so-called the “Red Zone”. Violence such as daily ambush, bombing on soldiers and civilians, caused people living in terror. This violence has affected cancer service. Many cancer patients gave up on their lives due to struggle with the disease itself, security concerns, traveling and caregiving burden led to a high loss to follow-up rate. We, an oncology service team working at Songklanagarind hospital, the only one radiation and oncology center located in this area, in cooperation with doctors and nurses working in the Red Zone created a network and utilized an electronic consultation and referral system to alleviate these suffering. We preliminarily reported its real-life performance in 3 years period. Methods Electronic consultation system(E-consult) was a web-based program designed and developed to provide advice and facilitate the referral process in cancer care. Since October 2015, we prospectively surveyed the impact of this pilot project on the quality of service by counting waiting time, the number of center visit until treatment, unnecessary referral avoidance, patient and potential cost saving compared to the normal referral system. Results E-consult reached out to 7 hospitals and 589 patient referred through E-consult. Among patients from the Red Zone, without E-consult, their average waiting time was 56.4 days, the number of visits was 6.5 visits. The estimated financial burden was $758.8 per patient. After the implementation of E-consult in 259 patients, the average time to treatment was 41.5 days (p = 0.006) and the number of counter visit was 2.3 visits (p Conclusions In this special context, the electronic referral system not only was helpful to improve medical access, timeliness to specialist care, saving the patients’ family time and resources but it also supports the doctors and nurses on duty in the Red Zone. Legal entity responsible for the study Nanthiya Rattanakhot. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

6572 Background: Cervical cancer is one of the most preventable cancers, not only presence of effective HPV vaccination but also simple and robust screening methods such as Pap test. Nevertheless, there were some women at risk whom were unable to access screening cause of incarceration. Hence, in 2018, together with Songkhla Woman Correctional Institute, we launched a cancer screening campaign including clinical breast exam, mobile mammography and Pap test. This is the first report of cervical cancer screening result demonstrated the essential of cervical cancer screening in these disadvantaged women. Methods: Due to the regulation of the jail, we had to limited bring-in tools, allowed staffs and operating-time, therefore we used a pre-screening questionnaire, included 5 items: HIV infection, number of partner, parity, age at first sexual intercourse and number of term baby and each of them scored as 2 for “high-risk” and 1 for “low-risk”, total score ranged from 5 to 10. We ranked and chose the volunteer participants, who have HIV infection and/or with highest risk score, to undergo Pap test. Results: Of the 1328 questionnaire responders, Their mean risk score was 7.3 (SD= 1.3). HIV infected participants number were 34 (2.5%). Of the 200 screened-participants, None of them had ever received HPV vaccination before, and all participant did not have Pap test since imprisonment. (mean 53.8 m, range 13-236 m, SD 36.7). Their score ranged between 8 to 10, 42.5% of them had score level 8, 54.5% had score level 9 and 3% had score level 10. Mean age was 37.7 years. 10 (5%) of them had abnormal Pap test; 1 of them showed ASC-US, 1 was LSIL, 1 was ASC-H, 5 of them showed HSIL and 2 of them showed squamous cell carcinoma and small round cell carcinoma. Final histopathological test resulted in 6 of cervical intraepithelial neoplasia (CIN) I, metaplasia and cervicitis, 3 were diagnose CIN III and 1 diagnosed microinvasive carcinoma. Incidence of cervical cancer was higher than normal population in this region. (0.5% vs 0.02%). Conclusions: Incarcerated women were at high risk of cervical cancer compared to normal population. Unfortunately, in many places, they were unconditionally inaccessible to the cervical cancer preventive healthcare system for years. Social should increase awareness to decrease this health disparity.

Background: Cisplatin-based chemotherapy followed by surgical resection of the residual tumor remains the standard of care for patients with mediastinal germ cell tumors (MGCTs). To prevent pulmonary complications, a non-bleomycin-containing regimen is generally preferred. This study aims to review the clinical characteristics and outcomes of these patients. Methods: A retrospective chart review was undertaken in patients treated for MGCTs between 2003 and 2013. Results: A total of 40 patients were enrolled; 7 patients were diagnosed with seminoma, while 33 patients had non-seminoma. 92% of patients received chemotherapy as a first treatment modality: 87% bleomycin, etoposide and cisplatin; 13% etoposide and cisplatin, with an objective response rate of 61.3%. Among these, 44% achieved a complete serological response. 17 patients underwent surgical resection of the residual tumor. No patient suffered from pulmonary complications after surgery. The 5-year overall survival (OS) was 71.4 and 27.3% in seminoma and non-seminoma patients, respectively (p = 0.051). For those who received chemotherapy followed by surgical resection with no viable tumor or only mature teratoma detected, the 5-year OS was 72.7% compared with 20.7% in patients not treated with surgery (p = 0.02). Conclusion: Our study confirmed the importance of a multimodality approach with primary chemotherapy followed by surgical resection of the residual tumor. A bleomycin-containing regimen can be safely used in this setting.

Squamous cell carcinoma antigen (SCCA) and CYFRA 21-1 have been reported as useful tumor markers for esophageal squamous cell carcinoma (ESCC), but no information has yet been reported about the relationship between these serum tumor markers and tissue proliferative activity (Ki-67) in ESCC patients.To study the correlation between SCCA, CYFRA 21-1, Ki-67, and clinicopathological factors in ESCC patients.Pretreatment SCCA and CYFRA 21-1 serum levels were measured, while the expression of Ki-67 was assessed on tumor tissue. The associations between these biomarkers, clinicopathological factors, and overall survival were analyzed.One hundred sixty six patients participated in this study. Elevated SCCA and CYFRA 21-1 were found in 78.9% and 50.0% of the patients, respectively, while 42.8% had both serum markers elevated. The SCCA and CYFRA 21-1 levels were not correlated (p = 0.128) to each other nor to age, sex, T N, M location, grade, or Ki-67. High Ki-67 expression levels were significantly correlated with T4 (p = 0.010), M1 (p = 0.010), and poor grade (p = 0.015) but not to age, sex, N, or location. Levels of SCCA, CYFRA 21-1, and Ki-67, alone or in any combination, were not correlated to survival of patients.The authors showed that Ki-67 in tumor tissue is probably a more reliable marker than serum SCCA and CYFRA 21-1 in predicting the clinical course of ESCC.

Purpose The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. Patients and Methods In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. Results OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). Conclusion EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation–positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

Purpose Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. This phase III study assessed the efficacy of vandetanib versus erlotinib in unselected patients with advanced non–small-cell lung cancer (NSCLC) after treatment failure with one to two prior cytotoxic chemotherapy regimens. Patients and Methods One thousand two hundred forty patients were randomly assigned to receive vandetanib 300 mg/d (n = 623) or erlotinib 150 mg/d (n = 617). The primary objective was to show superiority in progression-free survival (PFS) for vandetanib versus erlotinib. If the difference did not reach statistical significance for superiority, a noninferiority analysis was conducted. Results There was no significant improvement in PFS for patients treated with vandetanib versus erlotinib (hazard ratio [HR], 0.98; 95.22% CI, 0.87 to 1.10; P = .721); median PFS was 2.6 months for vandetanib and 2.0 months for erlotinib. There was also no significant difference for the secondary end points of overall survival (HR, 1.01; P = .830), objective response rate (both 12%), and time to deterioration of symptoms for pain (HR, 0.92; P = .289), dyspnea (HR, 1.07; P = .407), and cough (HR, 0.94; P = .455). Both agents showed equivalent PFS and overall survival in a preplanned noninferiority analysis. Adverse events (AEs; any grade) more frequent with vandetanib than erlotinib included diarrhea (50% v 38%, respectively) and hypertension (16% v 2%, respectively); rash was more frequent with erlotinib than vandetanib (38% v 28%, respectively). The overall incidence of grade ≥ 3 AEs was also higher with vandetanib than erlotinib (50% v 40%, respectively). Conclusion In patients with previously treated advanced NSCLC, vandetanib showed antitumor activity but did not demonstrate an efficacy advantage compared with erlotinib. There was a higher incidence of some AEs with vandetanib.

Overexpression of the epidermal growth factor receptor-related gene ErbB2 occurs in 18% to 25% of patients with breast cancer in Western countries and is associated with a poor prognosis. The prevalence of ErbB2-positive tumors in Asia is unclear, partly because data are limited. The objective of this review was to summarize the reported prevalence of ErbB2-positive tumors from a large sample of Asian patients and to examine ErbB2 assessment methods in Asia. From searches of MEDLINE, local language journals, and local and international conference proceedings as well as locoregional breast cancer experts' recommendations, the authors selected up to 5 studies each from India, Korea, Malaysia, the Philippines, Singapore, Taiwan, and Thailand that reported ErbB2 results based on assessment with immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). The reported prevalence of ErbB2-positive tumors in 22 studies on 24,671 patients, of whom 14,398 patients were assessed for ErbB2 status, varied widely (range, 6%-65%) as did the assessment methods used. Most studies (n = 21) used IHC to assess ErbB2 status, but definitions for positivity varied. When robust assessment methods were used, the median prevalence was 19% based on strong IHC staining (IHC3+; n = 9812 patients) and 25% based on FISH (n = 681 patients). Data on the prevalence of ErbB2-positive breast cancer in Asia are limited. The current survey indicated that the prevalence in Asia may be similar to that in Western countries; thus, up to 1 in 4 Asian patients with breast cancer potentially could benefit from ErbB2-targeted treatment. A standard, reliable ErbB2 assessment method available to patients across Asia is urgently required. Cancer 2010;116:5348–57. © 2010 American Cancer Society.

The biology of breast cancer is complex, and the increasing knowledge of its molecular biology is having a great impact on the clinical management of this serious condition. This review looks at new findings on the role of various critical genes, including BRCA1, BRCA2, HER2 and p53, in the development of breast cancer and their clinical implications.

To assess the status of EGFR, HER-2, and CCND1 at the gene and protein levels in esophageal squamous cell carcinoma. Dual-color FISH assays were performed using DNA probes for EGFR/CEP 7, HER-2/CEP 17, and CCND1/CEP 11. The respective proteins, furthermore, was assessed in IHC assays and correlated with patient and tumor characteristics. From 55 ESCCs, 8 (15%) tumors showed gene amplification and 20 (36%) had gene overrepresentation (balanced gene and chromosome 7 polysomy) for EGFR. High-level protein expression was frequent (49%), positively correlated with gene copy numbers (kappa=0.4), and associated with well-differentiated histology (p=0.02). For HER-2, gene amplification was detected in a single tumor (2%) and protein overexpression was rare (9%). CCND1 gene was amplified in 23 (42%) tumors; likewise, CCND1 protein overexpression was common (58%) and prevailed in gene overrepresentation or amplification. Only 1 patient showed gene amplification for both EGFR and CCND1. Survival was not associated with EGFR or CCND1 gene/protein status, whereas negative patients for HER-2 protein had a better survival than positive patients (p=0.04). Frequent overexpression and gene amplification of EGFR and CCND1 make these molecules and their pathways potential therapeutic targets for ESCC. In addition, EGFR and CCND1 appeared to be independently altered suggesting alternative mechanisms for pathway activation. Therapeutic agents targeting these molecules are urged to be tested in clinical trials and comprehensive biological analyses should be included to properly interpret the outcome.

This article provides a unique perspective on thymoma by describing the clinical scenarios from 2 diverse patient populations followed by an update. A comparative chart review was conducted on patients diagnosed at 2 university-based hospitals, 1 in the United States and 1 in Thailand. A comprehensive review of the literature was then performed through MEDLINE for articles between 1980 and 2002. During the last 23 years, charts from 16 patients at each institution were available for review. The most common presenting symptoms were myasthenia gravis (47%), dyspnea (25%), and chest discomfort (19%) and are similar to those reported in the literature. The primary treatment of stages I-III disease included surgery with or without radiation. Trimodality therapy with surgery, radiotherapy, and chemotherapy was pursued in 43% of patients with stage IV disease in the United States, whereas no patients from Thailand underwent this regimen. Median overall survivals were 124 and 76 months in the Thai and the US groups, respectively (P = 0.76). No major differences in the clinical features were observed between the 2 institutions, although a trend toward more advanced disease was seen in the United States. Surgery and radiation remain the backbone of treatment, but the role for chemotherapy is increasing.

Introduction First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non–small-cell lung cancer with EGFR -activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes. Patients and Methods We performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR -mutation positive, advanced non–small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival. Results After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results. Conclusion Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer.

Concurrent chemoradiotherapy (CCRT) induces toxicities from inflammation and immunological suppression. Omega-3 fatty acids, glutamine, and arginine are therapeutic factors that can attenuate such inflammation and promote cellular immunity. The question is whether immunonutrition (IN) during CCRT reduces inflammation and improves the immune function in patients with esophageal squamous cell carcinoma (ESCC). Seventy-one locally advanced ESCC patients being treated with CCRT (5-FU and cisplatin) were randomized into 2 groups. The IN group received a combination of omega-3 fatty acids, glutamine, and arginine, whereas the control group received standard formula. The levels of C-reactive protein (CRP), tumor necrosis factor (TNF), interferon-gamma (IFN), interleukin (IL-6, IL-10), CD3, CD4, CD8, white blood cells, neutrophils, and total lymphocytes were measured before and during treatment. The levels of CRP (P = 0.001) and TNF (P = 0.014) increased more during treatment in the control group than the treatment group, whereas IFN, IL-6, and IL-10 were similar but not significantly. CD3, CD4, CD8, white blood cells, neutrophils, and total lymphocytes decreased more in the control group than in the treatment group, but not significantly. Enteral IN during CCRT reduced the increase of inflammatory cytokine levels.

e20514 Background: The mainstay treatment of primary GIST is surgery, but GIST often recurs even after complete resection. This study assessed the safety and efficacy of adjuvant IM in patients (pts) with resected GIST at intermediate/high risk of tumor recurrence. Methods: This open-label, single arm, prospective Ph II study (NCT01172548) was conducted in Asia Pacific/Africa/Russia/Middle East/Europe in eligible pts: aged ≥18 years (yrs), having had complete gross resection of primary GIST within 70 days of enrollment, with CD117 +ve, WHO PS ≤1, and no other adjuvant therapy. The planned sample size was 150 pts. Pts were to receive IM (400 mg/day, po) for 2 yrs post surgery. Dose modifications were allowed for toxicity. The primary endpoint was recurrence-free survival (RFS) rate at 2 yrs (based on CT/MRI and survival) in ITT pts (all pts who received ≥1 dose of study drug); null hypothesis based on historic data controls treated with surgery alone: RFS rate at 2 yrs of 0.7 (1 yr rate 0.98) (NCT00041197). A protocol-planned analysis at 1 yr in all enrolled pts (mITT) included safety, RFS, and overall survival. The study was approved by IRB/IEC/REB; all pts provided written informed consent. Results: Pt accrual was complete with 127 pts in the mITT population. Most pts (n=94, 74%) were

To identify differences of Galectin-3 (Gal-3) immunostaining, clinical profiles, and images in patients with intrahepatic cholangiocarcinoma (IHC) and adenocarcinoma liver metastasis, and be able to recognize these parameters as diagnostic tools for differentiating these two diseases.Histological slides from patients with IHC and adenocarcinoma liver metastasis were reviewed Immunohistochemical staining for Gal-3, Cytokeratin-7 (CK-7), and Cytokeratin-20 (CK-20) was performed and the results categorized. Moreover clinical characteristics and liver images of the patients were reviewed.Eighty-two patients were evaluated, 31 IHC and 51 adenocarcinoma liver metastasis. Patients who strongly expressed Gal-3 were positive for CK-7 and negative for CK-20. Finding showed that 86% of them were IHC whereas only 14% were in adenocarcinoma liver metastasis. All patients with liver images showing a single lesion, located at central site, and having intrahepatic duct dilatation were IHC. On the other hand, 77% of patients with liver imaging showing multiple liver masses, located at peripheral site and having no intrahepatic duct dilatation were adenocarcinoma liver metastasis while only 23% were in IHC.Adding Gal-3 to CK-7 and CK-20 immunohistochemistry has benefits to differentiate IHC from adenocarcinoma liver metastasis. Furthermore, liver imaging profiles also give benefits for differentiating between these two diseases.

The epidermal growth factor receptor (EGFR) has become a promising target for novel anticancer therapy Evaluation of its biological profiles including gene mutation, amplification, and protein expression in esophageal squamous cell carcinoma (ESCC) is essential to establish the EGFR molecular feature(s) suitable to select patients in anti-EGFR therapy.The subjects' specimens of ESCC at Songklanagarind Hospital were obtained and investigated for EGFR protein expression and gene amplification. Polymerase chain reaction (PCR) was performed to amplify the EGFR DNA product. The mutational status of EGFR exons 19 and 21 was analyzed using direct sequencing. The entire biological profiles of the EGFR were then correlated.There were 48 eligible ESCC specimens. No somatic mutation in the tyrosine kinase domain of EGFR was detected A high level of EGFR protein was exhibited in 22 patients (46%). Twenty-three patients (48%) had shown a high gene copy numbers. However, no direct correlation between EGFR protein and gene status was observed.EGFR mutations in the tyrosine kinase domain of exons 19 and 21 were absent in ESCC, whereas, protein overexpression and gene amplification was prevalent. Therefore, selection of ESCC patients for studies with anti-EGFR agents based on protein expression or gene copy number, not gene mutation, is rational.

Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer.In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival.The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group.Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

e17080Background: The prognoses of HNSCC and ESCC are poor, especially when two primary tumors occur at the same time. In an earlier study, we found 12.4% of all HNSCC patients had a synchronous ESCC at the time of diagnosis. To confirm whether these second tumors were of metastatic origin or a separate second primary tumor (SPT), we employed genome-wide SNP array analysis to analyze the differential LOH pattern of each synchronous tumor pair. The clinical information of the patients with synchronous tumors was also summarized. Methods: Twenty-one synchronous HNSCC formalin-fixed paraffin-embedded (FFPE) tissue samples and their ESCC counterparts were subjected to DNA extraction, quality assessment, and subsequent SNP array experiments using Illumina HumanCytoSNP12 FFPE BeadChip, which contains 300,000 probes. Signal intensity and B-allele frequency data of each pair were analyzed to identify Copy Number Variation (CNV) and LOH using Nexus Copy Number software suite. Results: Comparing the LOH pattern of ...

Limited stage small cell lung cancer (LS-SCLC) is an infrequent but aggressive tumor. No major advances in the treatment of this disease have been achieved in recent years. This study was conducted to determine the maximum-tolerated dose (MTD) and efficacy of docetaxel, etoposide, and carboplatin (DEC) given before definitive chest radiotherapy with concurrent cisplatin and etoposide. Seventeen untreated LS-SCLC patients received docetaxel 50 mg/m2, etoposide 50–80 mg/m2, and carboplatin AUC = 5–6, intravenously on day 1 followed by etoposide 100–160 mg/m2 orally on days 2 and 3 every 21 days for two cycles followed by once daily radiotherapy to a total dose of 50 Gy given concurrently with cisplatin (60 mg/m2, d1) and etoposide (120 mg/m2, d1 and 240 mg/m2 day 2–3) for 2 cycles. All patients were assessable for toxicity and 15 for response. The most frequent toxicity was grade 3 and 4 neutropenia in 41% of patients during DEC and in 57% with chemoradiation. The MTD for DEC was docetaxel 50 mg/m2 plus carboplatin AUC = 5 and etoposide 50/100 mg/m2 with growth factor support. Significant nonhematologic toxicities were primarily radiation-related esophagitis (43%). One patient (6%) died from toxicity. The overall response rate was 82% with 10 patients (59%) achieving a complete response. The median survival was 12.1 months (95% CI, 6.4–17.8 months) and the 1-year survival rate was 47%. This novel approach produced similar efficacy results to current two drug regimens but was associated with significant neutropenia. Alternative strategies to increase complete response rates and survival are needed.

The newly developed UroVysion fluorescence in situ hybridization (FISH) probe was applied to urine specimens from 19 patients being monitored for recurrence of bladder cancer. The results for the multi-target DNA FISH assay were compared with independent analyses of urine cytology and flexible cystoscopy. Patients with tumors identified through the cystoscopy exam were biopsied and/or underwent surgery. In 12 patients with normal cytoscopy, cytology and FISH were also normal. Therefore, the specificity of these two tests was 100%. In 7 patients, a tumor was diagnosed by cystoscopy, and 3 of them had abnormal urine cytology while 6 of them had an abnormal result in the FISH assay. Accordingly, the sensitivity was 43% for the cytology and 87% for the FISH test. Interestingly, a pT1G3 tumor in a bladder diverticulum was not detected by cytology or the FISH test. These results agreed with a large series previously published using similar FISH probes and support the proposal for a multicenter trial to confirm the usefulness of the UroVysion probe as a screening tool to select patients for cystoscopy. © 2004 Elsevier Inc. All rights reserved., National Cancer Institute: P30-CA46934 Cancer Center, University of Colorado, The authors acknowledge Vysis Inc. (Downers Grove, IL) for providing a UroVysion kit for optimization of the FISH protocol. The study was partially supported by the National Cancer Institute Grant P30-CA46934 to the University of Colorado Cancer Center.

e15048 Background: Telomeres are the ends of chromosomes and their function is to preserve chromosomal integrity and prevent terminal end-to-end fusions. Telomere loss or dysfunction results in bre...

389 Background: Mediastinal germ cell tumors (MGCTs) account for 20% of all mediastinal tumors. Cisplatin-based chemotherapy followed by surgical resection of residual tumor remains the standard of care. To prevent pulmonary complications secondary to extensive thoracic surgery, non-bleomycin containing regimen is generally preferred. This study aims to review clinical characteristics and outcomes of these patients. Methods: A retrospective chart review was undertaken in patients with MGCTs treated in our institution between 1993 and 2013. Results: A total of 40 patients were enrolled with a median age of 24. Only one patient is female. Stratified by histology; eight patients (20%) had pure seminoma, 25 patients (62.5%) had pure non-seminoma, four patients (10%) had mixed seminoma and non-seminoma, and three patients (7.5%) had malignant transformation (two adenocarcinoma, one sarcoma). Median tumor size was 13 centimeters. Ninety-two percent of patients received chemotherapy as a first treatment modality, whereas 8% underwent upfront surgery. All patients received cisplatin-based chemotherapy: Eighty seven percent bleomycin, etoposide and cisplatin; 13% etoposide and cisplatin. Seventy-two percent of patients completed four planned cycles of chemotherapy. Thirty-one patients were able to assess radiological response: 3.2% complete response, 58.1% partial response, 29.0% stable disease, and 9.7% progressive disease. Forty-four percent of patients achieved completely serological response with chemotherapy. Seventeen patients underwent surgical resection of residual tumor. Among these, viable tumor was seen in 35% (6 out of 17 patients). No patients complicated with clinically significant pulmonary complications after thoracic surgery. The five year overall survival (OS) of patients with seminoma was 72.9% as compared with 19.9% in those with non-seminoma (p=0.012). For those who received chemotherapy followed by surgical resection with no viable tumor or only mature teratoma detected (N=11), the five year OS was 64.9%. Conclusions: Our study confirmed the importance of multi-modality approaches with primary chemotherapy followed by surgical resection of residual tumor. Bleomycin-containing regimen can be safely used in this setting.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer related death worldwide. Survival of NSCLC patients remains unfavorable prompting a better understanding of its molecular biology and causality, along with advances in diagnostic methods and multidisciplinary therapeutic approaches. Aberrant three-dimensional (3D) nuclear telomere organization can identify patient subgroups in various cancers and its correlation with tumor and patient characteristics may play a major role as a predictive and prognostic factor in NSCLC of different subgroups. This study aimed to explore the clinical application of 3D nuclear telomeric organization in NSCLC patients of different EGFR mutational status and smoking backgrounds. Paraffin-embedded NSCLC tissue specimens from non-smoking (N=6) and smoking (N=4) patients who underwent surgical resections at the British Columbia Cancer Research Centre of Canada were examined using the 3D fluorescent in situ hybridization (FISH). 3D nuclear-telomeric architecture analyses were performed using the TeloView program (Vermolen et al., 2005). The 3D nuclear telomere organization of 100 interphase nuclei per specimen was quantified by telomere numbers, telomere signal intensities, and frequencies of telomeric aggregates. Comparisons of 3D nuclear telomere organization between patient subgroups are shown below. In the smoking group, more telomeres, higher signal intensities, and greater numbers of aggregates were observed, compared to the non-smokers. The same pattern of 3D nuclear telomere organization was observed in the EGFR-negative/unknown group, compared to the EGFR-positive patients. This study provides a better understanding of 3D telomeric organization in NSCLC patients with different smoking backgrounds and EGFR mutational status, leading to a rationale of further exploration of this molecular profile in this cancer. 3D Telomeric parameters Average number of telomere per cell : Non-smokers 77.71, Smokers 80.37 Average number of aggregates per cell : Non-smokers 21.36, Smokers 27.59 Percentage of cells with aggregates : Non-smokers 2.16, Smokers 3.03 Average number of telomere per cell : Pos. EGFR 73.69, Neg./Unknown EGFR 80.95 Average number of aggregates per cell : Pos. EGFR 19.97, Neg./Unknown EGFR 25.52 Percentage of cells with aggregates : Pos. EGFR 1.96, Neg./Unknown EGFR 2.75 Citation Format: Patrapim Sunpaweravong, Chirawadee Sathitruangsak, Kelsie Thu, Wan L. Lam, Sabine Mai. Three-dimensional nuclear telomere organization and clinical significance in non-small cell lung cancer patients. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B19.

e14548^ Background: Cisplatin and 5-FU combined with radiation is standard for locally-advanced esophageal squamous cell carcinoma. Cetuximab has shown synergism with cisplatin and radiation. This ...