The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 21% of gastric and 33% of gastroesophageal junction (GEJ) adenocarcinomas. Trastuzumab has been approved for metastatic HER2-positive gastric/GEJ cancer in combination with chemotherapy. This retrospective analysis was undertaken to better define the clinicopathologic features, treatment outcomes, and prognosis in patients with HER2-positive adenocarcinoma of the esophagus/GEJ. Pathologic specimens from 156 patients with adenocarcinoma of the esophagus/GEJ treated on clinical trials with chemoradiation and surgery were tested for HER2. Seventy-six patients also received 2 years of gefitinib. Baseline characteristics and treatment outcomes of the HER2-positive and negative patients were compared both in aggregate and separately for each of the two trials. Of 156 patients, 135 had sufficient pathologic material available for HER2 assessment. HER2 positivity was found in 23%; 28% with GEJ primaries and 15% with esophageal primaries (P= 0.10). There was no statistical difference in clinicopathologic features between HER2-positive and negative patients except HER2-negative tumors were more likely to be poorly differentiated (P < 0.001). Locoregional recurrence, distant metastatic recurrence, any recurrence, and overall survival were also statistically similar between the HER2-positive and the HER2-negative groups, in both the entire cohort and in the gefitinib-treated subset. Except for tumor differentiation, HER2-positive and negative patients with adenocarcinoma of the esophagus and GEJ do not differ in clinicopathologic characteristics and treatment outcomes. Given the demonstrated benefit of trastuzumab in HER2-positive gastric cancer and the similar incidence of HER2 overexpression in esophageal/GEJ adenocarcinoma, further evaluation of HER2-directed therapy in this disease seems indicated.

71 Background: HER2 is overexpressed in 21% of gastric and 33% of GEJ ACA, and pts with advanced HER2pos disease survive longer after chemotherapy and trastuzumab than after chemotherapy alone. This retrospective analysis was undertaken to better define the clinicopathologic features and treatment outcomes in pts with HER2pos ACA of the E and GEJ. Methods: Between 11/99 and 7/06, 156 pts with T3 or N1 or M1a ACA of the E or GEJ were entered on one of two Cleveland Clinic trials. Induction chemoradiation, with 96 hour infusions of cisplatin (20 mg/m2/d) and fluorouracil (1,000 mg/m2/d) beginning on day 1 of radiation (30 Gy at 1.5 Gy bid), was followed by surgery and identical post-operative chemoradiation. 76 pts also received 2 years of oral gefitinib. Pathology was tested for HER2 by immunohistochemistry using PATHWAY anti-HER-2/neu 4B5 rabbit monoclonal primary antibody (Ventana, Tucson AZ) and in situ hybridization with the inform HER2 dual ISH DNA probe cocktail assay (Ventana, Tucson AZ). Baseline characteristics and outcomes after treatment of the HER2pos and negative (neg) pts were compared. Results: Of the 156 pts, 136 pts had either initial biopsy or resection specimen available. HER2 was deemed pos if either was pos. Discordance between biopsy and resection was found in only 6/65 pts (9%). 32 pts (24%) were HER2pos; 27% of 82 pts with GEJ, and 19% of 54 pts with E tumors (p=0.31). There was no statistical difference between HER2pos and neg pts in age, gender, race, stage, or pathological response. The only difference was that HER2neg tumors were more likely poorly differentiated (p<0.001). Locoregional control, distant metastatic control, freedom from recurrence and overall survival were statistically the same in both the entire cohort, and in the gefitinib-treated subset. Conclusions: Except for tumor differentiation, HER2pos and neg pts with ACA of the E and GEJ do not differ in clinicopathologic characteristics and treatment outcomes. Given the demonstrated benefit of trastuzumab in HER2pos gastric cancer and the similar incidence of HER2 overexpression in the E and GEJ, further evaluation of HER2 directed therapy in this disease seems indicated. No significant financial relationships to disclose.

4069 Background: CCRT has modest curative potential for LRA esophageal cancer and is commonly used preoperatively to improve surgical outcome. Although this approach can be curative, most patients (pts) experience only limited benefit from the surgery. This retrospective review was undertaken to identify clinical features after induction CCRT that might predict surgical futility. Methods: Between 11/99 and 7/06, 155 pts with T3, N1, or M1a ACA of the esophagus or GEJ were entered on one of two consecutive Cleveland Clinic trials, using CCRT with 96 hour infusions of cisplatin (20 mg/m2/d) and fluorouracil (1,000 mg/m2/d) beginning on day 1 of radiation (30 Gy at 1.5 Gy bid). Surgery followed in 4-6 weeks with identical CCRT planned post- operatively. 75 pts also received 2 years of gefitinib. Initial and post-induction endoscopic (EGD) tumor length and endosonographic (EUS) TNM stage were recorded. Symptomatic response to induction was characterized as resolved or unresolved. Prognostic factors for freedom from recurrence (FFR) and overall survival (OS) were identified. Results: 4 pts were medically unresectable and not analyzed. The remaining 151 pts had a median age of 59 years; 89% were male and 97% Caucasian. Pretreatment stage was II in 34%, III in 42%, and IVa in 24%. 140 pts underwent resection; 11 developed unresectable disease. With a median follow-up of 62 (range 38-105) months (m), 36 m FFR was 31% and OS 32%. Postinduction change in EGD tumor length and EUS TNM stage was not prognostic. Symptomatic resolution, which occurred in 86%, was the strongest predictor for FFR (p < 0.001) and OS (p < 0.001). At 24 m, pts with unresolved symptoms and pretreatment stage III/IVa disease had a recurrence rate (RR) of 100% and OS of 7%. Conversely, stage II pts with symptomatic resolution had a 24 m RR of 45% and OS of 57%. Conclusions: EGD and EUS restaging of locoregional disease after induction CCRT provides little useful information. Only symptomatic response to induction proved important. When coupled with advanced pretreatment stage, persistence of symptoms after induction is ominous and should be factored into surgical decision making. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, sanofi-aventis