Objectives

1. Comparison of HER-2 expression in diagnostic biopsies and surgical specimens of gastric and esophageal adenocarcinoma: Influence of neoadjuvant chemotherapy (NAC)Sarah Watson, Pierre Validire, Pascale Cervera, Nabila Zorkani, Frederic Lemay, Thierry Perniceni, François Paye, Christophe Tournigand, Christophe LouvetInstitut Mutualiste Montsouris, Hôpital Saint-Antoine, Paris, France Relative increase in HER2 positive cases when adding biopsy to surgical specimen analysis The overall concordance rate in HER2 status between biopsies and surgical specimens reached 94%. 13/218 (6%) patients showed discrepancies between biopsies and surgical specimens, with mostly positive conversions (HER2 - on the biopsy that turned HER2 + on the surgical specimen) for no NAC patients, and the same number of positive and negative conversions ( HER2 + on biopsy that turned HER2- on the surgical specimen) for NAC patients. In NAC patients, all negative conversions concerned patients with clinical and histological response to NAC. Materials & Methods Abstract Pathological specimens from biopsies of patients operated on with a curative aim in two French hospitals between 2004 and 2011 were collected; two cohorts treated or not with a NAC were constituted. Two independent pathological HER-2 analyses on biopsies and on surgical specimens were blindly performed using immunohistochemistry (IHC) and chromogenic in situ hibridization (CISH). Background: HER2 is overexpressed in 10 to 20% of gastro-esophageal adenocarcinoma (GE-ADK), and is a target for trastuzumab in metastatic patients1. We conducted a study to compare HER2 expression between diagnostic biopsies (DB) and surgical specimens (SS) of GE-ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression. Methods: Pathological specimens from biopsies of 228 patients operated on with a curative aim in two French hospitals between 2004 and 2011 were collected. Two cohorts treated (n=141) or not (n=87) with a NAC were constituted. Two blind independent pathological HER2 analyses on DB and on SS were performed using IHC and CISH. HER-2 overexpression (HER2 +) was defined by a score 3+ in IHC, or 2+ with a positive CISH test, and according to the specific HER2 scoring guidelines for GE-ADK2. Results: Paired HER2 status could be determined for 218 out of the 228 patients (95.6%). HER2 + rates were 13.3% on DB (29/218) and 14.7% on SS (32/218). HER2 + tumors were mainly cardial or esophageal adenocarcinomas, with a well-differentiated, intestinal histological type. HER2 status differed between DB and SS in 13 patients (6%). When DB analyses were added to SS analyses, 5 additional patients were HER2 +, the relative increase in HER2 + cases being 13.5% (17.1% for patients with NAC versus 7.1% for patients without NAC, p=0.4, NS). Differences between DB and SS HER2 expression could be explained by the intratumoral heterogeneity and also by a possible HER2 expression decrease in SS after NAC. Conclusions: The determination of HER2 status on DB provides results that complete those obtained with SS. Combining the analysis of DB and of SS enables to optimize the selection of trastuzumab-eligible patients in case of metastatic relapse, especially in patients previously treated with NAC. Concordance between biopsies and surgical specimens Characteristics of the population at baseline Summary • 228 paired samples analyzed. • HER-2 overexpression rates: 13,3% on biopsies and 14,7% on surgical specimens. • HER-2 discordance between biopsies and surgical specimens : 6% of cases, likely due to intratumoral heterogeneity and response to NAC. • After NAC, less HER-2 positive tumors identified on surgical specimens than on biopsies, particularly in NAC-responding patients. • Relative increase in HER-2 positive tumors when adding biopsy to surgical specimen analysis: 17,4% in patients with NAC, 23,5% in patients with pathological response to NAC, and only 7,1% for patients without NAC. • In conclusion: biopsy analyses for HER-2 are complementary to those of surgical specimen. Combining both analyses increases the number of patients that will benefit from trastuzumab therapy, especially for those who have received a neaodjuvant treatment. The rate of HER-2 positive cases showed notable changes whether the analysis had been carried out on diagnostical biopsies, surgical specimens, or both. Adding the analyses of biopsies to those of surgical specimens enabled to increase the number of HER-2 positive cases, especially in patients presenting pathological response to NAC.. HER2 overexpression rates Impact of the sample used for HER2 analysis Background HER-2 expression shows pathological specificities in GE-ADK, with a high frequency of intratumoral heterogeneity which has led to the establishment of a different scoring than the one used in breast cancer3. The concordance between HER-2 expression in biopsies and surgical specimen is not well established and the influence of NAC has never been documented. HER-2 overexpression was defined by a score 3+ in IHC or by a score 2+ in IHC with a positive CISH test. References Objectives HER-2 positive tumors were mostly located on the eso-gastric junction (low part of esophagus or cardia), and showed preferentially a well-differentiated, intestinal histological type. These characteristics were significantly more frequent in HER-2 positive tumors than in HER-2 negative tumors (p<0,01) • Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER-2 positive advanced gastric or gastro-oesophageal junction cancer (ToGA), Lancet, 2010. • HER2 testing in gastric cancer: a practical approach, Mod Pathol, 2012. • Assessment of a HER2 scoring system for gastric cancer: results from a validation study, Histopathology, 2008 To compare the expression of HER-2 in IHC and CISH between diagnostic biopsies and surgical specimen and to determine the influence of NAC on this expression. Printed by