Identification of Adenosquamous Carcinoma as a Rare Aggressive HER2-negative Subgroup of Esophageal/Gastroesophageal Junction Adenocarcinoma.
ABSTRACT: BACKGROUND:Our purpose was to evaluate the prognostic impact of pathologically confirmed esophageal adenosquamous carcinoma (ASC) and its association with HER2 status and clinicopathologic characteristics. METHODS:Among 796 patients with esophageal or gastroesophageal junction adenocarcinoma who underwent curative resection, surgical pathology reports were reviewed, and suspected ASC was confirmed utilizing p63 and CK5/6 immunostaining. HER2 status was determined using immunohistochemistry and fluorescence in situ hybridization. Cox models were used to assess the impact of ASC on disease-specific survival and overall survival. RESULTS:Overall, 2.0% (16/796) of patients had esophageal ASC, mostly demonstrating a close intermingling of squamous and adenocarcinoma cells within the same tumor. The percentage of squamous versus adenocarcinoma cells in the primary was generally recapitulated in nodal metastases, and intrapatient internodal heterogeneity was uncommon. Patients with esophageal ASC were statistically significantly more likely to be female (vs. male), have normal (vs. excess) body mass index, and harbor HER2-negative (vs. positive) tumors, as compared with patients with adenocarcinoma only. No ASC tumor was HER2-positive as compared with 16% of adenocarcinoma only tumors (P=0.018). Compared with patients with adenocarcinoma only, those with ASC demonstrated profoundly worse disease-specific survival (5-year event-free rate, 34% vs. 6%; multivariate hazard ratio, 2.87 [95% confidence interval, 1.59-4.76]; P=0.0010) and overall survival (P=0.0027) that was independent of known prognostic factors and HER2 status. CONCLUSION:ASC identifies a rare aggressive HER2-negative subgroup of esophageal/gastroesophageal junction adenocarcinoma.
Project description:Metastatic or unresectable esophageal and gastroesophageal junction adenocarcinoma represent a devastating disease with 5-year survival rate of <5%. Although cytotoxic chemotherapy with platinum-doublet-based regimens is initially effective, patients inevitably progress. Patients often decline rapidly after this initial progression, making later lines of therapy a challenge to successfully administer There have been multiple efforts to incorporate biologic agents, targeting pathways known to be dysregulated in esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma, into existing chemotherapy backbones. Other than therapeutics targeting human epidermal growth factor receptor-2 (HER2) and vascular endothelial growth factor receptor (VEGFR), other strategies have failed. Given the mixed success of biologic agents, along with the promise of immunotherapy to generate durable and sometimes complete responses, immune-agent based trials are a major area of interest for patients with this disease. Checkpoint inhibitors blocking programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have demonstrated modest single-agent efficacy in patients with progressive esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma. However, other approaches such as novel checkpoint combinations, vaccine-based approaches and autologous T cells hold more promise to change the trajectory of disease.
Project description:Amplification of the human epidermal growth factor receptor 2 (HER2) gene and overexpression of the HER2 protein is found in 15%-20% of patients with gastric and gastroesophageal junction cancer. The degree of HER2 overexpression and amplification varies with the location of the carcinoma, with higher expression in the gastroesophageal and proximal parts compared to the distal parts of the stomach. Further, HER2 overexpression and amplification also seems to be related to the Lauren histological classification, with higher levels found in the intestinal phenotype compared to the diffuse and mixed types. The prognostic properties of HER2 overexpression and amplification are still under debate, but a large number of studies seem to indicate that HER2 is a negative prognostic factor. The usefulness of HER2 targeted therapy in gastric cancer was demonstrated in the ToGA trial, where HER2-positive patients with advanced gastric and gastroesophageal junction adenocarcinoma were randomized to receive 5-FU/capecitabine and cisplatin, either alone or in combination with trastuzumab. A statically significant gain in overall survival was seen in patients who received the combined treatment of trastuzumab and chemotherapy. Patients with a strong overexpression of the HER2 protein (IHC3+) specifically benefited from the treatment, with a median overall survival of 17.9 mo. As a consequence of the positive results of the ToGA trial, patients with advanced gastric or gastroesophageal junction adenocarcinoma are now routinely tested for HER2. The ToGA trial must be characterized as a landmark in the treatment of gastric cancer and it has paved the way for a number of new HER2 targeted compounds such as pertuzumab, ado-trastuzumab emtansine, lapatinib, afatinib, and dacomitinib, which are currently undergoing phase II and III clinical testing. Overall, this review will discuss the current status of HER2 in gastric and gastroesophageal junction cancer and the future direction in relation to HER2 target therapy.
Project description:Correlative analysis using RNA-seq was performed on tumor samples from patients with locally advanced esophageal and gastroesophageal junction adenocarcinoma treated with adjuvant durvalumab as part of a Phase II trial. The primary goal of this correlative analysis was to perform immune deconvolution using CIBERSORTx in order to determine the relative proportion of immune cell types in each sample. The immune components were then associated with relapse free survival. Overall design: RNA-seq analysis of tumor samples from patients with locally advanced esophageal and gastroesophageal junction adenocarcinoma treated with adjuvant durvalumab
Project description:Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.
Project description:The blockade of HER2 signaling has significantly improved the outlook for esophagogastric cancer patients. However, targeting HER2 still remains challenging due to complex biology of this receptor in gastric and esophageal cancers. Areas covered: Here, we review complex HER2 biology, current methods of HER2 testing and tumor heterogeneity of gastroesophageal cancer. Ongoing and completed clinical research data are discussed. Expert opinion: HER2 overexpression is a validated target in gastroesophageal cancer, with therapeutic implications resulting in prolonged survival when inhibited in the front-line setting. With standardized HER2 testing in gastro-esophageal cancer, the ongoing trials are testing newer agents and combinations including combination of anti-HER2 antibodies with immunotherapy. Clonal heterogeneity and emergence of resistance will challenge our approach to treating these patients beyond the frontline settings.
Project description:Although the positivity of human epidermal growth factor receptor 2 (HER2) is low in colorectal cancer (CRC), anti-HER2 is becoming a new target therapy in metastatic colorectal cancer (mCRC). However, assessment of the HER2 scoring system was still not established in CRC. The purpose of our study was to evaluate HER2 status and its correlation with clinicopathological characteristics and survival according to the HER2 diagnostic criteria for gastroesophageal adenocarcinoma (GEA criteria) and the HERACLES diagnostic criteria (HERACLES criteria) in a large cohort of Chinese CRC patients. The HER2 positivity was 2.9% (43/1490) and 2.6% (39/1490) in CRCs based on the GEA criteria and the HERACLES criteria, and 3.7% (9/243) in mCRC according to both criteria. HER2 status was associated with primary tumor location (P =?0.037), regional lymph node metastasis (P =?0.035), and TNM stage (P =?0.022) in CRCs based on the HERACLES criteria. No such association was found based on the GEA criteria. Furthermore, HER2 positive only presented in patients with RAS gene wild type (P =?0.001). Significant difference was only observed between the HER2-positive and HER2-negative groups in terms of disease-free survival for stage II-III CRCs (P =?0.048) according to the HERACLES criteria, but not based on the GEA criteria. Our findings suggest that the frequency of HER2 overexpression or amplification was low in Chinese CRC patients, and provide a rationale for further evaluation of HER2 in CRC based on the HERACLES criteria and the HER2 diagnostic criteria for gastroesophageal adenocarcinoma.
Project description:BACKGROUND:Addition of trastuzumab to first-line palliative chemotherapy in gastroesophageal cancer patients with HER2 overexpression has shown to improve survival. Real-world data on HER2 assessment and administration of trastuzumab are lacking. The aim of this study was to assess HER2 testing, trastuzumab administration, and overall survival (OS) in a nationwide cohort of metastatic gastroesophageal cancer patients. METHODS:Data of patients with synchronous metastatic gastroesophageal adenocarcinoma diagnosed in 2010-2016 that received palliative systemic treatment (n?=?2846) were collected from the Netherlands Cancer Registry and Dutch Pathology Registry. The ToGA trial criteria were used to determine HER2 overexpression. Proportions of HER2 tested patients were analyzed between hospital volume categories using Chi-square tests, and over time using trend analysis. OS was tested using the Kaplan Meier method with log rank test. RESULTS:HER2 assessment increased annually, from 18% in 2010 to 88% in 2016 (P?<?0.01). Median OS increased from 6.9 (2010-2013) to 7.9 months (2014-2016; P?<?0.05). Between the hospitals, the proportion of tested patients varied between 29-100%, and was higher in high-volume hospitals (P?<?0.01). Overall, 77% of the HER2 positive patients received trastuzumab. Median OS was higher in patients with positive (8.8 months) and negative (7.4 months) HER2 status, compared to non-tested patients (5.6 months; P?<?0.05). CONCLUSION:Increased determination of HER2 and administration of trastuzumab have changed daily practice management of metastatic gastroesophageal cancer patients receiving palliative systemic therapy, and possibly contributed to their improved survival. Further increase in awareness of HER2 testing and trastuzumab administration may improve quality of care and patient outcomes.
Project description:NCCN states that chemotherapies for advanced esophageal and gastric cancers may be used interchangeably. Biomarkers from gastroesophageal cancer patients were interrogated to identify actionable alterations with therapeutic implications.666 gastric and 640 esophageal cancer cases referred to Caris Life Sciences between 2009 thru 2013 were evaluated. Specific testing was performed, which included a combination of sequencing (Sanger, NGS) and protein expression (IHC).In the complete cohort (n = 1306), 30 of 45 genes tested harbored mutations; highest rates were seen in TP53 (54%), APC (10%), SMAD4 (5.9%), KRAS (5.9%), and PIK3CA (5.1%). IHC of TOP2A was high in 76% of cases, TOPO1 in 51% and SPARC in 25%; low IHC of ERCC1 was seen in 65%, RRM1 in 62%, TS in 61% and MGMT in 45%, indicating potential benefit from epirubicin, irinotecan, nab-paclitaxel, platinum-based agents, gemcitabine, 5FU/capecitabine and temozolomide, respectively. In the HER2+ cohort (n = 88), 50% of patients demonstrated possible benefit from a combination of trastuzumab with 5FU/capecitabine based on concurrent low TS, 53% with irinotecan (high TOPO1), 63% with cisplatin (low ERCC1) and 55% with gemcitabine (low RRM1). Subgroup analysis by tumor origin demonstrated significant differences in actionable biomarker profiles with HER2 (13% vs. 4.6%), SPARC (34% vs. 15%), TOP2A (86% vs. 67%), and TOPO1 (55% vs. 46%) in esophageal and gastric adenocarcinoma cases respectively (P < 0.05).A comprehensive multiplatform biomarker analysis suggested significant biomarker differences between gastric and esophageal cancers. These results can assist in the development of future clinical trials.
Project description:In the Trastuzumab for GAstric cancer (ToGA) study, trastuzumab plus chemotherapy improved median overall survival by 2.7 months in patients with human epidermal growth factor receptor 2 (HER2)-positive [immunohistochemistry (IHC) 3+/fluorescence in situ hybridization-positive] gastric/gastroesophageal junction cancer compared with chemotherapy alone (hazard ratio 0.74). Post hoc exploratory analyses in patients expressing higher HER2 levels (IHC 2+/fluorescence in situ hybridization-positive or IHC 3+) demonstrated a 4.2-month improvement in median overall survival with trastuzumab (hazard ratio 0.65). The ToGA study provides the largest screening dataset available on HER2 overexpression/amplification in this indication. We further analyzed correlation(s) of HER2 overexpression/amplification with clinical and epidemiological factors.HER2-positivity was analyzed by histological subtype, tumor location, geographic region, and specimen type. Exploratory efficacy analyses were performed.The HER2-positivity rate was 22.1 % across analyzed tumor samples. Rates were similar between European and Asian patients (23.6 % vs. 23.9 %), but higher in intestinal- vs. diffuse-type (31.8 % vs. 6.1 %), and gastroesophageal junction cancer versus gastric tumors (32.2 % vs. 21.4 %). Across all IHC scores, variability in HER2 staining (?30 % stained cells) was observed in almost 50 % of cases, with increasing rates in lower IHC categories, and did not affect treatment outcome. The polysomy rate was 4 %.HER2 expression varies by tumor location and type. All patients with advanced gastric or gastroesophageal junction cancer should be tested for HER2 status, preferably using IHC initially. Due to the unique characteristics of gastric cancer, specific testing/scoring guidelines should be adhered to.
Project description:Trastuzumab, a monoclonal antibody against HER2, has become standard of care for metastatic HER2-overexpressing esophagogastric adenocarcinoma and is currently investigated as (neo)adjuvant treatment option in HER2-positive esophagogastric adenocarcinoma. The HER2 status is commonly determined on archived material of the primary tumor. However, this status may change over the course of treatment or disease progression. The aim of this study was to assess the dynamics of HER2 status in esophageal adenocarcinoma (EAC) in patients with resectable and recurrent disease, and to determine the associations of these changes with clinical outcome. Discordance, defined as any change in HER2 status between matched biopsy and post-neoadjuvant chemoradiation therapy resection specimen (N = 170), or between matched resection specimen and recurrence of patients not eligible for curative treatment (N = 61), was determined using the standardized HER2 status scoring system. Clinically relevant positive discordance was defined as a change to HER2 positive status, as this would imply eligibility for HER2-targeted therapy. A difference in HER2 status between biopsy and resection specimen and resection specimen and metachronous recurrence was observed in 2.1% (n = 3) and 3.3% (n = 2) of the paired cases, respectively. Clinically relevant discordance was detected in 1.4% (n = 2) of the resectable patients and 1.6% (n = 1) of the patients with recurrent disease. Patients with HER2-positive status tumors before start of neoadjuvant treatment showed better overall survival, but not statistically significant. No association between HER2 status discordance and survival was found. Clinically relevant HER2 status discordance was observed and in order to prevent under-treatment of patients, the assessment of HER2 status in the metastatic setting should preferably be performed on the most recently developed lesions if the previous HER2 assessment on archival material of the primary tumor was negative.