Abstract 3797
Background
To reveal candidate signaling pathways for targeted therapy in esophageal cancer (EC), and esophageal adenocarcinoma (EAC) in particular, we investigated key signal transduction pathways in material available in clinical routine, before and after neoadjuvant chemoradiation (nCRT), and for primary tumor and recurrent disease.
Methods
Paraffin-embedded material from three cohorts was used; (i) resectable EC; patients treated with an esophagectomy or receiving nCRT prior to resection, including cases with an available pre-nCRT biopsy of the primary tumor and corresponding resection; (ii) recurrent EC; patients of whom a resection and metachronous recurrence could be obtained. In addition, to explore the possibility to use patient-derived-xenografts (PDX) as a model to identify novel therapies, (iii) PDX of matched patient material was analyzed. Digitally annotated tumor areas ≥2 mm2 were transferred to a consecutive hematoxylin-stained slide and scraped for RNA extraction. Subsequently, a panel of qPCRs was performed, to infer signal transduction activity of the AR-, ER-, PI3K- (inverse of FOXO), HH-,TGF-β- and Wnt pathway.
Results
In pre-treatment EAC biopsies (i), high PI3K- and low TGF-β-pathway activity were correlated with poor pathological response. During treatment, a significant increase in PI3K- and decrease in TGF-β activity was observed in EAC poor nCRT responders compared to good responders (p = 0.003 and p = 0.042, respectively). Patients with a post-nCRT poor responder profile (high PI3K/ low TGF-β pathway activity) showed inferior disease free survival (median 17 vs. 97 months p = 0.055). Moreover, in nCRT treated patients, higher PI3K and lower TGF-β activities were seen in metachronous recurrences compared to resected tumors (ii) (p = 0.001 and p = 0.007, respectively). Pathway activity profiles were conserved between PDX and primary patient material (iii).
Conclusions
Loss of tumor-suppressive TGF-β and concurrent high PI3K pathway activity are associated with poor response to nCRT in EAC. This poor-responder profile is preserved in recurrences of nCRT pre-treated patients and PDX models, providing a valuable tool to experimentally test targeting candidate signal pathways such as PI3K.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Philips Research.
Funding
Philips Research.
Disclosure
L. Holtzer: Full / Part-time employment: Philips. M. Stoffels: Research grant / Funding (self), Full / Part-time employment: Philips. H. van Ooijen: Licensing / Royalties, Full / Part-time employment: Philips. A.G.C. van Brussel: Research grant / Funding (self), Licensing / Royalties, Full / Part-time employment: Philips. E.M.G. Aussems-Custers: Research grant / Funding (self), Licensing / Royalties, Full / Part-time employment: Philips. A. van de Stolpe: Licensing / Royalties, Full / Part-time employment: Philips. M.F. Bijlsma: Research grant / Funding (self): Celgene; Advisory / Consultancy: Servier. H.W.M. van Laarhoven: Advisory / Consultancy, Research grant / Funding (self): Celgene; Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): Nordic; Advisory / Consultancy, Research grant / Funding (self): Lilly; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Bayer; Research grant / Funding (self): MSD; Research grant / Funding (self): Philips; Research grant / Funding (self): Roche. All other authors have declared no conflicts of interest.
Resources from the same session
4304 - A user-friendly nomogram to predict relapse-free survival (RFS) in western patients with resected gastric cancer (GC)
Presenter: Massimiliano Salati
Session: Poster Display session 2
Resources:
Abstract
4546 - Efficacy and toxicity of weekly carboplatin and paclitaxel as induction or palliative treatment in advanced esophageal cancer patients
Presenter: Femke de Man
Session: Poster Display session 2
Resources:
Abstract
5908 - Perioperative chemotherapy with Docetaxel, Oxaliplatin, Fluorouracil and Leucovorin (FLOT) versus Epirubicin, Platinum and Capecitabine or Flourouracil (EOX/ECF) in Resectable Gastric or Gastroesophageal Junction Adenocarcinoma- Safety and response data from India.
Presenter: Tanuj Chawla
Session: Poster Display session 2
Resources:
Abstract
937 - Phase II Study of Preoperative Radiotherapy Combined with S-1 plus Cisplatin in Clinically Resectable Type 4 or Large Type 3 Gastric Cancer: OGSG1205
Presenter: Shunji Endo
Session: Poster Display session 2
Resources:
Abstract
1119 - Observational Study of the Peritoneal Washing Cytology Positive Gastric Cancer without Gross Peritoneal Metastasis Underwent Radical D2 Gastrectomy.
Presenter: Jun Eul Hwang
Session: Poster Display session 2
Resources:
Abstract
3744 - Primary results of multicenter phase II study of neoadjuvant chemotherapy with S-1 and oxaliplatin for locally advanced gastric cancer (Neo G-SOX PII)
Presenter: Akira Miki
Session: Poster Display session 2
Resources:
Abstract
5091 - Multicenter Phase I/II Feasibility Study of Adjuvant Treatment with S-1 in Patients after R0-Resection of Adenocarcinoma of the Stomach and Esophagogastric Junction (GMBH-STO-0114)
Presenter: Kathrin Heinrich
Session: Poster Display session 2
Resources:
Abstract
2891 - A phase I study of Docetaxel/Oxaliplatin/S-1 (DOS) combination neoadjuvant chemotherapy for patients with locally advanced adenocarcinoma of the esophagogastric junction
Presenter: Kei Hosoda
Session: Poster Display session 2
Resources:
Abstract
2994 - Apatinib combined with docetaxel in second-line treatment of advanced gastric cancer: a prospective clinical study (Data updated)
Presenter: Mudan Yang
Session: Poster Display session 2
Resources:
Abstract
3000 - A multicenter phase II study of TAS-114 in combination with S-1 in patients with pre-treated advanced gastric cancer (EPOC1604)
Presenter: Daisuke Takahari
Session: Poster Display session 2
Resources:
Abstract