Title: Validating tumour infiltrating lymphocytes as biomarker of chemotherapy benefit in patients with oesophagogastric cancer recruited to 7 multicentre randomised phase III trials
Funder: Cancer Research UK

Abstract: Background Current treatment of patients with oesophago-gastric cancer (OGCa) is based on disease stage, patient performance status and patient preferences. OGCa patients with locally advanced, resectable disease are treated with radical surgery and chemotherapy; patients with metastatic disease receive combination chemotherapy or best supportive care. In order to improve patient outcome and personalise existing treatment options, we need to identify patients with relatively indolent disease, those with aggressive disease and high likelihood of response to chemotherapy and those with chemotherapy resistant disease. There is evidence that the level of tumour infiltrating lymphocytes (TILs) impacts on patient survival. Studies in breast cancer suggest that the level of TILs measured in the Haematoxylin/Eosin (HE) section can also predict benefit from chemotherapy. In OGCa data on TILs and prognosis are contradictory, data on TILs and response to chemotherapy are non existing. In a pilot study, we measured TILs in the HE stained section of 545 OGCa from the CLASSIC trial. We discovered that patients with high levels of HE-TILs/mm2 survived longer and that patients with low levels of HE-TILs/mm2 benefitted most from cytotoxic chemotherapy. Multivariate analysis confirmed HE-TILs/mm2 as independent prognostic and predictive marker. Aims Validation of HE-TILs/mm2 as predictive and prognostic biomarker in the OE02, OE05, SAMIT, MAGIC, ST03, REAL2 and REAL3 trial comprising more than 5000 patients with different disease stages, treated with different chemotherapy regimens with or without surgery. Methods Retrospective analyses of HE slides from pre-treatment tumour biopsies and one representative resection slide with highest tumour content. Image analysis software will count TILs/mm2. In a subset of 200 slides, we will compare manual semi-quantitative TIL scoring with software based calculation of TILs/mm2. A multidisciplinary team including six pathologists, scientists, technicians, statisticians, surgeons, oncologists and a patient representative from the UK, NL, Japan and Korea will drive this study forward. Results will be related to overall survival (primary endpoint), treatment and clinicopathological variables. How the results of this research will be used. If we can validate our pilot study results, the clinicians of this study confirmed that they would want to use HE-TIL/mm2 in the clinical routine to improve patient stratification for treatment options as soon as possible. Depending on the result of the comparison between manual scoring by a pathologist and software-based scoring, we will either develop a web based training platform for pathologists or approach a commercial provider with interest in setting HE-TIL scoring up as a service.

Lay abstract: Background Current treatment of patients with oesophago-gastric cancer (OGCa) is based on disease stage, patient performance status and patient preferences. OGCa patients with locally advanced, resectable disease are treated with radical surgery and chemotherapy; patients with metastatic disease receive combination chemotherapy or best supportive care. In order to improve patient outcome and personalise existing treatment options, we need to identify patients with relatively indolent disease, those with aggressive disease and high likelihood of response to chemotherapy and those with chemotherapy resistant disease. There is evidence that the level of tumour infiltrating lymphocytes (TILs) impacts on patient survival. Studies in breast cancer suggest that the level of TILs measured in the Haematoxylin/Eosin (HE) section can also predict benefit from chemotherapy. In OGCa data on TILs and prognosis are contradictory, data on TILs and response to chemotherapy are non existing. In a pilot study, we measured TILs in the HE stained section of 545 OGCa from the CLASSIC trial. We discovered that patients with high levels of HE-TILs/mm2 survived longer and that patients with low levels of HE-TILs/mm2 benefitted most from cytotoxic chemotherapy. Multivariate analysis confirmed HE-TILs/mm2 as independent prognostic and predictive marker. Aims Validation of HE-TILs/mm2 as predictive and prognostic biomarker in the OE02, OE05, SAMIT, MAGIC, ST03, REAL2 and REAL3 trial comprising more than 5000 patients with different disease stages, treated with different chemotherapy regimens with or without surgery. Methods Retrospective analyses of HE slides from pre-treatment tumour biopsies and one representative resection slide with highest tumour content. Image analysis software will count TILs/mm2. In a subset of 200 slides, we will compare manual semi-quantitative TIL scoring with software based calculation of TILs/mm2. A multidisciplinary team including six pathologists, scientists, technicians, statisticians, surgeons, oncologists and a patient representative from the UK, NL, Japan and Korea will drive this study forward. Results will be related to overall survival (primary endpoint), treatment and clinicopathological variables. How the results of this research will be used. If we can validate our pilot study results, the clinicians of this study confirmed that they would want to use HE-TIL/mm2 in the clinical routine to improve patient stratification for treatment options as soon as possible. Depending on the result of the comparison between manual scoring by a pathologist and software-based scoring, we will either develop a web based training platform for pathologists or approach a commercial provider with interest in setting HE-TIL scoring up as a service.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS