ABSTRACT
BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.
Subject(s)
Adenocarcinoma/genetics , Esophageal Neoplasms/genetics , Mutation/genetics , Stomach Neoplasms/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Class I Phosphatidylinositol 3-Kinases , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/mortality , Genetic Markers/genetics , Humans , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinases/genetics , Prognosis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , Stomach Neoplasms/drug therapy , Stomach Neoplasms/mortality , Survival Analysis , ras Proteins/geneticsABSTRACT
BACKGROUND: Perioperative epirubicin, cisplatin and fluorouracil (ECF) chemotherapy improves survival in operable oesophago-gastric cancer [Adjuvant Gastric Cancer Infusional Chemotherapy (MAGIC) trial HR 0.75 (0.6-0.93)]. HER2 amplification is reported to predict enhanced benefit from anthracyclines in breast cancer. We sought to define whether HER2 predicts benefit from ECF in oesophago-gastric cancer. PATIENTS AND METHODS: Diagnostic biopsies and/or resection specimens were collected from 415 of 503 MAGIC trial patients (82.5%). HER2 was evaluated by immunohistochemistry (IHC) and brightfield dual in situ hybridisation (BDISH) in tissue microarrays. The prognostic and predictive impact of HER2 status was investigated. RESULTS: Concordance between HER2 over-expression (IHC3+) and amplification was 96%. Results of HER2 assessment in biopsy and resection specimens were concordant in 92.9% (145/156). HER2 positive rate (IHC3+, or IHC2+/BDISH positive) was 10.9% in the whole cohort and 10.4% in resection specimens. A further 4.0% of resections were IHC negative/BDISH positive. HER2 status was neither prognostic, nor (in pre-treatment biopsies) predicted enhanced benefit from chemotherapy [HER2 positive HR 0.74 (0.14-3.77); HER2 negative HR 0.58 (0.41-0.82), interaction P = 0.7]. However, the power of the predictive analysis was limited by the small number of HER2 positive pre-treatment biopsies. CONCLUSIONS: HER2 status is not an independent prognostic biomarker in early oesophago-gastric adenocarcinoma.
Subject(s)
Adenocarcinoma/drug therapy , Esophageal Neoplasms/drug therapy , Receptor, ErbB-2/metabolism , Stomach Neoplasms/drug therapy , Adenocarcinoma/genetics , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Cisplatin/therapeutic use , Combined Modality Therapy , Epirubicin/therapeutic use , Esophageal Neoplasms/genetics , Esophageal Neoplasms/surgery , Female , Fluorouracil/therapeutic use , Humans , Male , Middle Aged , Perioperative Period , Prognosis , Receptor, ErbB-2/genetics , Stomach Neoplasms/genetics , Stomach Neoplasms/surgery , Young AdultABSTRACT
A 4 week study of medical inpatients was performed to look at prevalence of alcohol-related problems in three different sub-specialties. Alcohol-related conditions accounted for 51% of gastroenterology inpatients, and 65% of these patients had alcoholic liver disease. In contrast, the cardiologists and respiratory physicians managed for less alcohol-related pathology, accounting for only 6% of inpatients in each specialty. Alcohol-related conditions were three times commoner in men. Patients admitted due to alcohol had longer lengths of stay, and experienced higher morbidity and mortality. These findings have important implications for health care planning and provision. They highlight a need for specialist training to be given to staff who deal with alcohol-related conditions on a daily basis. There is also a significant public health issue raised by these results regarding public attitudes in Scotland towards alcohol abuse and the increasing burden it is placing on the NHS.
