Date: 2014-05-31
Type of information: Results
phase:
Announcement: presentation of results at the 50th American Society of Clinical Oncology (ASCO) Annual Meeting, May 30 to June 3, 2014, in Chicago
Company: Almac Group (UK)
Product: ALM AADx assay
Action
mechanism: ALM AADx assay is a 63 gene test that can prospectively identify the good prognosis angiogenesis inactive subgroup.
Disease: ovarian cancer
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On May 31, 2014, Almac has announced the validated results of the ALM AADx assay, a gene expression test that identifies a subgroup of high grade serous ovarian cancer (HGSOC) patients that have a good prognosis following standard of care chemotherapy. The molecular subgroup identified by this test is defined by absence of angiogenesis and represents 40% of the HGSOC population. The molecular subgroup was identified by Almac in collaboration with Professor Charlie Gourley from the University of Edinburgh and was initially reported at ASCO 2011. The current work represents an independent validation of the assay and was carried out in collaboration with the Medical Research Council in the UK. Unsupervised hierarchical clustering by Almac found three molecular subgroups within HGSOC; one with angiogenic gene inactivation and immune gene upregulation with better overall survival rates; and two with angiogenic gene upregulation and a corresponding worse overall survival rate following standard of care first line chemotherapy. These latest validation results were presented at the 2014 ASCO Annual Meeting in Chicago by Professor Gourley. In this study, researchers extracted mRNA from 265 formalin-fixed paraffin-embedded samples taken from Scottish patients with high-grade serous ovarian cancer (treated with primary debulking then platinum-based chemotherapy) and performed transcriptional analyses. Using unsupervised hierarchical clustering, they identified three major subgroups of patients: two with angiogenic gene upregulation (the proangiogenic groups) and one with angiogenic gene repression and immune gene upregulation (the immune molecular subgroup). A survival analysis of this group of patients indicated that those patients in the immune subgroup had a significantly improved overall survival (OS) compared with the combined proangiogenic groups (p = 0.001 for both). Based on these results, a 63-gene signature was developed to distinguish patients in the immune subgroup from those in the two proangiogenic subgroups. Using this gene signature, Dr. Gourley and colleagues applied their findings to the Tothill dataset in silico. This analysis confirmed that patients in the immune subgroup had significantly improved progression-free survival (PFS; hazard ratio [HR] 0.661, 95 % CI 0.439, 0.996; p = 0.048) and OS (HR 0.357, 95% CI 0.219, 0.582; p < 0.001) compared with the proangiogenic groups. The results were further validated in 284 samples taken from the ICON7 study, which assigned patients to paclitaxel/carboplatin with or without concomitant and maintenance bevacizumab. Looking at just those patients in the control arm of ICON7, patients in the immune subgroup again had significantly improved PFS (HR 0.47, 95% CI 0.32, 0.71; p < 0.001) and OS (HR 0.45, 95% CI 0.26, 0.79; p = 0.005) compared with the proangiogenic groups. Dr. Gourley suggested two possible explanations for these improved outcomes. “Firstly, as this subgroup has repression of angiogenic processes the survival may be better because the blood supply to the tumor is less well developed,” Dr. Gourley said. “Secondly, it is possible that in these patients the active engagement of the tumor by the host immune system results in more indolent disease.” However, in the group of patients treated with bevacizumab, those patients in the immune subgroup had significantly worse PFS (p = 0.015), with a median PFS of 18.5 months when treated with bevacizumab compared with 35.8 months on carboplatin/paclitaxel alone. In contrast, the proangiogenic group had a trend toward a better PFS when treated with bevacizumab, with a median PFS of 12.3 months on carboplatin/paclitaxel alone compared with 17.4 months with the addition of bevacizumab.In his discussion of the abstract, Jonathan A. Ledermann, MD, FRCP, of University College London Cancer Institute, United Kingdom, said that very little is currently understood about the mechanism of action by which these results might occur, but that it is very important moving forward to study the interaction further.
