Abstract 1524: Mutations and gene copy number variations landscape of metastases of various cancer types from patients enrolled in the SHIVA trial
Authors: Kamal Maud , Servant Nicolas , Pierron Gaelle , Callens Celine , Gentien David , Lermine Alban , Lucotte Georges , Bernard Virginie , Vincent-Salomon Anne , Bièche Ivan , Le Tourneau Christophe 
Published: July 2016

Background

The molecular landscape of primary tumors of several cancer types is available and tissue-independent classification of tumors on the basis of genetic and epigenetic alterations is emerging1. The molecular profile of metastatic cancers remains to be unraveled. Here we present mutations and gene copy number variations (CNV) of metastases across tumor types from patients enrolled in the SHIVA trial2.

Patients and methods

The SHIVA trial is a multicentric randomized proof-of-concept phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with any type of refractory cancer. Mutations using targeted NGS (AmpliSeq cancer panel on Ion Torrent / PGM (Life)), and CNV using Cytoscan HD (Affymetrix) were assessed on a mandatory biopsy from a metastatic site with ≥30% of tumor cell content. Sequencing data were processed in order to detect actionable somatic mutations. Detected variants were filtered according to their frequency (≥4% for SNVs and 5% for indels), strand ratio (≥0.2), and reads coverage (≥30X for SNVs and 100X for indels). Non polymorphic deleterious mutations were reported. Copy number and allele difference profiles were processed taking into account% of tumor cells and ploidy of the sample. Homozygous and heterozygous deletions and focal amplifications were reported for tumor suppressor genes and oncogenes. Between October 2012 and July 2014, 741 patients with any type of solid cancer were enrolled in the SHIVA trial. Among these, 507 and 496 patients had high quality NGS and CNV profiling, respectively.

Results

Major cancer types for which molecular analyses were possible on a metastatic biopsy were: breast (14%), colorectal (11%), lung (11%), ovarian (11%), pancreatic (8%), sarcoma (6%), head and neck (4%), cervical (4%), urothelial (4%), endometrial (3%), oesogastric (3%) cancers, adenoid cystic carcinoma (3%) and others (18%). TP53 mutations were present in 44% of metastatic patients. Major mutated oncogenes were KRAS (20%), PIK3CA (12%), MET (6%), FGFR3 (5%), EGFR (2%) and BRAF (2%). Tumor suppressor genes PTEN, FBXW7 and CDKN2A were mutated in 3% of patients. Alternatively, homozygous and heterozygous deletions of PTEN, FBXW7 and CDKN2A were observed in around half of the patients analyzed (40%, 40% and 54%, respectively).

Conclusions

Mutations and CNV analyses on metastatic tumors from patients enrolled in the SHIVA trial showed similar results in terms of frequency of previously reported genetic alterations1,3. The frequency of KRAS mutations (20%) was however higher than the frequency (7%) reported in the pan cancer cohort of the tumors portal3. This result needs to be interpreted in accordance with tumor types before suggesting potential resistance mechanisms in heavily pretreated patients. Clustering of these alterations in specific signaling pathways is currently ongoing.

Citation Format: Maud Kamal, Nicolas Servant, Gaelle Pierron, Celine Callens, David Gentien, Alban Lermine, Georges Lucotte, Virginie Bernard, Anne Vincent-Salomon, Ivan Bièche, Christophe Le Tourneau. Mutations and gene copy number variations landscape of metastases of various cancer types from patients enrolled in the SHIVA trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1524.