Comprehensive Genomic Profiling of Relapsed and Metastatic Adenoid Cystic Carcinomas (ACC) by Next Generation Sequencing (NGS) Reveals New Routes to Targeted Therapies
Janne V Rand, Christine E Sheehan, Timothy A Jennings, Rami N Al-Rohil, Geoff Otto, John Curran, Gary Palmer, Sean Downing, Roman Yelensky, Doron Lipson, Sohail Balasubramanian, Lazaro Garcia, Kristin Mahoney, Vincent Miller, Philip Stephens, Jeffrey S Ross. Albany Medical College, Albany, NY; Foundation Medicine Inc., Cambridge, MA
Background: ACC of the head and neck (HN) and upper respiratory tract features a highly variable clinical course with systemic chemotherapy of limited value for patients with metastatic disease. The recent discovery of a MYB-NFIB gene fusion in ACC led us to hypothesize that comprehensive clinical NGS could reveal actionable genomic alterations (GA) and potentially expand treatment options for ACC.
Design: DNA was extracted from 4 formalin-fixed paraffin embedded sections cut at 10 microns from 8 primary HN ACC and 1 tracheal ACC. NGS was performed on hybridization-captured, adapter ligation libraries derived from 2 primary parotid tumors, 1 recurrent lesion in the mouth and 6 metastatic lesions, including 4 lung and 1 each in a lymph node and bone. The exons of 182 cancer-related genes were fully sequenced using the Illumina HiSeq 2000 at an average sequencing depth of 776X All classes of genomic alterations (GA) were evaluated including point mutations (mut), insertions, deletions, copy number alterations, and select gene fusions/rearrangements. Actionable GA were identified as impacting targeted anti-cancer therapies on the market or in registered clinical trials.
Results: The 6 male (67%) and 3 female (33%) ACC patients had a mean age of 58 years. Four (44%) tumors were Stage III and 5 (56%) were Stage IV time of NGS. Three of nine (33%) ACC featured a total of 12 GA (average of 4.0 GA per tumor). Three of three (100%) of ACC with GA were Stage IV. Mut in TP53 was identified in 2/3 (67%) ACC with GA. GA in BAP1, KDM6A, KDR, KIT, PDGFRA, PTCH1, ARID1A, EPHA6, and KDM6A were each identified once in one of the 3 ACC with GA. Of the 3 ACC with GA, 2 (67%) had GA potentially associated with clinical benefit of targeted therapies including potential entry into 11 CT. Two of nine (22%) of ACC had actionable GA including one ACC that featured amp of KIT and PDGFR genes which directed the patient to tyrosine kinase inhibitor therapy (imatinib, dasatinib) and one ACC with a PTCH1 mutation which potentially directed the patient to an FDA-approved hedgehog pathway inhibitor (vismodegib) used to treat cutaneous basal cell carcinoma.
Conclusions: Although GA in ACC are a relatively uncommon occurrence possibly reflecting their generally well-differentiated histologic appearance, deep NGS of ACC can discover actionable GA that could influence therapy especially in advanced stage tumors that are difficult to characterize by other diagnostic methods in a single comprehensive test.
Category: Head & Neck
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 196, Monday Morning