Comprehensive Genomic Profiling of Relapsed and Metastatic Adenoid Cystic Carcinomas by Next-generation Sequencing Reveals Potential New Routes to Targeted Therapies Jeffrey S. Ross, MD,*w Kai Wang, MD, PhD,w Janna V. Rand, MD,* Christine E. Sheehan, MS,* Timothy A. Jennings, MD,* Rami N.Al-Rohil, MD,* Geoff A. Otto, PhD,w John C. Curran, PhD,w Gary Palmer, MD,w Sean R. Downing, PhD,w Roman Yelensky, PhD,w Doron Lipson, PhD,w Sohail Balasubramanian, BS,w Lazaro Garcia, BS,w Kristen Mahoney, BS,w Siraj M. Ali, MD, PhD,w Vincent A. Miller, MD,w and Philip J. Stephens, PhDw Abstract: We hypothesized that next-generation sequencing could reveal actionable genomic alterations (GAs) and poten- tially expand treatment options for patients with advanced adenoid cystic carcinoma (ACC). Genomic profiling using next- generation sequencing was performed on hybridization-cap- tured, adapter ligation libraries derived from 28 relapsed and metastatic formalin-fixed paraffin-embedded ACC. The 3230 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer were fully sequenced using the Illumina HiSeq 2000. All classes of GAs were evaluated. Ac- tionable GAs were defined as those impacting targeted anti- cancer therapies on the market or in registered clinical trials. A total of 44 GAs were identified in the 28 ACC tumors, with 12 of 28 (42.9%) of tumors harboring at least 1 potentially actionable GA. The most common nonactionable GAs were identified in KD6MA (5 cases; 18%), ARID1A (4 cases; 14%), RUNX1 (2 cases; 7%), and MYC (2 cases; 7%). Actionable GAs included NOTCH1 (3 cases; 11%), MDM2 (2 cases; 7%), PDGFRA (2 cases; 7%), and CDKN2A/B (p16) (2 cases; 7%). Other poten- tially actionable GAs identified in a single case included: mu- tations in AKT1, BAP1, EGFR, and PIK3CA, homozygous deletion of FBXW7, and amplifications of CDK4, FGFR1, IGF1R, KDR, KIT, and MCL1. The frequency of GA in ACC is lower than that seen in the more common solid tumors. Com- prehensive genomic profiling of ACC can identify actionable GAs in a subset of patients that could influence therapy for these difficult-to-treat progressive neoplasms. Key Words: adenoid cystic carcinoma, head and neck, targeted therapy, next-generation sequencing (Am J Surg Pathol 2014;38:235–238) A denoid cystic carcinoma (ACC) is a relatively un- common malignant epithelial neoplasm characterized by the arrangement of angulated, small basophilic basaloid nuclei in a mixture of tubular, cribriform, and solid growth patterns. Low-grade and intermediate-grade ACCs may have a deceptively benign microscopic appearance yet fea- ture local recurrence and metastatic spread. High-grade ACCs are characterized by a solid growth pattern, which may be anaplastic and feature a desmoplastic stromal re- sponse. 1–4 Approximately 55% to 60% of ACCs originate in the head and neck region, including salivary glands, oropharynx, nasopharynx, and paranasal sinuses, and is the third common malignancy of salivary glands. 1–4 Twenty percent of ACCs originate from the mid respiratory tract, 10% to 15% develop in the female breast, and the re- maining small group of ACCs occur in a wide variety of sites predominantly localized to exocrine glands. 1–4 When first diagnosed, ACC is predominantly a surgical disease, and wide local excision can be curative in a significant number of patients. 1–4 In general, the early prognosis of ACC is excellent, with approximately 90% of patients surviving for 5 years. However, owing to its propensity to invade the perineural space, either complete surgical re- section may not be possible or indolent cases of ACC can transform into aggressive tumors with late local and systemic relapses, which significantly lower the 10-year From the *Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY; and wFoundation Medicine Inc., Cambridge, MA. Conflicts of Interest and Source of Funding: Funded by Foundation Medicine Inc., Cambridge, MA. Authors J.S.R., K.W., G.A.O., J.C.C., G.P., S.R.D., R.Y., D.L., S.B., L.G., K.M., S.M.A., V.A.M., and P.J.S. are employees and own stock in Foundation Medicine Inc. For the remaining authors none were declared. Correspondence: Jeffrey S. Ross, MD, Department of Pathology, Albany Medical College, Mail Code 81, 47 New Scotland Avenue, Albany, NY 12208 (e-mail: rossj@mail.amc.edu). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.ajsp.com. Copyright r 2013 by Lippincott Williams & Wilkins ORIGINAL ARTICLE Am J Surg Pathol  Volume 38, Number 2, February 2014 www.ajsp.com | 235