BackgroundPatients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers.MethodsIn this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR).ResultsA total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma–pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug.ConclusionsThe favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma–pheochromocytoma supports further evaluation of pembrolizumab in this patient population.Trial registration numberNCT02721732

Targeted therapies, lenvatinib, and dabrafenib plus trametinib (for BRAF mutants) may provide clinical benefit in ATC patients who are unable to participate in clinical trials, and toxicities are manageable.

Adrenocortical carcinoma (ACC) is a rare neoplasm with a heterogeneous outcome and limited treatment options. To understand its molecular and genomic landscape as a part of The Cancer Genome Atlas (TCGA) project, we performed the genomic, transcriptomic, epigenomic and proteomic profiling of 91 ACCs. We identified potential driving alterations including amplifications (TERT, TERF2 and CDK4), deletions (ZNRF3, CDKN2A and RB1) and point mutations in genes unknown to participate in adrenal disease (RPL22) and genes known to initiate familial syndromes that occasionally include adrenocortical neoplasms (TP53, CTNNB1, PRKAR1A, MEN1). The finding of PRKAR1A expands the catalogue of pathogenic pathways underlying ACC, suggesting of the protein kinase alpha signaling pathway as a potential target for molecular interventions. Novel transcript fusions potentially leading to overactive kinases included EXOSC10-MTOR and PPP1CB-BRE. DNA copy number analysis unveiled prevalent DNA losses leading to hypodiploidy as well as whole genome doubling (WGD) in 51% of ACC. The similar penetrance of loss of heterozygosity before and after WGD suggests a sequential development from hypodiploidy to polyploidy along the doubling in a subset of ACCs, which was endorsed by the worse outcome for WGD samples relative to nonWGD ACCs. An association between TERT expression and WGD was observed, suggesting a role for telomere regulation. These findings present ACC as a model disease for studies of WGD which is a frequent event in many tumor types. Unsupervised clustering of DNA methylation, copy number, gene expression, miRNA expression and protein abundance converged into three classes with specific biological characteristics and a respective median event free survival of 8, 38 and >100 months (p-value 1.7e-13). Comparison of the subtypes suggested additional drivers such as protein kinase C (PKC) phosphorylation and upregulation of a miRNA cluster at chromosome Xq27.3, which complemented the genomic alterations identified in these subtypes. To gain more insights into this rare cancer type, we placed ACC in a broader context of cancer genomic profiles including an array of other cancer types. These analyses revealed interesting shared features, including beta-catenin activation with a subset of endometroid cancer, DNA mismatch repair gene mutational signature with gastrointestinal cancers and a smoking signature with lung cancer. These findings highlight the commonalities between ACC and other lineages of cancer. Taken together, we found Wnt signaling pathway and p53/Rb signaling pathway were the most frequently altered pathways in ACC. Meanwhile, new players surfaced from our analyses including the PKA and PKC pathways. Our results present a comprehensive genomic landscape and refined molecular classification of ACC improve our understanding of its pathogenesis, and will ultimately improve the care of patients. Citation Format: Siyuan Zheng, Andrew D. Cherniack, Ninad Dewal, Richard A. Moffitt, Ludmila Danilova, Bradley A. Murray, Antonio M. Lerario, Tobias Else, Theo A. Knijnenburg, Giovanni Ciriello, Seungchan Kim, Guillaume Assie, Olena Morozova, Rehan Akbani, Juliann Shih, Katherine A. Hoadley, Toni K. Choueiri, Jens Waldmann, Ozgur Mete, Gordon A. Robertson, Matthew Meyerson, Michael J. Demeure, Felix Beuschlein, Anthony Gill, Ana C. Latronico, Maria C. Fragosa, Leslie Cope, Electron Kebebew, Mouhammed A. Habra, Timothy G. Whitsett, Kimberly J. Bussey, William E. Rainey, Sylvia Asa, Jérôme Bertherat, Martin Fassnacht, David A. Wheeler, The Cancer Genome Atlas Research Network, Gary D. Hammer, Thomas J. Giordano, Roel Verhaak. Comprehensive Pan-Genomic characterization of adrenocortical carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2976. doi:10.1158/1538-7445.AM2015-2976

Background: In the face of the COVID-19 pandemic, cancer care has had to adapt rapidly given the Centers for Disease Control and Prevention and the American College of Surgeons (ACS) issuing recommendations to postpone nonurgent surgeries. Methods: An institutional multidisciplinary group of Head and Neck Surgical Oncology, Surgical Endocrinology, and Medical Endocrinology devised Surgical Triaging Guidelines for Endocrine Surgery during COVID-19, aligned with phases of care published by the ACS. Results: Phases of care with examples of corresponding endocrine cases are outlined. Most cases can be safely postponed with active surveillance, including most differentiated and medullary thyroid cancers. During the most acute phase, all endocrine surgeries are deferred, except thyroid tumors requiring acute airway management.Conclusions: These guidelines provide context for endocrine surgery within the spectrum of surgical oncology, with the goal of optimal individualized multidisciplinary patient care and the expectation of significant resource diversion to care for patients with COVID-19. K E Y W O R D S coronavirus, COVID, endocrine, guideline, surgery Yelda Jozaghi and Mark E. Zafereo are co-first authors.

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