Targeted therapies in neuroendocrine tumors (NET): clinical trial challenges and lessons learned.

In the past 3 years, we have witnessed the completion of four randomized phase III studies in neuroendocrine tumors and the approval of two new drugs, everolimus and sunitinib, for the treatment of patients with well-differentiated pancreatic neuroendocrine tumors. These studies demonstrate a shift from case series and single-arm studies toward prospective, randomized controlled clinical trials and evidence-based therapy in the neuroendocrine tumor field. However, the clinical development of these agents also highlights the potential challenges awaiting other new drugs in this area. Herein, we discuss the strengths and weaknesses of the most recent phase II and phase III neuroendocrine tumor studies and discuss how limitations inherent in current trial design can lead to potential pitfalls. We also discuss how trial design can be improved, with the hope of increasing the number of drugs successfully developed to treat patients with neuroendocrine tumors.

TERT Copy Number Alterations, Promoter Mutations and Rearrangements in Adrenocortical Carcinomas.

Molecular characterization of adrenocortical carcinomas (ACC) by The Cancer Genome Atlas (TCGA) has highlighted a high prevalence of TERT alterations, which are associated with disease progression. Herein, 78 ACC were profiled using a combination of next generation sequencing (n = 76) and FISH (n = 9) to assess for TERT alterations. This data was combined with TCGA dataset (n = 91). A subset of borderline adrenocortical tumors (n = 5) and adrenocortical adenomas (n = 7) were also evaluated. The most common alteration involving the TERT gene involved gains/amplifications, seen in 22.2% (37/167) of cases. In contrast, "hotspot" promoter mutations (C > T promoter mutation at position -124, 7/167 cases, 4.2%) and promoter rearrangements (2/165, 1.2%) were rare. Recurrent co-alterations included 22q copy number losses seen in 24% (9/38) of cases. Although no significant differences were identified in cases with and without TERT alterations pertaining to age at presentation, tumor size, weight, laterality, mitotic index and Ki67 labeling, cases with TERT alterations showed worse outcomes. Metastatic behavior was seen in 70% (28/40) of cases with TERT alterations compared to 51.2% (65/127, p = 0.04) of cases that lacked these alterations. Two (of 5) borderline tumors showed amplifications and no TERT alterations were identified in 7 adenomas. In the borderline group, 0 (of 4) patients with available follow up had adverse outcomes. We found that TERT alterations in ACC predominantly involve gene amplifications, with a smaller subset harboring "hotspot" promoter mutations and rearrangements, and 70% of TERT-altered tumors are associated with metastases. Prospective studies are needed to validate the prognostic impact of these findings.

A case report of a patient with advanced acinar cell carcinoma of the pancreas: long-term survival with regional, systemic and targeted therapy.

Acinar cell carcinoma of the pancreas is an uncommon malignancy for which there are no prospective, randomized data to guide therapy. We describe the clinical course and management of a patient with advanced pancreatic acinar cell carcinoma who is alive seven years after diagnosis using systemic and regional chemotherapies as well as molecularly targeted agents.

Adenocarcinoma of unknown primary in a 20-year-old African American male.

A 20-year-old African American male presented with a history of left flank pain and passing of light pink urine. Medical history included sickle cell trait. Urine analysis was positive for protein and blood. Metabolic profile, autoantibody screen, and complement levels were normal. Hemoglobin electrophoresis revealed an 41.8% HbS diagnostic of sickle cell trait. Creatinine clearance was normal and proteinuria was nonnephrotic. A noncontrast computed tomography (CT) scan showed left proximal hydronephrosis. Urology follow-up was arranged and the differential included renal papillary necrosis, or renal cyst rupture. He presented 3 months later with sudden onset left flank pain and gross hematuria. Serum creatinine was 1.8 mg/dL. Computed tomography scan with contrast revealed innumerable lung lesions, an enlarged heterogenously enhancing left kidney, and retroperitoneal adenopathy. Ultrasound revealed an obstructed left collecting system and a 14-cm enlarged left kidney with no discrete mass. Testicular markers/ultrasound, upper/lower endoscopies were normal. Lung biopsy revealed poorly differentiated adenocarcinoma positive for cytokeratin 7. Renal, sarcoma, and gastrointestinal markers were negative. By exclusion, it appeared that the patient had a carcinoma of unknown primary. However, with the clinical and personal history, a diagnosis of renal medullary carcinoma (RMC) was made. RMC is a rare and highly malignant tumor that should always be included in the differential of a patient with sickle cell disorder and hematuria. Renal biopsy typically fails to sample the renal medulla and radiologic findings might not raise the suspicion of a renal tumor. Thus, clinical suspicion must always be high in order to preserve the patient's only chance of prolonged survival.