Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with high risk of recurrence despite macroscopically complete surgical resection. The main predictors of ACC recurrence include advanced disease stage, incomplete surgical resection, cortisol production, certain genetic alterations, and high proliferation rate (Ki-67 proliferation index). Mitotane has been the mainstay adjuvant therapy of ACC. However, the use of mitotane is based on retrospective and occasionally conflicting evidence. As mitotane levels can take a few months before reaching therapeutic levels, there is an emerging practice of combining platinum-based chemotherapy with mitotane in the adjuvant setting. Retrospective data indicate that radiotherapy is an option for select patients, particularly those with positive resection margins. There are multiple knowledge gaps in selecting patients for adjuvant therapy. It is of great importance to establish risk calculators to predict recurrence and to implement molecular profiling of ACC to guide adjuvant therapy. The role of immunotherapy in metastatic ACC is emerging and if deemed efficacious, then future studies will be needed to ascertain the role of adjuvant immunotherapy in ACC.

4599 Background: In resectable hepatocellular carcinoma (HCC) surgical resection is associated with high recurrence rates. However, there is no approved neoadjuvant or adjuvant therapies yet. Neoadjuvant immunotherapy effect has never been reported in this setting in HCC. Methods: This is a randomized phase II trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as peri-operative treatment for patients (pts) with HCC who are eligible for surgical resection. Pts in Arm A are given nivolumab 240 mg iv, every 2 weeks (wks) for a total of 3 doses followed by surgery on week 6. Pts in Arm B are treated with nivolumab per same schedule as arm A plus concurrent ipilimumab 1 mg/kg on day 1. Adjuvant part of study starts 4 weeks after surgery, with Nivolumab at 480 mg iv every 4 weeks for 2 years in arm A. Pts in Arm B are treated with nivolumab per same schedule as arm A plus concurrent ipilimumab 1 mg/kg every 6 weeks times 4 doses after resection. The primary objective was the safety/tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, pathologic complete response (pCR) rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood. Results: 30 patients were enrolled, 2 patients withdrew consent, one patient was not eligible at time of therapy, and 27 randomized (13 to Arm A and 14 to Arm B). 21 patients proceeded with resection as planned and surgery was aborted for 6 patients; 1 for frozen abdomen due to old surgery, 2 for small residual volume, and 3 for progressive disease. Pts age ranged between 32-83 yo, 75 % were males, 7 pts had HCV, 7 had HBV and 7 had no hepatitis. Pathologic complete response (pCR) was observed in 5/21 pts (24% pCR rate) – 2 in Arm A and 3 Arm B, and 3/21 pts (16%) – 1 in Arm A, 2 in Arm B, achieved major pathologic response (necrosis effect of 50-99%). 5 patients in Arm B and 1 in Arm A experienced grade 3 or higher toxicity prior to surgery. No grade 4 or higher toxicity were observed and surgery was not delayed or cancelled due to oxicity. Conclusions: Our study reached its primary endpoint of safety. Importantly, we report a 40% pathologic response rate = pCR rate of 24%, and major necrosis rate of 16% for resectable HCC after preoperative immunotherapy in a randomized phase II pilot trial. After future validation, these promising results may contribute to a paradigm shift in the perioperative treatment of resectable HCC. Clinical trial information: NCT03222076 .

The novel coronavirus disease 2019 (COVID-19) pandemic has led to an unprecedented threat to the international community and raised major concerns in terms of public health safety. Although our current understanding of the complexity of COVID-19 pathogenesis remains limited, the infection is largely mediated by the interaction of viral spike protein and angiotensin-converting enzyme 2 (ACE2). The functional importance of ACE2 in different demographic and comorbid conditions may explain the significant variation in incidence and mortality of COVID-19 in vulnerable groups, and highlights its candidacy as a potential therapeutic target. We provide evidence supporting the idea that differences in incidence and severity of COVID-19 infection may be related to ACE2. Emerging data based on the prevalence and severity of COVID-19 among those with established high levels of ACE2 expression strongly support our hypothesis. Considering the burden of COVID-19 infection in these vulnerable groups and the impact of the potential therapeutic and preventive measures that would result from adopting ACE2-driven anti-viral strategies, our hypothesis may expedite global efforts to control the current COVID-19 pandemic.

BackgroundThere is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC.MethodsA retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/metastatic ACC.ResultsEight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21–49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2–9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression-free survival was 5.5 months (95% CI 1.8–not reached) and median duration of therapy was 8.5 months (range 2–22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events.ConclusionsIn our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response.

Introduction: Most thyroid cancers (TC) are due to mutually exclusive somatic driver mutations. NTRK fusions are rare oncogenic drivers in papillary TC (PTC), poorly differentiated TC (PDTC) and anaplastic TC (ATC), estimated to be in 2.3% of all TC. However, the clinical presentation and behavior of TRK-fusion TC remains largely unknown. Methods / Case Presentation: Using institutional databases, we identified all TC patients (pts) with an NTRK fusion reported on somatic testing performed by a CLIA-certified laboratory. Data from the medical records were collected. The objective of this study was to investigate the clinical and pathological features of TC pts whose tumors harbored an NTRK fusion. Results / Discussion: We identified 36 TC pts with somatic NTRK fusions. Fusion testing was generally done in pts with advanced or radioactive iodine refractory (RAI-R) disease. Median age at diagnosis was 27.4 years (range 4–75 years), 21 (58%) were female and 16 (44%) were pediatric. 28/36 (78%) pts had PTC, 2/36 (5%) PDTC and 6/36 (17%) ATC. There were a total of 12 (33%) NTRK1, 24 (67%) NTRK3, and no NTRK2 fusions. In ATC and PDTC pts NTRK3 was the most common NTRK fusion 7/8 (87%). In PTC pts, 11 (39%) had NTRK1 and 17 (61%) had NTRK3. In the adult pts NTRK3 was more common 17/20 (85%) (Odds Ratio 7.2, P=0.013), however, in pediatric pts rate of NTRK1 and NTRK3 were similar. One pt had additional mutations along with the NTRK fusion, an ATC pt with multiple mutations including BRAF V600E. Of the 30 PTC/PDTC pts, 23 (77%) had distant metastases (mets). 14 (38%) pts had distant mets at diagnosis and 11 (69%) pediatric pts had distant mets. Lung 21 (70%) and bone 9 (30%) were the most common distant mets sites. In the PTC pts with distant mets, 9 (41%) had RAI-avid and 11 (50%) had RAI-R disease. In the entire cohort of 36 pts, 17 (53%) were on a systemic therapy of whom 11 pts were PTC. NTRK directed was the most common systemic therapy 16 (94%). All PTC pts were alive with a median time from diagnosis of 46 months (Interquartile 1–3: 25–118 months). Four ATC and one PDTC pts had died at the time of the analysis. Conclusions: In this study we confirmed that NTRK fusions occur primarily in PTC but also in less differentiated tumors. Most were young pts but NTRK fusions were identified in tumors from adults as old as 75 years. NTRK1 and NTRK3 were the most common NTRK fusions with NTRK3 being more common in adults. In thyrocyte-derived TC pts, NTRK fusions are mutually exclusive genetic events that occur in pts of all ages and varying histologies. Given the availability of NTRK targeted therapy, consideration should be given to testing for NTRK fusions in advanced thyroid cancer pts, especially those in whom prior genetic testing did not identify an oncogenic driver.

Background Reporting temporal trends in adrenocortical carcinoma (ACC) helps guiding management strategies. Methods A retrospective study of ACC patients seen at a referral cancer center between February 1998 and August 2019. Clinical outcomes were compared between an early cohort (February 1998 to June 2007) and a late cohort (July 2007 to August 2019). Results A total of 621 patients included with a median age at diagnosis of 49.3 years (range, 0.5-86.6 years). 285 (45.9%) with hormonal overproduction. More patients in the late cohort had stage IV disease compared to the early cohort (36.8% vs. 23.1%; P < .0001). Resection of the primary tumor was done in 502 patients (80.8%). Complete resection (R0) was more common in the late cohort (165 [60.2%]) than in the early cohort (100 [44.6%]; P = .0005). Of 475 patients with metastatic disease (stage IV or recurrent metastatic disease), 352 (74.1%) received mitotane, 320 (67.4%) received chemotherapy, and 53 (11.2%) received immunotherapy. In the early cohort, 70 (33%) received ≥2 lines of therapy, whereas in the late cohort, 127 (48%) received ≥ 2 lines of therapy. The 5-year overall survival rates were 65%, 58%, 45%, and 10% for stage I, II, III, and IV disease, respectively, whereas the 2-year overall survival rates in patients with stage IV disease was 24% in the early cohort and 46% in the late cohort (P = .0114). Conclusions ACC clinical outcomes improved over the past two decades as more patients had complete resection or received more lines of systemic therapy.

Purpose To identify prognostic clinical and radiologic features in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab. Patients and Methods Clinical and imaging records of patients with unresectable HCC were retrospectively reviewed, and baseline features were recorded. Patients’ records and imaging studies were used to determine the patients’ overall survival (OS) and progression-free survival (PFS). Univariate and multivariate analyses were performed to determine prognostic features. Subanalyses of treatment-naïve patients (who never received local or systemic therapy) and previously treated patients were also performed. Results Fifty-five patients were included in the final analysis, 23 (41.8%) of whom were treatment naïve. The median PFS and OS for the entire cohort were 3.0 months and 7.9 months. The 3-, 6- and 12-month OS rates were 85.5%, 79.8% and 45.7%, respectively. The 3-, 6- and 12-month PFS rates were 50.1%, 41.2% and 20.1%, respectively. On multivariate analysis, independent prognostic features for poor PFS of the entire cohort were pleural effusions (p = 0.047, HR: 6.3; CI: 1.03–38.90) and hepatic vein tumor thrombus (p = 0.005; HR: 23.37; CI: 2.63–207.67); independent prognostic features for poor OS were ascites (p = 0.008; HR: 37.37; CI: 2.53–467.64), pleural effusion (p = 0.003; HR: 110.17; CI: 5.00–2426.54), and low (<40HU) pre-contrast attenuation on CT images (p = 0.007; HR: 0.09; CI: 0.02–0.53). On subanalysis of treatment-naïve patients, the median OS and PFS were 7.4 months and 2.8 months, respectively. The 3-, 6- and 12-month PFS rates were 43.5%, 38.6% and 24.8%, respectively. Pleural effusion was the only independent poor prognostic feature (p = 0.036; HR: 206.34; CI: 1.41–30,167.58). Conclusion Independent prognostic features for survival outcomes include the presence of ascites, pleural effusions, hepatic vein tumor thrombus, and HCC with low attenuation (<40 HU) on unenhanced CT images. Although several biochemical variables were significant on univariate analysis, none were independent predictors of OS or PFS.

Introduction: Hepatocellular carcinoma (HCC) has limited systemic therapy options when discovered at an advanced stage. Thus, there is a need for accessible and minimally invasive biomarkers of response to guide the selection of patients for treatment. This study investigated the biomarker value of plasma growth hormone (GH) level as a potential biomarker to predict outcome in unresectable HCC patients treated with current standard therapy, atezolizumab plus bevacizumab (Atezo/Bev). Materials and Methods: Study included unresectable HCC patients scheduled to receive Atezo/Bev. Patients were followed to determine progression-free survival (PFS) and overall survival (OS). Plasma GH levels were measured by ELISA and used to stratify the HCC patients into GH-high and GH-low groups (the cutoff normal GH levels in women and men are ≤3.7 μg/L and ≤0.9 μg/L, respectively). Kaplan-Meier method was used to calculate median OS and PFS and Log rank test was used to compare survival outcomes between GH-high and -low groups. Results: Thirty-seven patients were included in this analysis, of whom 31 were males and 6 females, with a median age of 67 years (range: 37–80). At the time of the analysis, the one-year survival rate was 70% (95% CI: 0.51, 0.96) among GH low patients and 33% (95% CI: 0.16, 0.67) among GH high patients. OS was significantly superior in GH-low compared to GH-high patients (median OS: 18.9 vs. 9.3 months; p = 0.014). PFS showed a non-significant trend in favor of GH-low patients compared to the GH-high group (median PFS: 6.6 vs. 2.9 months; p = 0.053). Discussion and conclusions: Plasma GH is a biomarker candidate for predicting treatment outcomes in advanced HCC patients treated with Atezo/Bev. This finding should be further validated in larger randomized clinical trials in advanced HCC patients.