Tumor Mutational Burden Is a Potential Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Patients With Advanced Biliary Tract Cancer.

PURPOSE: Patients with advanced biliary tract cancers (BTCs) have a dismal prognosis. This multisite, single-institution study analyzed the efficacy and safety of immune checkpoint inhibitors (ICIs) in patients with advanced BTC. MATERIALS AND METHODS: The prospectively maintained institutional database was searched for patients with advanced BTC. Electronic medical records of the patients with advanced BTC treated with an ICI that included programmed death-1 or programmed death-ligand 1 blockers were retrospectively reviewed to obtain data on patient characteristics, tumor characteristics including molecular biomarkers, detailed treatment, response characteristics, survival, and toxicities. The analysis included overall response rate, survival, and correlation between survival and molecular biomarkers. RESULTS: The institutional database query identified 47 patients with advanced BTC who received at least one dose of an ICI; 11 (24%) patients in the first-line setting and the rest of the patients had refractory disease. The median age of the cohort was 62 years, and 51% were female. The overall response rate was 10.6%, with a disease control rate of 53.2%. The median progression-free survival (PFS) and overall survival were 3.6 months and 6.9 months, respectively. Biomarker analysis revealed improved PFS in patients with tumor mutational burden > 5 mutations per megabase (median PFS: 6.4 v 2.2 months; P = .0027). No unexpected adverse events were observed. CONCLUSION: ICIs are well tolerated and have modest antitumor activity in patients with advanced BTC. The study result supports the exploration of tumor mutational burden as a potential predictive biomarker for response to ICIs in patients with advanced BTC.

Isocitrate Dehydrogenase-Mutated Cholangiocarcinoma: Natural History and Clinical Outcomes.

PURPOSE: Clinical-pathologic features and natural history of patients with isocitrate dehydrogenase (IDH)-mutant intrahepatic cholangiocarcinoma (CCA) are not well characterized. Here, we sought to describe the natural history, clinical phenotype, and prognostic impact of advanced, IDH-mutated CCA. METHODS: We conducted a multicentric, retrospective analysis of patients with IDH-mutated (IDH1 or IDH2) CCA between 2010 and 2020. Median overall survival (OS) and progression-free survival (PFS) analyses were performed using the Kaplan-Meier method. Chi-square test was used to analyze disease control rate (DCR) and overall response rate (ORR). Matched controls were used for comparing survival between patients with and without IDH mutations (mIDH). RESULTS: Sixty-five patients with IDH-mutated CCA were included. All patients had intrahepatic CCA. On first-line chemotherapy, median OS and median PFS were 21.2 months and 8.3 months, respectively. Notably, median OS (32.4 v 19.5 months, P = .12) and PFS (18.0 v 8.0 months, P = .12) were not significantly affected by disease status at presentation (locally advanced v metastatic, respectively). Median OS was significantly longer in patients with mIDH (21.2 v 10.5 months; P < .01). First-line gemcitabine-containing regimens had a significantly higher DCR and ORR than non-gemcitabine-containing regimens (DCR: 75% v 33%, P = .01; ORR: 39% v 0%, P = .02). In patients receiving IDH inhibitor therapy, median PFS was 4.6 months with a DCR of 29%. CONCLUSION: CCA with mIDH confers a unique subtype resulting in a better survival compared with that of counterparts. IDH inhibitors represent a promising therapeutic option in later lines of therapy in this subgroup.

Receptivity to a Nurse-Led Symptom Management Intervention Among Highly Symptomatic Patients With Cancer.

BACKGROUND: The symptom burden associated with cancer and its treatment can negatively affect patients' quality of life and survival. Symptom-focused collaborative care model (CCM) interventions can improve outcomes, but only if patients engage with them. We assessed the receptivity of severely symptomatic oncology patients to a remote nurse-led CCM intervention. METHODS: In a pragmatic, cluster-randomized, stepped-wedge trial conducted as part of the National Cancer Institute IMPACT Consortium (E2C2, NCT03892967), patients receiving cancer care were asked to rate their sleep disturbance, pain, anxiety, emotional distress, fatigue, and limitations in physical function. Patients reporting at least 1 severe symptom (≥7/10) were offered phone consultation with a nurse symptom care manager (RN SCM). Initially, patients had to "opt-in" to receive a call, but the protocol was later modified so they had to "opt-out" if they did not want a call. We assessed the impact of opt-in vs opt-out framing and patient characteristics on receptiveness to RN SCM calls. All statistical tests were 2-sided. RESULTS: Of the 1204 symptom assessments (from 864 patients) on which at least 1 severe symptom was documented, 469 (39.0%) indicated receptivity to an RN SCM phone call. The opt-out period (odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.12 to 2.32, P = .01), receiving care at a tertiary care center (OR = 3.59, 95% CI = 2.18 to 5.91, P < .001), and having severe pain (OR = 1.80, 95% CI = 1.24 to 2.62, P = .002) were associated with statistically significantly greater willingness to receive a call. CONCLUSIONS: Many severely symptomatic patients were not receptive to an RN SCM phone call. Better understanding of reasons for refusal and strategies for improving patient receptivity are needed.

TAS-102: A resurrected novel Fluoropyrimidine with expanding role in the treatment of gastrointestinal malignancies.

TAS-102 is an orally administered fixed-dose formulation consisting of trifluorothymidine (TFT), a fluoropyrimidine antimetabolite, and tipiracil (TPI), an inhibitor of thymidine phosphorylase (TP) that prevents rapid degradation of TFT and ensures its bioavailability. The novelty of TAS-102 lies in its antitumor activity against 5-fluorouracil (5-FU) resistant tumors, demonstrated both in the in vitro models and xenografts. The cytotoxic activity of TFT relies primarily on extensive incorporation of the TFT metabolite into the cellular DNA inducing DNA dysfunction and cell death. In contrast, 5-fluorouracil (5-FU) interferes with DNA biosynthesis by inhibiting thymidylate synthase(TS), which partly explains the absence of cross-resistance between TAS-102 and 5-FU. TAS-102 is currently approved in the third-line setting for patients with metastatic colorectal and gastric cancer based on phase III randomized clinical trial data confirming an overall survival benefit with TAS-102. The preliminary data from recently reported studies suggest a potential expanding role of TAS-102 in a variety of gastrointestinal (GI) cancers. The current article presents an overview of the pharmacology, clinical development of TAS-102, and its emerging role in the treatment of GI cancers. In addition, we discussed the rationale underlying the ongoing clinical trials investigating various combinations of TAS-102 with other anticancer agents, including targeted therapies, in a wide range of GI tumors.

Epidemiology of Thyroid Cancer: A Review of the National Cancer Database, 2000-2013.

Objective  To show the recent trends in thyroid cancer in the United States, elucidate the characteristics of stage IV thyroid cancer, and consider the effects of diagnostic testing on the rising incidence of thyroid cancer. Design  A retrospective population-based study conducted using the National Cancer Database from 2000-2013 (NCDB). Demographics of patients presenting with stage IV thyroid cancer were compared to patients presenting with all other stages using the chi-square testing. The incidence rates were examined with the trend graphs. Results  When compared to stages I-III, there was an increased incidence of stage IV thyroid cancer in: Medicare, lower level of education, lower income, advanced age, male sex, increased number of comorbidities, further distance from a treatment facility, and medullary/anaplastic histology. The incidence of thyroid cancer increased from 7.1 per 100,000 in 2000 to 17.6 per 100,000 in 2013. During this same time period, stage IV disease increased 1 per 100,000. The increase in the incidence of thyroid cancer was almost entirely due to an increase in papillary cancer. Conclusions  The United States has continued to see a rise in the incidence of thyroid cancer over the last decade, largely due to the detection of papillary cancers. During this same time, the incidence of stage IV thyroid cancer increased as well. Because early diagnosis and treatment of an increasing number of potentially lethal cancers should lead to a decrease in metastatic disease, we suggest that the increasing incidence of thyroid cancer in the United States is due to overdiagnosis and that more aggressive disease is not being removed by early detection.