Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62.

Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development.

The Development of an Infrastructure to Facilitate the Use of Whole Genome Sequencing for Population Health.

The clinical use of genomic analysis has expanded rapidly resulting in an increased availability and utility of genomic information in clinical care. We have developed an infrastructure utilizing informatics tools and clinical processes to facilitate the use of whole genome sequencing data for population health management across the healthcare system. Our resulting framework scaled well to multiple clinical domains in both pediatric and adult care, although there were domain specific challenges that arose. Our infrastructure was complementary to existing clinical processes and well-received by care providers and patients. Informatics solutions were critical to the successful deployment and scaling of this program. Implementation of genomics at the scale of population health utilizes complicated technologies and processes that for many health systems are not supported by current information systems or in existing clinical workflows. To scale such a system requires a substantial clinical framework backed by informatics tools to facilitate the flow and management of data. Our work represents an early model that has been successful in scaling to 29 different genes with associated genetic conditions in four clinical domains. Work is ongoing to optimize informatics tools; and to identify best practices for translation to smaller healthcare systems.

Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS: Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS: Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION: Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.

Telehealth Is a Sustainable Population Health Strategy to Lower Costs and Increase Quality of Health Care in Rural Utah.

PURPOSE: A telehealth oncology practice was created to care for patients in rural communities to improve access to health care, decrease financial burdens, and save time. PATIENTS AND METHODS: Patients with cancer at Sevier Valley Hospital in Richfield, Utah, were treated with a real-time video-based telehealth program under the care of an oncologist at a tertiary medical center. Data on financial savings, travel hours, mileage avoided, carbon emissions reduced, and revenue retained by Sevier Valley Hospital were collected from 2015 to 2018. RESULTS: From 2015 to 2018, 119 patients with cancer in Richfield, Utah, were treated with telehealth for oncology visits, accounting for 1,025 patient encounters. On average, patients saved 4 hours and 40 minutes and 332 miles roundtrip per encounter. In total, patients' savings were estimated to be $333,074. Carbon emissions were reduced by approximately 150,000 kg. Of new patient referrals, 59% were for solid tumors (70 of 119 referrals; 42 metastatic and 28 nonmetastatic cancers), and 41% were hematology consultations (49 of 119 referrals; 28 classical and 21 malignant hematologic conditions). We estimate that Sevier Valley Hospital retained $3,605,500 in revenue over this 4-year period. CONCLUSION: Using a telehealth program in rural Utah, patients with cancer benefited from substantial time and monetary savings. The local medical center was able to retain revenue it would have otherwise lost to outsourcing cancer care. Recent regulatory changes to address the COVID-19 pandemic should increase the number of patients with cancer treated via telehealth nationwide.

Whole genome analysis identifies the association of TP53 genomic deletions with lower survival in Stage III colorectal cancer.

DNA copy number aberrations (CNA) are frequently observed in colorectal cancers (CRC). There is an urgent need for CNA-based biomarkers in clinics,. n For Stage III CRC, if combined with imaging or pathologic evidence, these markers promise more precise care. We conducted this Stage III specific biomarker discovery with a cohort of 134 CRCs, and with a newly developed high-efficiency CNA profiling protocol. Specifically, we developed the profiling protocol for tumor-normal matched tissue samples based on low-coverage clinical whole-genome sequencing (WGS). We demonstrated the protocol's accuracy and robustness by a systematic benchmark with microarray, high-coverage whole-exome and -genome approaches, where the low-coverage WGS-derived CNA segments were highly accordant (PCC >0.95) with those derived from microarray, and they were substantially less variable if compared to exome-derived segments. A lasso-based model and multivariate cox regression analysis identified a chromosome 17p loss, containing the TP53 tumor suppressor gene, that was significantly associated with reduced survival (P = 0.0139, HR = 1.688, 95% CI = [1.112-2.562]), which was validated by an independent cohort of 187 Stage III CRCs. In summary, this low-coverage WGS protocol has high sensitivity, high resolution and low cost and the identified 17p-loss is an effective poor prognosis marker for Stage III patients.

Precision oncology in advanced cancer patients improves overall survival with lower weekly healthcare costs.

The impact of precision oncology on guiding treatment decisions of late-stage cancer patients was previously studied in a retrospective analysis. However, the overall survival and costs were not previously evaluated. We report the overall survival and healthcare costs associated with precision oncology in these patients with advanced cancer. Building on a matched cohort study of 44 patients with metastatic cancer who received all of their care within a single institution, we evaluated the overall survival and healthcare costs for each patient. We analyzed the outcomes of 22 patients who received genomic testing and targeted therapy (precision oncology) between July 1, 2013 and January 31, 2015, and compared to 22 historically controlled patients (control) who received standard chemotherapy (N = 17) or best supportive care (N = 5). The median overall survival was 51.7 weeks for the targeted treatment group and 25.8 weeks for the control group (P = 0.008) when matching on age, gender, histological diagnosis and previous treatment lines. Average costs over the entire period were $2,720 per week for the targeted treatment group and $3,453 per week for the control group, (P = 0.036). A separate analysis of 1,814 patients with late-stage cancer diagnoses found that those who received a targeted cancer treatment (N = 93) had 6.9% lower costs in the last 3 months of life compared with those who did not. These findings suggest that precision oncology may improve overall survival for refractory cancer patients while lowering average per-week healthcare costs, resource utilization and end-of-life costs.

A Retrospective Analysis of Precision Medicine Outcomes in Patients With Advanced Cancer Reveals Improved Progression-Free Survival Without Increased Health Care Costs.

PURPOSE: The advent of genomic diagnostic technologies such as next-generation sequencing has recently enabled the use of genomic information to guide targeted treatment in patients with cancer, an approach known as precision medicine. However, clinical outcomes, including survival and the cost of health care associated with precision cancer medicine, have been challenging to measure and remain largely unreported. PATIENTS AND METHODS: We conducted a matched cohort study of 72 patients with metastatic cancer of diverse subtypes in the setting of a large, integrated health care delivery system. We analyzed the outcomes of 36 patients who received genomic testing and targeted therapy (precision cancer medicine) between July 1, 2013, and January 31, 2015, compared with 36 historical control patients who received standard chemotherapy (n = 29) or best supportive care (n = 7). RESULTS: The average progression-free survival was 22.9 weeks for the precision medicine group and 12.0 weeks for the control group ( P = .002) with a hazard ratio of 0.47 (95% CI, 0.29 to 0.75) when matching on age, sex, histologic diagnosis, and previous lines of treatment. In a subset analysis of patients who received all care within the Intermountain Healthcare system (n = 44), per patient charges per week were $4,665 in the precision treatment group and $5,000 in the control group ( P = .126). CONCLUSION: These findings suggest that precision cancer medicine may improve survival for patients with refractory cancer without increasing health care costs. Although the results of this study warrant further validation, this precision medicine approach may be a viable option for patients with advanced cancer.

Video capsule endoscopy compared with standard endoscopy for the evaluation of small-bowel polyps in persons with familial adenomatous polyposis (with video).

BACKGROUND: Video capsule endoscopy (VCE) may be useful for surveillance of small-bowel polyps in patients with familial adenomatous polyposis (FAP). OBJECTIVE: To compare VCE to standard endoscopy for diagnosing small-bowel polyps in a defined segment of small bowel (proximal to a tattoo) and the entire examined small bowel. DESIGN: Prospective. SETTING: Single tertiary referral center. PATIENTS: Participants with FAP (n = 32). The majority were selected for their high number of proximal small-bowel polyps and prior endoscopic tattoo placement in the proximal small bowel. INTERVENTIONS: VCE (interpreted by 2 readers), push enteroscopy (PE), and lower endoscopy (LE) to count and measure small-bowel polyps. RESULTS: In the defined segment, VCE detected a median of 10.0 (interquartile range [IQR], 5.0-19.0) and 9.0 (IQR, 6.0-16.0) polyps for each reader compared with a median of 41.0 (IQR, 19.0-64.0) polyps on PE (P = .002). Agreement between the 2 methods was fair (kappa = 0.34, 0.36). Agreement between VCE and PE was poor to fair (kappa = 0.10, 0.22) for estimating the size of the largest polyp and poor (kappa = -0.20, -0.27) for detecting large polyps (> or =1 cm). In the entire examined small bowel, VCE diagnosed a median of 38.0 (IQR, 10.5-71.5) and 54.0 (IQR, 13.0-100.0) polyps for each reader compared with a median of 123.0 (IQR, 38.5-183.0) for combination endoscopy (PE and LE) (P < .001). Agreement between the 2 methods was fair to moderate (kappa = 0.21, 0.56). LIMITATIONS: Participants selected for high polyp burden, and results may not be applicable to all patients with FAP. CONCLUSIONS: VCE underestimates the number of small-bowel polyps in persons with FAP and does not reliably detect large polyps.