Search

PURPOSE: As the largest integrated health care system in the United States, the Veterans Health Administration (VA) is a leader in telehealth-delivered care. All 10 million Veterans cared for within the VA are eligible for telehealth. The VA cares for approximately 46,000 Veteran patients with newly diagnosed cancer and an estimated 400,000 prevalent cases annually. With nearly 38% of VA health care system users residing in rural areas and only 44% of rural counties having an oncologist, many Veterans lack local access to specialized cancer services. METHODS: We describe the VA's National TeleOncology (NTO) Service. NTO was established to provide Veterans with the opportunity for specialized treatment regardless of geographical location. Designed as a hub-and-spoke model, VA oncologists from across the country can provide care to patients at spoke sites. Spoke sites are smaller and rural VA medical centers that are less able to independently provide the full range of services available at larger facilities. In addition to smaller rural spoke sites, NTO also provides subspecialized oncology care to Veterans located in larger VA medical facilities that do not have subspecialties available or that have limited capacity. RESULTS: As of fiscal year 2021, 23 clinics are served by or engaged in planning for delivery of NTO and there are 24 physicians providing care through the NTO virtual hub. Most NTO physicians continue to provide patient care in separate traditional in-person clinics. Approximately 4,300 unique Veterans have used NTO services. Approximately half (52%) of Veterans using NTO lived in rural areas. Most of these Veterans had more than one remote visit through NTO. CONCLUSION: NTO is a state-of-the-art model that has the potential to revolutionize the way cancer care is delivered, which should improve the experience of Veterans receiving cancer care.

ImportanceExtended-interval dosing of pembrolizumab (400 mg every 6 weeks) was approved by US Food and Drug Administration (FDA) in April 2020 as an alternative to standard-interval dosing (200 mg every 3 weeks). Extended-interval dosing may enhance access, alleviate patient and health system financial toxicity, and improve patient quality of life, particularly during the COVID-19 pandemic. Neither adoption nor effectiveness of extended interval in the US has been adequately described.ObjectiveTo describe adoption of extended-interval dosing of pembrolizumab since its FDA approval and to measure its preliminary real-world effectiveness compared with standard-interval dosing.Design, Setting, and ParticipantsThis was a retrospective cohort study that used data from the Veterans Health Administration (VHA), a US-based, nationwide single-payer health system. Participants were veterans who were prescribed single-agent pembrolizumab within the VHA between April 1, 2020, and July 1, 2021. Patients receiving combinations of pembrolizumab and cytotoxic chemotherapy or tyrosine kinase inhibitors were excluded. A subcohort of veterans with non−small cell lung cancer (NSCLC) was also identified using claims-based codes.ExposuresSingle-agent pembrolizumab at extended or standard intervals.Main Outcomes and MeasuresThe number and proportion of single-agent pembrolizumab prescriptions that were extended compared with standard interval. Effectiveness was described in terms of time-to-treatment discontinuation (TTD) and extended- to standard-interval pembrolizumab prescriptions were compared using Cox proportional hazards regression.ResultsA total of 835 veterans (mean age [SD], 70.9 [8.7] years; 809 [96.9%] men) began single-agent pembrolizumab during the study period (all-diseases cohort), and of these, 234 (mean [SD] age, 71.6 [7.3] years; 225 [96.2%] men) had NSCLC (NSCLC cohort). Extended-interval adoption reached its steady state plateau of approximately 35% by January 2021; 65% of participants who began standard-interval single-agent pembrolizumab received only standard-interval dosing during the treatment course. In analysis consistent with the intention-to-treat principle, no differences in TTD were observed between standard- and extended-interval dosing in either the all-diseases cohort (HR, 1.00; 95% CI, 1.00-1.00) or the NSCLC cohort (HR, 1.00; 95% CI, 1.00-1.00).Conclusions and RelevanceThis retrospective cohort study found that extended-interval dosing comprised a minority of single-agent pembrolizumab prescriptions despite the FDA approval and its potential health system and public health benefits. The findings support the TTD equivalence of standard- and extended-interval pembrolizumab across indications, complementing clinical pharmacology and single-arm clinical trial data in melanoma. This study provides further support for extended-interval pembrolizumab dosing.

Genetic tests have become widely available. We sought to understand the use of genetic tests in the practice of frontline clinicians within the United States Department of Veterans Affairs (VA).We administered a web-based survey to clinicians at 20 VA facilities. Physicians, nurse practitioners, physician assistants, and pharmacists were eligible. We excluded genetics providers and clinicians not seeing patients. We used multiple logistic regression to evaluate the associations between clinician characteristics and experience with genetics.The response rate was 11.3% (1207/10,680) and of these, 909 respondents were eligible. Only 20.8% of the respondents reported feeling prepared to use genetic tests and 13.0% of the respondents were currently ordering genetic tests; although, it was usually only 1 or 2 a year. Delivery of genetic tests without involving genetics providers was preferred by only 7.9% of the respondents. Characteristics positively associated with currently ordering genetic tests included practice in clinical and research settings, believing improving genetics knowledge could alter their practice, feeling prepared to use genetic tests, and referral of at least 1 patient to genetics in the past year.Most VA clinicians don't feel prepared to use genetic tests. Those with genetic testing experience are more likely to consult genetics providers. The demand for genetics providers should increase as frontline clinicians use genetic tests in their practice.

Patients with advanced head and neck squamous cell carcinoma (HNSCC) associated with human papillomavirus (HPV) demonstrate favorable clinical outcomes compared to patients bearing HPV-negative HNSCC. We sought to characterize the association between HPV status and mutational profiles among patients served by the Veterans Health Administration (VHA).We performed a retrospective analysis of all Veterans with primary HNSCC tumors who underwent next-generation sequencing (NGS) through the VHA's National Precision Oncology Program between July 2016 and February 2019. HPV status was determined by clinical pathology reports of p16 immunohistochemical staining; gene variant pathogenicity was classified using OncoKB, an online precision oncology knowledge database, and mutation frequencies were compared using Fisher's exact test.A total of 79 patients met inclusion criteria, of which 48 (60.8%) had p16-positive tumors. Patients with p16-negative HNSCC were more likely to have mutations in TP53 (p0.0001), and a trend towards increased mutation frequency was observed within NOTCH1 (p = 0.032) and within the composite CDK/Rb pathway (p = 0.065). Mutations in KRAS, NRAS, HRAS, and FBXW7 were exclusively identified within p16-positive tumors, and a trend towards increased frequency was observed within the PI3K pathway (p = 0.051). No difference in overall mutational burden was observed between the two groups.In accordance with the previous studies, no clear molecular basis for improved prognosis among patients harboring HPV-positive disease has been elucidated. Though no targeted therapies are approved based upon HPV-status, current efforts to trial PI3K inhibitors and mTOR inhibitors across patients with HPV-positive disease bear genomic rationale based upon the current findings.

One year of adjuvant durvalumab following concurrent chemoradiotherapy significantly improves progression-free survival (PFS) and overall survival (OS) for patients with stage III non-small cell lung cancer (NSCLC). However, the optimal length of adjuvant therapy has not been determined.We identified patients with stage III NSCLC treated with definitive chemoradiation and adjuvant durvalumab from November 2017 to April 2021 from the United States Veterans Affairs system. Predictors of early durvalumab discontinuation were evaluated with Cox proportional hazards regression. The effect of differing durations of durvalumab treatment (up to 6, 9, and 12 months) on PFS and OS were compared with a marginal structural model and time-dependent Cox modelling.We included 1006 patients with stage III non-small cell lung cancer who received concurrent chemoradiotherapy and at least one dose of adjuvant durvalumab. The median duration of durvalumab treatment was 7 months (interquartile range 2.8-11.5) and 31% completed the intended durvalumab course. The most common reasons for early discontinuation were tumour progression (22%), immune-related adverse events (15%), and non-immune-related toxicity (6.0%), Marginal structural models suggested similar PFS for 9 months versus 12 months of durvalumab treatment and inferior PFS for 6 months versus 12 months.A substantial proportion of patients undergoing adjuvant durvalumab discontinue therapy early due to toxicity, and shorter durvalumab treatment durations may provide similar disease control to 12 months of therapy. Prospective randomised controlled studies are needed to characterise the optimal durvalumab treatment duration in locally advanced NSCLC patients.

PURPOSE Telegenetics services can expand access to guideline-recommended cancer genetic testing. However, access is often not distributed equitably to all races and ethnicities. We evaluated the impact of an on-site nurse-led cancer genetics service in a diverse Veterans Affairs Medical Center (VAMC) oncology clinic on likelihood of germline testing (GT) completion. METHODS We conducted an observational retrospective cohort study of patients who were referred for cancer genetics services at the Philadelphia VAMC between October 1, 2020, and February 28, 2022. We evaluated the association between genetics service (on-site v telegenetics) and likelihood of GT completion in a subcohort of new consults, excluding patients with prior consults and those referred for known history of germline mutations. RESULTS A total of 238 Veterans, including 108 (45%) seen on site, were identified for cancer genetics services during the study period, with the majority referred for a personal (65%) or family (26%) history of cancer. In the subcohort of new consults, 121 Veterans (54% self-identified race/ethnicity [SIRE]-Black), including 60 (50%) seen on site, were included in the analysis of germline genetic testing completion. In a univariate analysis, patients who were seen by the on-site genetics service had 3.2-fold higher likelihood of completing GT (relative risk, 3.22; 95% CI, 1.89 to 5.48) compared with the telegenetics service. In multivariable regression analysis, the on-site genetics service was associated with higher likelihood of GT completion, but this association was only statistically significant in SIRE-Black compared with SIRE-White Veterans (adjusted RR, 4.78; 95% CI, 1.53 to 14.96; P < .001; P-interaction of race × genetics service = .016). CONCLUSION An on-site nurse-led cancer genetics service embedded in a VAMC Oncology practice was associated with higher likelihood of germline genetic testing completion than a telegenetics service among self-identified Black Veterans.

Detection of surface contamination on niobium materials used in superconducting radio frequency (SRF) applications is difficult due to quantitative sensitivity and near-atomic depth resolution needed. Inspection of samples known to have experienced surface contamination was found to have inconsistent nitride coverage after high-temperature nitrogen gas exposure (“doping”). We compare contaminating species found on samples treated in several different vacuum furnaces, both “exposed” directly in the chamber and “protected” by containment shielding from evaporative sources with “furnace caps.” Typically, furnace caps are used to impede contamination from reaching the interior surface of cavities during the high-temperature vacuum bake that immediately precedes exposure to nitrogen gas. Although, to date, little is known about the effectiveness of these caps, SIMS results showed that they were effective in limiting contamination arising from the furnace environment. Inspection of sample surfaces by SEM showed a lack of nitrides present on contaminated specimens. TEM with energy dispersive spectroscopy performed on these samples revealed that a carbon-rich layer now existed, indicating that a relatively high contaminant load prevents the nucleation and growth of surface nitrides, while thus inhibiting interstitial nitrogen uptake. Except in extreme cases, subsequent removal of the top several micrometers of the surface via electropolishing appears to effectively eliminate any strong influence on the subsequent SRF cavity performance. With the absence of furnace cleaning, carbon contamination was found to be nearly 10× higher for protected nitrogen-doped and electropolished samples, with minimal metallic contamination detected for both processes. SIMS analysis was also performed to compare the cleanliness of samples fully prepared by such nitrogen “doping” with those prepared by a related process, involving the dissolution of niobium surface oxide and diffusion of oxygen into the surface. This oxygen doping or alloying process offers attractive advantages.

Black Veterans have higher a incidence of localized and metastatic prostate cancer compared to White Veterans yet are underrepresented in reports of frequencies of somatic and germline alterations. This retrospective analysis of somatic and putative germline alterations was conducted in a large cohort of Veterans with prostate cancer (N = 835 Black, 1613 White) who underwent next generation sequencing through the VA Precision Oncology Program, which facilitates molecular testing for Veterans with metastatic cancer. No differences were observed in gene alterations for FDA approved targetable therapies (13.5% in Black Veterans vs. 15.5% in White Veterans, P = .21), nor in any potentially actionable alterations (25.5% vs. 28.7%, P =.1). Black Veterans had higher rates of BRAF (5.5% vs. 2.6%, P < .001) alterations, White Veterans TMPRSS2 fusions (27.2% vs. 11.7%, P < .0001). Putative germline alteration rates were higher in White Veterans (12.0% vs. 6.1%, P < .0001). Racial disparities in outcome are unlikely attributable to acquired somatic alterations in actionable pathways.

1000 SNPs with greatest statistical association with cumulative docetaxel dose at grade 3+ neuropathy in CALGB 90401 discovery GWAS.

Peripheral neuronal cells (Peri.4U) treated with docetaxel were found to have a significant decrease in sensitivity for A) mean process lengths but not for B) mean outgrowth intensity or C) relative straightness as measured after 24 hours post-drug treatment. For paclitaxel treatment at the same time point, the cells were also found to have significantly decreased sensitivity for D) relative mean process length and E) mean outgrowth intensity but not for F) relative straightness. Neurite parameters measured with MetaXPress® software were averaged from 3 independent experiments. Error bars represent the standard error of the mean from three independent transfection experiments. NTC = non-targeting control, UT= untransfected control.

Number of patients who experienced neuropathy, completed treatment without neuropathy and discontinued treatment early without having neuropathy while on study and within each range of cumulative treatment.

Sensitivity to mechanical stimuli with Von Frey filaments for C57BL/6J mice and litter-mates heterozygous for VAC14 prior to docetaxel treatment. The figure displays the estimate of the proportion of mice without a hind-paw withdrawal response to stimulation by each Von Frey fiber weight, e.g., no mice respond to fibers {less than or equal to}0.2 g and all mice respond to fibers{greater than or equal to}1.4 g. The VAC14 heterozygous mice (hatched line) are more likely than wild-type mice (solid line) to respond, meaning they are more sensitive to nociceptive stimuli (p=0.0012). Gray lines denote 95% confidence intervals.

CONSORT diagram illustrating patient flow from enrollment on parent study to population included in pharmacogenetic discovery analysis and quality control filtering of SNPs from the Illumina HumanHap610-Quad into the pharmacogenetic analysis.

Most Highly Enriched Canonical Pathways

Supplementary Figure 1. Unadjusted Kaplan-Meier curve for overall survival among all CRC patients by diabetes and diabetic treatment status (n=21292). Supplementary Table S1. Diabetes treatment and overall survival among patients with diabetes, stratified by BMI. Supplementary Table S2. Diabetes treatment and overall survival among patients with diabetes, stratified by primary site

Background: Metformin has been associated with improved colorectal cancer survival, but investigations are limited by small numbers of patients and confounding by diabetic severity. We examined the association between metformin use and overall survival (OS) in patients with diabetes and colorectal cancer in a large population of U.S. veterans, while adjusting for measures of diabetic severity.Methods: Patients diagnosed with colorectal cancer from January 2001 to December 2008 were identified from the Veterans Affairs Central Cancer Registry. Multivariable models were used to examine the adjusted association of OS with diabetes and use of antidiabetic medications.Results: There were 21,352 patients diagnosed with colorectal cancer identified (n = 16,355 nondiabetic patients, n = 2,038 diabetic patients on metformin, n = 2,136 diabetic patients on medications other than metformin, n = 823 diabetic patients not on antidiabetic medication). Diabetic patients had a significantly worse OS than nondiabetic patients, but metformin users had only a 10% increase in death (HRadj 1.10; 95% CI, 1.03–1.17, P = 0.004), as compared with 22% for users of other antidiabetic medications (HRadj 1.22; 95% CI, 1.15–1.29, P < 0.0001). Among colorectal cancer patients with diabetes, metformin users had a 13% improved OS versus patients taking other antidiabetic medications (HRadj 0.87; 95% CI, 0.79–0.95, P = 0.003), while diabetic patients not on any antidiabetic medications did not differ with respect to OS (HRadj 1.02; 95% CI, 0.90–1.15, P = 0.76).Conclusions: Among diabetics with colorectal cancer, metformin use is associated with improved survival, despite adjustments for diabetes severity and other risk factors.Impact: These data lend further support to the conduct of randomized studies of possible anticancer effects of metformin among patients with colorectal cancer. Cancer Epidemiol Biomarkers Prev; 25(10); 1418–25. ©2016 AACR.

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy.Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy.Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001).Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.

PURPOSE Increasing utilization of comprehensive genomic profiling (CGP) and a growing number of targeted agents (TAs) have led to substantial improvements in outcomes among patients with cancer with actionable mutations. We sought to evaluate real-world experience with off-label TAs among Veterans who underwent CGP. METHODS The National Precision Oncology Program database and VA Corporate Data Warehouse were queried to identify patients who underwent CGP between February 2019 and December 2021 and were prescribed 1 of 73 TAs for malignancy. OncoKB annotations were used to select patients who received off-label TAs based upon CGP results. Chart abstraction was performed to review response, toxicities, and time to progression. RESULTS Of 18,686 patients who underwent CGP, 2,107 (11%) were prescribed a TA and 169 (0.9%) were prescribed a total of 183 regimens containing off-label TAs for variants in 31 genes. Median age was 68 years and 83% had prior systemic therapy, with 28% receiving three or more lines. Frequency of off-label TA prescriptions was highest for patients undergoing CGP for thyroid (8.6%) and breast (7.6%) cancers. Most patients harbored alterations in BRCA1/BRCA2/ATM (22.5%), ERBB2 (19.5%), and BRAF (19.5%). Among the 160 regimens prescribed > 4 weeks, 43 (27%) led to response. Median progression-free survival and overall survival were 5.3 (4.2-6.5) and 9.7 (7.5-11.9) months, respectively. Patients with OncoKB level 2/3A/3B annotations had longer median progression-free survival (5.8 [4.5-7] months v 3.7 [1.6-7.7] months; hazard ratio, 0.45; 95% CI, 0.24 to 0.82; P = .01) compared with those receiving level 4 treatments. CONCLUSION Although administration of off-label TAs is infrequent after CGP, more than one quarter of treatment regimens led to response. TAs associated with level 4 annotations lead to worse outcomes than TAs bearing higher levels of evidence.

Aim: The first Plan-Do-Study-Act cycle for the Veterans Affairs Pharmacogenomic Testing for Veterans pharmacogenomic clinical testing program is described. Materials & methods: Surveys evaluating implementation resources and processes were distributed to implementation teams, providers, laboratory and health informatics staff. Survey responses were mapped to the Consolidated Framework for Implementation Research constructs to identify implementation barriers. The Expert Recommendation for Implementing Change strategies were used to address implementation barriers. Results: Survey response rate was 23–73% across personnel groups at six Veterans Affairs sites. Nine Consolidated Framework for Implementation Research constructs were most salient implementation barriers. Program revisions addressed these barriers using the Expert Recommendation for Implementing Change strategies related to three domains. Conclusion: Beyond providing free pharmacogenomic testing, additional implementation barriers need to be addressed for improved program uptake.

PURPOSEAdvances in precision oncology, including RAS testing to predict response to epidermal growth factor receptor monoclonal antibodies (EGFR mAbs) in colorectal cancer (CRC), can extend patients’ lives. We evaluated uptake and clinical use of KRAS molecular testing, guideline recommended since 2010, in the Veterans Affairs Healthcare System (VA).MATERIALS AND METHODSWe conducted a retrospective cohort study of patients with stage IV CRC diagnosed in the VA 2006-2015. We gathered clinical, demographic, molecular, and treatment data from the VA Corporate Data Warehouse and 29 commercial laboratories. We performed multivariable analyses of associations between patient characteristics, KRAS testing, and EGFR mAb treatment.RESULTSAmong 5,943 patients diagnosed with stage IV CRC, only 1,053 (17.7%) had KRAS testing. Testing rates increased from 2.3% in 2006 to 28.4% in 2013. In multivariable regression, older patients (odds ratio, 0.17; 95% CI, 0.09 to 0.32 for ≥ age 85 v < 45 years) and those treated in the Northeast and South regions were less likely, and those treated at high-volume CRC centers were more likely to have KRAS testing (odds ratio, 2.32; 95% CI, 1.48 to 3.63). Rates of potentially guideline discordant care were high: 64.3% (321/499) of KRAS wild-type (WT) went untreated with EGFR mAb and 8.8% (401/4,570) with no KRAS testing received EGFR mAb. Among KRAS-WT patients, survival was better for patients who received EGFR mAb treatment (29.6 v 18.8 months; P < .001).CONCLUSIONWe found underuse of KRAS testing in advanced CRC, especially among older patients and those treated at lower-volume CRC centers. We found high rates of potentially guideline discordant underuse of EGFR mAb in patients with KRAS-WT tumors. Efforts to understand barriers to precision oncology are needed to maximize patient benefit.

BackgroundThe Veterans Health Administration (VHA) is the largest integrated health care system in the United States (US). Among VHA patients, the rate of use of concurrent chemoradiation therapy (CCRT) among those with unresectable, stage III non-small cell lung cancer (NSCLC) is unknown. The objective was to report recent CCRT treatment patterns in VHA patients and identify characteristics associated with receipt of CCRT.MethodsUsing Department of Veteran Affairs (VA) Cancer Registry System data linked to VA electronic medical records, we determined rates of CCRT, sequential CRT (SCRT), radiation therapy (RT) only, chemotherapy (CT) only, and neither treatment.ResultsAmong 4054 VHA patients who met study criteria, CCRT rates slightly increased from 44 to 50% between 2013 and 2017. Factors associated with decreased odds of CCRT receipt compared to any other treatment included increasing age (adjusted odds ratio [aOR] per 10 years = 0.67; 95% CI: 0.60–0.76) and Charlson-Deyo comorbidity score (aOR = 0.94; 95% CI: 0.91–0.97). White race was associated with increased odds of CCRT receipt (aOR = 1.24; 95% CI: 1.004–1.53). In a chart review sample of 200 patients, less than half (n = 85) had a documented reason for not receiving CCRT. Among these, 29% declined treatment, and 71% did not receive CCRT due to “not being a candidate” for reasons related to frailty or lung nodules being too far apart for radiation therapy.ConclusionsCCRT rates among VHA patients with unresectable, stage III NSCLC slightly increased from 2013 to 2017; however in 2017, only half were receiving CCRT. Older patients and those with multiple comorbidities were less likely to receive CCRT and even when controlling for these factors, non-white patients were less likely to receive CCRT.

PURPOSE: Next-generation sequencing (NGS) gene panels are frequently completed for patients with advanced non–small-cell lung cancer (NSCLC). Patients with highly actionable gene variants have improved outcomes and reduced toxicities with the use of corresponding targeted agents. We sought to identify barriers to targeted agent use within the Veterans Health Affairs' National Precision Oncology Program (NPOP). METHODS: A retrospective evaluation of patients with NSCLC who underwent NGS multigene panels through NPOP between July 2015 and February 2019 was conducted. Patients who were assigned level 1 or 2A evidence for oncogenic gene variants by an artificial intelligence offering (IBM Watson for Genomics [WfG]) and NPOP staff were selected. Antineoplastic drug prescriptions and provider notes were reviewed. Reasons for withholding targeted treatments were categorized. RESULTS: Of 1,749 patients with NSCLC who successfully underwent NGS gene panel testing, 112 (6.4%) patients were assigned level 1 and/or 2A evidence for available targeted treatments by WfG and NPOP staff. All highly actionable gene variants were within ALK, BRAF, EGFR, ERBB2, MET, RET, and ROS1. Of these, 36 (32.1%) patients were not prescribed targeted agents. The three most common reasons were (1) patient did not carry a diagnosis of metastatic disease (33.3%), (2) treating provider did not comment on the NGS results (25.0%), and (3) provider felt that patient could not tolerate therapy (19.4%). No patients were denied access to level 1 or 2A targeted drugs because of rejection of a nonformulary drug request. CONCLUSION: A substantial minority of patients with NSCLC bearing highly actionable gene variants are not prescribed targeted agents. Further provider- and pathologist-directed educational efforts and implementation of health informatics systems to provide real-time decision support for test ordering and interpretation are needed.

In 2019, the Veterans Affairs (VA), the largest integrated US healthcare system, started the Pharmacogenomic Testing for Veterans (PHASER) clinical program that provides multi-gene pharmacogenomic (PGx) testing for up to 250,000 veterans at approximately 50 sites. PHASER is staggering program initiation at sites over a 5-year period from 2019 to 2023, as opposed to simultaneous initiation at all sites, to facilitate iterative program quality improvements through Plan-Do-Study-Act cycles. Current resources in the PGx field have not focused on multisite, remote implementation of panel-based PGx testing. In addition to bringing large scale PGx testing to veterans, the PHASER program is developing a roadmap to maximize uptake and optimize the use of PGx to improve drug response outcomes.

PURPOSE There are growing efforts to integrate patient-reported outcome (PRO) data into electronic health records (EHRs) to bring together disparate sources of patient information and improve medical care. PRO measures can be used to assess cancer symptom presence and severity. Integrating PRO tools in EHRs can alert providers to address symptoms, which is an essential component of comprehensive oncology care. METHODS We modified a PRO used to measure cancer and end-of-life symptoms, the Edmonton Symptom Assessment System to create the Veteran Symptom Assessment System (VSAS). VSAS was implemented as an integrated PRO as part of the Veterans Administration EHR system and was used at hematology-oncology clinics in Veteran Administration (VA) medical centers in the Southeast. RESULTS From 2013 to 2014, VSAS was introduced, underwent usability testing and modifications, and was finally implemented in the EHR. Between 2015 and 2019, VSAS was administered 43,883 times in 9,058 patients. Eighty-nine percent of Veterans were male, 11% were female, 52% identified as non-Hispanic White, and 43% identified as African American. Fatigue, shortness of breath with exertion, and pain were most frequently reported initially (68%, 48%, and 45%, respectively) and were most frequently rated as severe (27%, 16%, and 17%, respectively). In patients diagnosed with stage IV cancer, higher symptom burden was significantly associated with shorter overall survival. The majority of Veterans with longitudinal measurements experienced improvement in symptoms, most frequently in severe symptoms. CONCLUSION To our knowledge, this is the first large-scale implementation of a PRO system, integrated in the VA EHR, in ambulatory patients with cancer and blood disorders. The integration of VSAS within the VA EHR is a significant demonstration and a necessary requirement for current and future systemic initiatives in cancer symptom management.

PURPOSE Poly ADP-ribose polymerase inhibitors (PARPi) are used for patients with advanced prostate cancer bearing alterations in homologous recombination repair (HRR) genes. We sought to characterize HRR gene variants and describe real-world outcomes for patients on PARPi. METHODS The US Department of Veterans Affairs’ National Precision Oncology Program’s database was reviewed to identify patients who underwent somatic DNA sequencing and were prescribed a PARPi before May 15, 2020. Somatic and germline variants within HRR genes were reported, and pathogenicity was reviewed via OncoKB. In patients treated with PARPi for > 4 weeks, the rate of those achieving a 30% decrease in prostate-specific antigen (PSA30) and composite progression-free survival (PFS) were compared between patients bearing pathogenic variants of BRCA2 and patients without these variants using Mann-Whitney and log-rank tests, respectively. RESULTS Forty-eight patients bearing 67 total HRR gene variants were prescribed PARPi for prostate cancer. Twenty-one patients (43.8%) were found to have at least one pathogenic HRR gene variant. Eight (16.6%) were referred to genetic counseling, and five (10.4%) were ultimately confirmed with germline variants. The median PFS was 4.0 months, and PSA30 was 25.6% (11 of 43) for all 43 evaluable patients. Patients with pathogenic BRCA2 variants (n = 13) had higher PSA30 (69.2% v 4.0%; P < .001) and longer PFS (7.2 v 2.8 months; P = .0291) than those without. CONCLUSION In a real-world setting, heavily pretreated patients with prostate cancer and pathogenic BRCA2 variants have a significant PSA response rate and a PFS > 7 months with PARPi. This work emphasizes the importance of determining pathogenicity and origin of HRR alterations to better inform clinical treatment decisions and highlights the need for provider education and other decision support tools.

The Veterans Health Administration (VHA) is a leader in generating transformational research across the cancer care continuum. Given the extensive body of cancer-related literature utilizing VHA data, our objectives are to: (1) describe the VHA data sources available for conducting cancer-related research, and (2) discuss examples of published cancer research using each data source.We identified commonly used data sources within the VHA and reviewed previously published cancer-related research that utilized these data sources. In addition, we reviewed VHA clinical and health services research web pages and consulted with a multidisciplinary group of cancer researchers that included hematologist/oncologists, health services researchers, and epidemiologists.Commonly used VHA cancer data sources include the Veterans Affairs (VA) Cancer Registry System, the VA Central Cancer Registry (VACCR), the Corporate Data Warehouse (CDW)-Oncology Raw Domain (subset of data within the CDW), and the VA Cancer Care Cube (Cube). While no reference standard exists for cancer case ascertainment, the VACCR provides a systematic approach to ensure the complete capture of clinical history, cancer diagnosis, and treatment. Like many population-based cancer registries, a significant time lag exists due to constrained resources, which may make it best suited for historical epidemiologic studies. The CDW-Oncology Raw Domain and the Cube contain national information on incident cancers which may be useful for case ascertainment and prospective recruitment; however, additional resources may be needed for data cleaning.The VHA has a wealth of data sources available for cancer-related research. It is imperative that researchers recognize the advantages and disadvantages of each data source to ensure their research questions are addressed appropriately.

PURPOSE: Increased access and utilization of tumor profiling of cancers in our veteran population uncovered a modest number of potentially pathogenic germline variants (PPGVs) that require genetics referral for follow-up evaluation and germline sequencing. Challenges identified specific to the veteran population include paucity of genetics providers, either at a veteran's VA facility or nearby non-VA facilities. We sought to investigate the number of veterans who would benefit from having such resources at both local and national levels. METHODS: Annotated clinical reports of mutations identified by tumor-only profiling and medical records of veterans with solid tumors at the Veterans Administration Ann Arbor Healthcare System (VA AAHS) between 2015 and 2020 were reviewed. PPGVs were identified according to society recommendations (such as ESMO and American Board of Medical Genetics and Genomics), expert review, and/or previously published criteria. After the analysis of our local VA population, these same criteria were then applied to veterans in the National Precision Oncology Program (NPOP). RESULTS: Two hundred eight veterans underwent tumor profiling at the VA AAHS over the defined time period. This included 20 different primary tumor sites with over half (n = 130) being advanced cancer at diagnosis. Of these, 18 veterans (8.5%) had mutations suggestive of a PPGV. Applying these criteria to the larger NPOP database (n = 20,014), a similar percentage (6%) of PPGVs were identified. CONCLUSION: These results indicate a PPGV frequency (6%-9% of veterans) consistent with the prevalence of inherited cancer predisposition syndromes in the general population, underscoring the need for medical genetics as part of standard oncologic care for veterans. We explore current and future care delivery models to optimize incorporation of medical genetics and genetic counseling to best serve veterans needing such services.

PURPOSE Next-generation sequencing (NGS) multigene panel testing has become widespread, including the Veterans Affairs (VA), through the VA National Precision Oncology Program (NPOP). The interpretation of genomic alterations remains a bottleneck for realizing precision medicine. We sought to examine the concordance for pathogenicity determination and clinical actionability of annotation services in NPOP. METHODS Unique gene variants were generated from NGS gene panel results using two sequencing services. For each unique gene variant, annotations were provided through N-of-One (NoO), IBM Watson for Genomics (WfG), and OncoKB. Annotations for pathogenicity (all three sources) and actionability (WfG and OncoKB) were examined for concordance. Cohen’s kappa statistic was calculated to measure agreement between annotation services. RESULTS Among 1,227 NGS results obtained between 2015 and 2017, 1,388 unique variants were identified in 117 genes. The genes with the largest number of variants included TP53 (270), STK11 (92), and CDKN2A (81). The most common cancer type was lung adenocarcinoma (440), followed by colon adenocarcinoma (113). For pathogenic and likely pathogenic variants, there was 30% agreement between WfG and NoO (kappa, −0.26), 76% agreement between WfG and OncoKB (kappa, 0.22), and 42% agreement between NoO and OncoKB (kappa, −0.07). For level 1 drug actionability of gene variant–diagnosis combinations, there was moderate agreement between WfG and OncoKB (96.9%; kappa, 0.44), with 27 combinations identified as level 1 by both services, 58 by WfG alone, and 6 variants by OncoKB alone. CONCLUSION There is substantial variability in pathogenicity assessment of NGS variants in solid tumors by annotation services. In addition, there was only moderate agreement in level 1 therapeutic actionability recommendations between WfG and OncoKB. Improvement in the precision of NGS multigene panel annotation is needed.

Polyimides (PIs) have a wide range of industrial and scientific applications due to their excellent thermal and mechanical stability and chemical resistance. Their response to ultraviolet (UV) irradiation is of further interest in high-value applications such as spacecraft technology and electronics packaging. In this work, we investigated the effect of 172-nm UV xenon excimer lamp irradiation on samples of pyromellitimido-oxydianiline (PMDA-ODA) commercial films in the absence of oxygen. The average irradiance received at the sample position was 90 mW/cm2, and the total radiation dosage varied from 0 to 64 J/cm2. X-Ray photoelectron spectroscopy, time-of-flight-secondary ion mass spectrometry, atomic force microscopy, and contact angle measurements were used to characterize the effect. Calculated UV-visible spectroscopy absorption spectra were obtained using the ZINDO//B3LYP/3-21G method to give an indication of which orbitals are involved in the transitions near 172 nm. The reactivity of the different UV-treated PI samples toward nitrogen-borne heptafluorodecene vapor was then investigated using the above techniques. Grafting reactions occurred on the surface of the photochemically activated polymer. This study explored the potential for modification of PI surfaces using UV-light-assisted grafting to impart valuable functionalities.

Background: Adjuvant chemotherapy (AC) after chemoradiation (CRT) and surgery for locoregionally advanced rectal cancer (LARC) is a standard of care in the United States. This study examined the role, optimal regimen, and duration of AC using data from the largest integrated health system in the United States. Patients and Methods: Using the Veterans Affairs Central Cancer Registry, patients with stage II–III rectal cancer diagnosed in 2001 through 2011 who received neoadjuvant CRT and surgery with or without AC were identified. Kaplan-Meier analysis, log-rank tests, and propensity score (PS) adjustment analysis were used to assess survival. Results: A total of 866 patients were identified; 417 received AC and 449 did not (observation [OBS] group). Median follow-up was 109 months. Median disease-specific survival (DSS) was not reached. Six-year DSS was 73.7%; 79.5% for the AC group versus 68.0% for the OBS group. PS-matched analysis for DSS favored AC (P=.0002). Median overall survival (OS) was 90.8 months. Six-year OS was 56.7%; 64.3% for AC versus 49.6% for OBS. In PS-matched analysis, median OS was 117.4 months for AC and 74.3 months for OBS (PP=.023). No difference in DSS or OS was seen with single-agent versus multiagent AC. Conclusions: In this population of patients with LARC treated with neoadjuvant CRT and surgery, OS and DSS were improved among those treated with AC versus OBS. DSS benefits were seen with ≥4 months of AC. No additional benefit was observed with multiagent therapy. In the absence of phase III data, these findings support the use of AC for LARC.

Lung cancer is the leading cause of cancer mortality in men and women. Genomic sequencing of non-small cell lung cancer (NSCLC) is critical for the optimal treatment of NSCLC. In this study we sought to describe the frequencies of highly actionable driver mutations in lung adenocarcinoma (LUAD), squamous cell (LUSQ) and other NSCLC histologies (LUOT) in Veterans tested through the VA's National Precision Oncology Program (NPOP) and compare these frequencies to other published datasets from highly specialized academic cancer centers. The NPOP cohort included 3,376 unique Veterans with a diagnosis of lung carcinoma tested between February 2019 and January 2021 including 1892 with LUAD, 940 with LUSQ, and 549 with LUOT. Among patients with LUAD, 27.5% had highly actionable genetic variants. The frequency of targetable mutations was as follows: ALK rearrangement 0.8%, BRAF V600E 2.1%, EGFR exon 20 insertion mutation 0.48%, EGFR sensitizing mutations 6.6%, ERBB2 small variants 1.2%, KRAS G12C 14.0%, MET exon 14 skipping mutation 1.5%, NTRK rearrangement 0.1%, RET rearrangement 0.4%, and ROS1 rearrangement 0.3%. The frequency of EGFR mutations, RET rearrangement, MET exon 14 and ERBB2 small variants frequencies were significantly lower in NPOP compared to other published reports while MET amplification was more common in NPOP. Combined rates of highly actionable genetic variants were 2.7% and 13.4% in LUSQ and LUOT, respectively. In this study, 27.5% of Veterans with lung adenocarcinoma have actionable genetic alterations eligible for FDA approved targeted therapies, a frequency only slightly lower than other published datasets despite higher smoking rates in Veterans. Genomic sequencing should be performed in all Veterans with advanced LUAD and LUOT.