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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.

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.

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.

Recent developments in precision oncology have increased the complexity of diagnostic and therapeutic decisions. Here, we broadly review the field of precision oncology and discuss common mutational drivers in non-small cell lung cancer (NSCLC) that directly relate to the diagnosis, evaluation, and treatment of patients with metastatic disease.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality in India. To clarify rates of actionable mutations, and thereby identify opportunities to improve the delivery of best available care for a large volume of patients, a comprehensive review of available data is warranted.Studies that reported prevalence of any actionable gene variant among adult Indian patients with advanced NSCLC were selected from three databases (PubMed, EMBASE, and Cochrane Library). Ranges in actionable variant prevalence were reported. Meta-analysis of proportions was completed among studies specifically evaluating mutational prevalence within ALK or EGFR. Sensitivity analyses were undertaken among populations sharing high heterogeneity.Twenty-six studies were selected. Ranges in actionable mutational prevalence among NSCLC patients were as follows: ALK: 4.1-21.4%, BRAF: 1.5-3.5%, EGFR: 11.9-51.8%, HER2: 0-1.5%, KRAS: 4.5-6.4%, NTRK: 0-.7%, and ROS-1: 3.5-4.1%. Following sensitivity analysis, pooled ALK mutational prevalence rates were 8.3% (95% CIs: 6.6-10.4%) and 4.01% (95% CIs: 2.3-7.0) for adenocarcinoma and NSCLC patients, respectively. Pooled EGFR mutational prevalence rates were 28.7% (95% CIs: 23.5-34.6%) and 24.2% (95% CIs: 19.9-29.1%) for adenocarcinoma and NSCLC patients, respectively.Nearly 40% of Indian patients with advanced adenocarcinoma and 30% with NSCLC share an actionable mutation in ALK or EGFR. Approximately one-half of adenocarcinoma patients have an actionable variant. Efforts should be directed toward efficiently identifying candidates for targeted agents and delivering such treatments.

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 majority of lung cancers are diagnosed at an advanced stage; the reasons for which are variable and unclear.Lung cancer patients were evaluated prospectively to quantify various timelines and establish reasons for delays. Timelines were defined as time intervals between symptom onset, first physician visit, first specialist visit, date of diagnosis and treatment.A total 410 patients were included, majority having advanced disease. The median period for a first visit to a physician was 30 days (interquartile range [IQR] 20-90), 50 days (IQR 20-110) for referral to our centre, 23 days (IQR 14-33) to reach diagnosis, and 24 days (IQR 14.5-34) to initiate treatment. Administration ofanti-tuberculosis treatment further delayed referral to specialist centre. Treatment delays were related to performance status, disease stage and treatment type. On multivariate analysis, education and histology affected diagnosis delay and treatment delay. Treatment delay was less in those who received targeted therapy compared to chemotherapy. Various time delays did not affect the overall survival.Poor education status and inappropriate anti-tubercular treatment were primary factors associated with longer diagnostic delays. Creating disease awareness and high clinical suspicion are essential to overcome these lacunae in lung cancer care.

Introduction: Over the past few years, the demographic profile of lung cancer has changed. However, most reports are limited by small numbers, short follow-up period, and show an inconsistent pattern. A comprehensive evaluation of changing trends over a long period has not been done. Materials and Methods: Consecutive lung cancer patients were studied over a 10-year period from January 2008 to March 2018 at the All India Institute of Medical Sciences, New Delhi, and relevant clinical information, and survival outcomes were analyzed. Results: A total of 1862 patients were evaluated, with mean (SD) age of 59 (11.1) years, and comprising 82.9% males. Majority were smokers (76.2%) with median smoking index of 500 (interquartile range [IQR]: 300–800). Adenocarcinoma (ADC) was the most common type (34%), followed by squamous cell carcinoma (SCC – 28.6%) and small cell lung cancer (SCLC) (16.1%). Over the 10-year period, ADC increased from 9.5% to 35.9%, SCC from 25.4% to 30.6%, and non-small cell lung cancer -not otherwise specified (NSCLC-NOS) decreased from 49.2% to 21.4%. The proportion of females with lung cancer increased although smoking rates remained similar. Majority of NSCLC (95%) continued to be diagnosed at an advanced stage (3 or 4). Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements were present in 25.3% and 11.5% ADC patients, respectively. The median overall survival was 8.8 months (IQR 3.7–19) for all patients and 12.57 (IQR 6.2–28.7) months among the 1013 patients who were initiated on specific treatment (chemotherapy, targeted therapy, radiotherapy, or surgery). Never-smokers were younger, more likely to be female and educated, had a higher prevalence of ADC and EGFR/ALK mutations, and had better survival. Conclusion: Among this large cohort, our center seems to follow the global trend with increasing incidence of ADC. EGFR mutation positivity was similar to existing reports, while higher ALK positivity was detected. A characteristic phenotype of never-smokers with lung cancer was elucidated which demonstrated better survival.

PURPOSE The Veterans Health Administration (VHA) is the largest cancer care provider in the United States, with the added challenge of serving more than twice the percentage of patients with cancer in rural areas than the national average. The VHA established the National Precision Oncology Program in 2016 to implement and standardize the practice of precision oncology across the diverse VHA system. METHODS Tumor or peripheral blood specimens from veterans with advanced solid tumors who were eligible for treatment were submitted for next-generation sequencing (NGS) at two commercial laboratories. Annotated results were generated by the laboratories and independently using IBM Watson for Genomics. Levels-of-evidence treatment recommendations were based on OncoKB criteria. RESULTS From July 2016 to June 2018, 3,698 samples from 72 VHA facilities were submitted for NGS testing, of which 3,182 samples (86%) were successfully sequenced. Most samples came from men with lung, prostate, and colorectal cancers. Thirty-four percent of samples were from patients who lived in a rural area. TP53, ATM, and KRAS were among the most commonly mutated genes. Approximately 70% of samples had at least one actionable mutation, with clinical trials identified as the recommended option in more than 50%. Mutations in genes associated with a neuroendocrine prostate cancer phenotype were expressed at increased frequency among veterans than in the general population. The most frequent therapies prescribed in response to NGS testing were immune checkpoint inhibitors, EGFR kinase inhibitors, and PARP inhibitors. CONCLUSION Clinical implementation of precision oncology is feasible across the VHA health care system, including rural sites. Veterans have unique occupational exposures that might inform the nature of the mutational signatures identified here. Importantly, these results underscore the importance of increasing clinical trial availability to veterans.

Objectives A cost-effectiveness analysis comparing comprehensive genomic profiling (CGP) of 10 oncogenes, targeted gene panel testing (TGPT) of 4 oncogenes, and no tumor profiling over the lifetime for patients with metastatic lung adenocarcinoma from the Centers for Medicare and Medicaid Services’ perspective was conducted. Methods A decision analytic model used 10 000 hypothetical Medicare beneficiaries with metastatic lung adenocarcinoma to simulate outcomes associated with CGP (ALK, BRAF, EGFR, ERBB2, MET, NTRK1, NTRK2, NTRK3, RET, ROS1), TGPT (ALK, BRAF, EGFR, ROS1), and no tumor profiling (no genes tested). First-line targeted cancer-directed therapies were assigned if actionable gene variants were detected; otherwise, nontargeted cancer-directed therapies were assigned. Model inputs were derived from randomized trials (progression-free survival, adverse events), the Veterans Health Administration and Medicare (drug costs), published studies (nondrug cancer-related management costs, health state utilities), and published databases (actionable variant prevalences). Costs (2019 US$) and quality-adjusted life-years (QALYs) were discounted at 3% per year. Probabilistic sensitivity analyses used 1000 Monte Carlo simulations. Results No tumor profiling was the least costly/person ($122 613 vs $184 063 for TGPT and $188 425 for CGP) and yielded the least QALYs/person (0.53 vs 0.73 for TGPT and 0.74 for CGP). The costs per QALY gained and corresponding 95% confidence interval were $310 735 ($278 323-$347 952) for TGPT vs no tumor profiling and $445 545 ($322 297-$572 084) for CGP vs TGPT. All probabilistic sensitivity analysis simulations for both comparisons surpassed the willingness-to-pay threshold ($150 000 per QALY gained). Conclusion Compared with no tumor profiling in patients with metastatic lung adenocarcinoma, tumor profiling (TGPT, CGP) improves quality-adjusted survival but is not cost-effective.

Objectives: Quality of life (QOL) among caregivers of cancer patients is often diminished. For lower-income caregivers, the deterioration in QOL may be of greater impact. We aimed to evaluate QOL among lower-income cancer caregivers in Delhi, India and to comprehensively review similar investigations conducted internationally.Methods: A Hindi-version of the Caregiver Quality of Life Cancer (CQOLC) index was administered to 89 caregivers of lung cancer patients. Bivariate analyses were employed to evaluate associations between baseline demographics and CQOLC index scores. A systematic review of PubMed, EMBASE, and PsychInfo was undertaken.Results: Reduced QOL was observed for caregivers residing in homes earning less than our center’s median annual income per capita (p < 0.01) and for caregivers providing aid for 4 months or longer (p < 0.01). The burden of caregiving contributed most to summative index scores (p < 0.01). Eleven studies were selected by systematic review. Lower-income caregivers in Asia and the Middle East experience reduced QOL and increased burden. Available evidence does not suggest that lower-income caregivers in Europe and North America share worse QOL.Conclusion: Lower-income caregivers suffer loss in QOL, particularly in the developing world. Resourceful interventions are warranted to mitigate burden for this underappreciated population.

In this paper, we show that the phase shift of spin waves propagating in the plane of the film can be controlled by a metasurface formed by an ultra-narrow non-magnetic spacer separating edges of the two thin ferromagnetic films. For this purpose, we exploit the strength of the exchange coupling of the RKKY type between the films which allows tuning the phase of the transmitted spin waves in the wide range of angles [-π/2; π/2]. We combined the phase-shift dependency along the interface with the lens equation to demonstrate numerically the metalens for spin waves.

3534 Background: Clinical trials have demonstrated improvements in survival with immune checkpoint inhibitors (ICIs) for advanced colorectal cancer patients with MSI-H/dMMR detected using PCR-based assays (PCR) or immunohistochemistry (IHC), respectively. MSI-H can also be assessed by next-generation sequencing (NGS). Evaluation of real-world outcomes among MSI-H patients by NGS treated with ICIs are warranted, particularly when results are discordant between these tests. Methods: The VA National Precision Oncology Program Database was accessed to select veterans with colorectal cancer and an MSI-H biomarker by NGS. Baseline patient variables, disease characteristics, and duration of ICI treatment were obtained from the VA’s Corporate Data Warehouse. Concordance between NGS and IHC or PCR testing was computed, and the response rate and duration of ICI treatment in patients with discordant test results were recorded from chart review. Results: Among 1,276 colorectal cancer patients, 71 (5.6%) were found to have MSI-H by NGS. Of these, 22 (30.1%) received ICI. Among 49 patients who did not receive ICI, 36 had stage I-III disease, 5 had limited performance status, 5 were actively being treated with chemotherapy and 3 had completely resected stage IV disease. Of the 71 patients, 29 had dMMR IHC testing, 8 had MSI-H PCR testing, 1 had both IHC and PCR testing, and 34 patients had only NGS testing. No PCR tests were discordant with NGS but 8 of 29 IHC tests were discordant. Among these 8 patients with discordant IHC MMR and MSI-H by NGS, 5 received pembrolizumab. There were 3 partial responses, 1 stable disease and 1 progressive disease. Durable responses were seen with 3 of 5 patients remaining on therapy without progression at the time of this analysis at a median follow up of 8.5 months. Conclusions: In a cohort of NGS MSI-H colorectal cancer patients, there was a high rate of discordant IHC results. Clinical benefit is seen in patients treated with ICI with discordant testing results, suggesting that NGS testing identifies patients with false negative dMMR IHC testing in the real-world clinical setting.

e18676 Background: The increasing availability of comprehensive genomic profiling (CGP) and a growing number of targeted agents (TAs) has led to substantial improvements in outcomes among cancer pts with actionable mutations. CGP has led to identification of both on-label (level 1) variants, for which TAs have known efficacy, and off-label variants with lesser strength of supporting data. We sought to evaluate real-world prescription patterns and outcomes of off-label TA prescriptions among pts who underwent CGP. Methods: The NPOP database and VA Corporate Data Warehouse were queried to identify pts who had underwent CGP between February 2019 and December 2021 and were prescribed at least 1 of 73 TAs before January 2022. TAs prescribed for FDA-approved indications not relying on CGP as a companion diagnostic were excluded. OncoKB was used to annotate gene variants and evaluated against prescriptions to select pts who received off-label TAs. The frequency of off-label TA use, and for those treated > 4 weeks, rate of pts treated for 6 months or longer, median treatment duration and overall survival (OS) were computed. Results: Of the 18686 patients who underwent CGP, 2107 (11%) were prescribed any TA, and 191 (1%) were prescribed off-label TAs, with 31 receiving multiple concurrent or sequential off-label TAs. Mean age was 65.5 years, and 88% were male. TAs were most often prescribed for cancers of unknown primary (CUP, 29), NSCLC (24), and colorectal cancer (22). Frequency of off-label prescriptions was highest for pts who completed CGP for thyroid cancer (9%), breast cancer (8%), and CUP (2%). Most common variants involved BRAF (21%), ERBB2 (18%), BRCA1/BRCA2/ATM (9%), and PIK3CA (6%). Among all 164 pts treated > 4 weeks, 40% received TAs for 6 months or longer, including 50%, 47%, and 46% of pts bearing BRAF-, ERBB2-, and PIK3CA-mutant disease, respectively. Median therapy duration and OS was 141 [78.5 – 317, IQR] days and 181 [96.5 – 304.5, IQR] days, respectively. Conclusions: Though overall use of off-label TAs following CGP is low, nearly 10% of advanced thyroid and breast cancer patients are prescribed TAs for off-label indications. Forty percent of all pts receiving off-label TAs continue for at least 6 months, with higher rates for pts bearing BRAF-, ERBB2-, and PIK3CA-mutant disease. CGP-guided off-label treatment approaches offer unique options for advanced stage cancer with amenable molecular profiles.

Purpose Given the increasing number of non-small cell lung cancer (NSCLC) patients in India, a comparative analysis between patients under 40 years and those of older age at a major public referral centre would provide insight into the phenotypic patterns of this group. Methods NSCLC patients who were accessioned within the lung cancer clinic database of the Pulmonary Medicine Department at the all India institute of medical sciences - Delhi between 2008 and 2019 were reviewed. Patients 40 years or younger and 60 years or older were selected and categorised as young and older patients, respectively. Baseline clinical characteristics, histologic profiles, treatments administered and survival outcomes were compared between both groups. Results Following the database review, 154 young and 1,058 older patients were selected for inclusion. Clinically, young patients were more often female (26.0% versus 14.5%, p < 0.001), retained a more independent performance status (64.1% versus 45.5%; p < 0.001) and never smoked (63.7 % versus 18.8%, p < 0.001). Regarding disease profiles, young patients were more frequently diagnosed with adenocarcinoma (p < 0.001) and 12 young patients had adenoid cystic carcinoma. Rates of stage IV disease at presentation were higher among young patients (78.0% versus 63.0%, p < 0.001). Regarding treatment, no differences in systemic therapies administered or survival were identified. Conclusion In India, young NSCLC patients are frequently non-smokers and diagnosed with advanced disease. Despite better performance status, young patients do not share better outcomes. Efforts should be directed towards optimising intensive treatment for young patients.

BackgroundTo support the rising need for testing and to standardize tumor DNA sequencing practices within the U.S. Department of Veterans Affairs (VA)'s Veterans Health Administration (VHA), the National Precision Oncology Program (NPOP) was launched in 2016. We sought to assess oncologists' practices, concerns, and perceptions regarding Next-Generation Sequencing (NGS) and the NPOP.Materials and methodsUsing a purposive total sampling approach, oncologists who had previously ordered NGS for at least one tumor sample through the NPOP were invited to participate in semi-structured interviews. Questions assessed the following: expectations for the NPOP, procedural requirements, applicability of testing results, and the summative utility of the NPOP. Interviews were assessed using an open coding approach. Thematic analysis was conducted to evaluate the completed codebook. Themes were defined deductively by reviewing the direct responses to interview questions as well as inductively by identifying emerging patterns of data.ResultsOf the 105 medical oncologists who were invited to participate, 20 (19%) were interviewed from 19 different VA medical centers in 14 states. Five recurrent themes were observed: (1) Educational Efforts Regarding Tumor DNA Sequencing Should be Undertaken, (2) Pathology Departments Share a Critical Role in Facilitating Test Completion, (3) Tumor DNA Sequencing via NGS Serves as the Most Comprehensive Testing Modality within Precision Oncology, (4) The Availability of the NPOP Has Expanded Options for Select Patients, and (5) The Completion of Tumor DNA Sequencing through the NPOP Could Help Improve Research Efforts within VHA Oncology Practices.ConclusionMedical oncologists believe that the availability of tumor DNA sequencing through the NPOP could potentially lead to an improvement in outcomes for veterans with metastatic solid tumors. Efforts should be directed toward improving oncologists' understanding of sequencing, strengthening collaborative relationships between oncologists and pathologists, and assessing the role of comprehensive NGS panels within the battery of precision tests.

Targeting and monitoring several acute myeloid leukemia mutations sequentially provides insights into optimal treatment plans.

Background: Genomic sequencing of tumor samples is often considered for patients diagnosed with metastatic malignancies. In July 2016, the Veterans Health Administration (VHA) created the VA National Precision Oncology Program (NPOP) to offer next generation sequencing (NGS) multigene panels for veterans with advanced solid tumors. We sought to assess the perceptions of NPOP among medical oncologists across VHA. Methods: Semi-structured interviews were designed to evaluate the following concepts: expectations for NGS testing, required workflow to conduct testing, applicability of testing results, and summative views of genomic sequencing. VHA medical oncologists who had previously sent at least one sample for testing through NPOP were solicited to participate for an in-person or telephonic conversation. Interviews were analyzed by an inductive narrative approach to code responses, which was then followed by thematic analysis for key findings that emerged. Results: 17 medical oncologists were interviewed from 16 different VA medical centers (VAMCs) in 12 states. 16 (94.1%) oncologists reported sending at least 5 samples for NGS testing; 4 (23.5%) oncologists practiced at VAMCs that sent over 100 samples. Clinicians collectively expected that testing would determine all clinically relevant genomic alterations in a reasonable time. Testing was expedited for oncologists who maintained a collaborative relationship with their local pathologists and proceduralists. 8 (47.1%) oncologists felt that testing reports should provide greater insight into the clinical significance of uncommon gene variants. 6 (35.3%) respondents expressed that educational efforts are warranted to describe optimal sample processing, indications for testing, and/or relevance of rare mutations. Twelve (70.6%) respondents felt strongly that NGS testing would improve outcomes for their patients, while 3 (17.6%) oncologists were wary that the current number of actionable mutations is too limited to offer widespread benefit. Conclusions: VHA medical oncologists opined that NGS testing through VA NPOP improved outcomes. The testing process is expedited with multidisciplinary involvement. Designed approaches to semi-algorithmically report testing results may improve efficiency of clinical decision-making. More education is warranted to detail the procedural requirements to conduct testing, indications for test ordering, and interpretation of results.

Purpose To perform a comprehensive comparison of overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), and treatment-related complications between radical cystectomy (RC) and combined modality treatment (CMT—radiation therapy, concurrent chemotherapy, and maximal transurethral resection of bladder tumor) in the setting of muscle-invasive bladder cancer. Methods and Materials We searched 7 databases (PubMed, Scopus, EMBASE, Proquest, CINAHL, and ClinicalTrials.gov) for randomized, controlled trials and prospective and retrospective studies directly comparing RC with CMT from database inception to March 2016. We conducted meta-analyses evaluating OS, DSS, and PFS with hazard ratios (HRs) and 95% confidence intervals (CIs). Results Nineteen studies evaluating 12,380 subjects were selected. For the 8 studies encompassing 9554 subjects eligible for meta-analyses, we found no difference in OS at 5 years (HR 0.96, favoring CMT, 95% CI 0.72-1.29; P =.778) or 10 years (HR 1.02, favoring cystectomy, 95% CI 0.73-1.42; P =.905). No difference was observed in DSS at 5 years (HR 0.83, favoring radiation, 95% CI 0.54-1.28; P =.390) or 10 years (HR 1.17, favoring cystectomy, 95% CI 0.89-1.55; P =.264), or PFS at 10 years (HR 0.85, favoring CMT, 95% CI 0.43-1.67; P =.639). The cystectomy arms had higher rates of early major complications, whereas rates of minor complications were similar between the 2 treatments. Conclusion Current meta-analysis reveals no differences in OS, DSS, or PFS between RC and CMT. Further randomized, controlled trials are necessary to identify the optimal treatment for specific patients.

BACKGROUND: Anemia remains a significant public health challenge, with a disproportionate impact on lower-income patients residing in areas of lesser healthcare resources. These patients frequently share limited access to routine laboratory testing, and as a result, physical examination still serves as a critical tool for anemia assessments. Significant efforts have been directed toward quantifying the accuracy of physical exam to diagnose anemia among pediatric patients, who may face developmental delays stemming from nutritional deficiencies. Nonetheless, the widespread prevalence of anemia contributes to substantial cardiovascular burden for a large volume of older patients. We sought to evaluate the accuracy of clinical exam techniques to diagnose anemia among patients 5 years of age or older. METHODS: A systematic review of five databases (MEDLINE via OVID, EMBASE, Scopus, Global Health and Global Health Archives, and WHO Global Index Medicus) was conducted to evaluate studies published before February 2020. Studies that 1) compared non-invasive physical exam techniques with anemia diagnoses using standard laboratory measurements and 2) solely assessed or separately reported the diagnostic accuracy of physical exam techniques for patients 5 years or older were considered for inclusion. Studies that 1) investigated patients with specific hematologic conditions, namely sickle cell anemia, thalassemia, and acute leukemia, and/or 2) evaluated the utility of novel non-invasive devices to measure hemoglobin concentration were excluded. Two authors initially screened titles and abstracts from the search results using the Covidence web-based software platform. The full-text publications of selected abstracts were reviewed thereafter. The diagnostic accuracies of individual and collective physical exam techniques to diagnose anemia were documented. This systematic review was registered with PROSPERO. RESULTS: The systemic literature search yielded 6,457 unique studies after removal of duplicates. Following screening of titles and abstracts, 97 studies were selected for full-text analysis. Fourteen studies were ultimately selected for inclusion. Evaluation of subjects under the age of 5 years and lack of comparison between physical exam findings and anemia diagnoses were the two most common reasons for exclusion at time of full-text analysis. Of the 14 selected publications, 8 studies solely assessed pregnant females, 3 solely assessed hospitalized patients, and 3 evaluated the general population. Five studies were conducted in South Asia, and 4 were conducted in Africa. The most frequently evaluated physical exam technique was assessment of clinical pallor, and the anatomical sites most often examined were conjunctivae, nail bed, and palms. The diagnostic accuracy ranged widely for pallor assessments of conjunctivae (sensitivity: 19% - 97%, specificity: 65% - 100%), nailbed (sensitivity: 41% - 65%, specificity: 58% - 93%), and palms (sensitivity: 33% - 91%, specificity: 54% - 93%). Similarly, sensitivity and specificity of collectivizing at least two or more physical exam findings to diagnose anemia ranged from 26% to 96% and 13% to 99%, respectively. CONCLUSIONS: Though frequently implemented in practice, the accuracy of assessing clinical pallor to diagnose anemia is unclear. The wide range in previously reported associations between exam findings and anemia diagnoses is likely due to heterogenous populations being investigated. More robust studies are required to identify the most optimal exam technique or combination of techniques to screen and/or diagnose anemia among patients without concurrent pregnancy or significant co-morbidities. Disclosures No relevant conflicts of interest to declare.

Background Delays that postpone the evaluation and management of malignancy may lead to considerable morbidity. The primary objective of this study was to assess the time required to diagnose and treat lung cancer at an Indian public referral center that predominantly serves lower-income patients. Methods A review of patients diagnosed with lung cancer between January 2008 and December 2016 was completed. We computed the median time intervals and inter-quartile ranges between symptom onset, definitive diagnostic investigation, confirmed histologic diagnosis, and chemotherapy initiation. Median intervals were correlated with baseline demographics and disease characteristics using Kruskal-Wallis test. Results One thousand, three hundred and-seventy patients were selected. A majority (94.5%) with non-small cell lung cancer were diagnosed with advanced disease. After developing symptoms, patients required 101 [56–168] days to undergo a definitive diagnostic study, 107 [60–173] days to confirm a diagnosis, and 126 [85–196.8] days to initiate treatment. Patients who were previously treated for tuberculosis required more time to receive chemotherapy compared to those who were not (187 [134–261.5] days vs. 113 [75–180] days, p Conclusion Among lower-income Indian patients, the most prominent delays occur prior to diagnosis. Efforts should be directed toward encouraging physicians to maintain a high index of clinical suspicion and educating patients to report concerning symptoms as early as possible.

Metasurface is a new concept to manipulate the amplitude and phase of the incoming wave locally from the surface. Metasurface is composed of 2D elements so called nanoantennas, which show practical solution for manipulation of light unlike 3D metamaterials devices which are difficult to fabricate at nano scale level. Many of the devices are already designed using the concept of metasurfaces which include meta-lens, vortex plates, holography, and color filters. Color filters designed using metasurfaces attract attention of researchers because of their significant advantages over pigment based printing technology such as high contrast, low power, and ultra-high resolution. Recently, a new trend is emerging to use all dielectric based metasurface filters, which are much more efficient compare to plasmonics color filters. These filters can be easily integrated with existing electronic circuitry, since these filters are designed using Si material. In this work, we propose polarization dependent widely tunable all dielectric color filters, whose basic constitute element is Si based cross shaped nanoantennas. These filters are designed using cross shaped nanoantennas with different arm lengths. Each arm of nanoantenna responds for different state of polarization of incoming light, which results in different color spectra. We illustrate a wide tunability of these filters in visible spectrum with numerical simulation.

e17033 Background: PARP inhibitors (PARPis) were approved by the FDA for the treatment of advanced prostate cancer (PC) among patients (pts) harboring mutations in genes responsible for homologous DNA repair. Increasing evidence has suggested that pts with BRCA2 gene alterations may derive the most benefit from these drugs. Study objectives were to evaluate real-world treatment outcomes among Veterans prescribed PARPis for PC and to compare outcomes between pts with BRCA2 gene variants and those with variants in other homologous DNA repair genes. Methods: The U.S. Department of Veterans Affairs (VA) National Precision Oncology Program database was reviewed to identify PC pts who successfully underwent tumor DNA sequencing and were prescribed olaparib, rucaparib, niraparib or talazaporib prior to FDA approval for PARPi use in PC (May 15, 2020). Only pts who received a PARPi for > 4 weeks were included in outcome assessments The VA’s Corporate Data Warehouse was reviewed to obtain clinical and disease characteristics, laboratory and imaging reports, and treatments administered. Assessed outcomes included PSA30, defined as the percentage of pts achieving 30% reduction in prostate-specific antigen (PSA) level, and composite progression-free survival (PFS), which included time to radiographic progression per RECIST criteria, discontinuation of therapy, and/or death. Pts who discontinued therapy due to toxicity were censored for PFS analyses. PSA30 and PFS were compared between pts bearing BRCA2 gene variants and those with variants in other homologous DNA repair genes using t-testing and log-rank testing, respectively. Results: 48 pts were prescribed a PARPi for PC; 43 (89.6%) received therapy for > 4 weeks. BRCA2 gene variants (43.8%) were most commonly observed followed by ATM (23.0%) and BRCA1 (16.7%). Forty-two pts (87.5%) received prior systemic therapy beyond androgen deprivation. Forty (83.3%) pts received olaparib, 6 (12.5%) received rucaparib, and 2 (4.2%) received both. Eleven (22.9%) discontinued therapy due to toxicity, with anemia being most common toxicity. Of the 43 pts treated for > 4 weeks, pts with BRCA2 variants had a higher rate of PSA30 than those without (47.9% vs. 4.5%; p = 0.004). The median PFS for all pts was 4.0 months. Pts with BRCA2 gene variants had longer PFS than those without BRCA2 gene variants (7.2 vs 3.3 months; p = 0.037). Pts with BRCA2 gene variants also had longer PFS than those with BRCA1 variants (7.2 vs 3.3, p = 0.031). No difference was observed in PFS between those with BRCA2 variants and those with ATM variants ( p = 0.51). Conclusions: Approximately one-quarter of PC pts with variants in homologous DNA repair genes treated with PARPis achieve a 30% reduction in PSA, and the median PFS is 4 months. Pts harboring BRCA2 gene variants have a significantly higher rate of PSA30 and a longer PFS than those with variants in other homologous DNA repair genes.

As the use of serotonergic agents to treat depression has increased, so too has the incidence of serotonin syndrome. We identify the common agents implicated in serotonin syndrome and the clinical tools to diagnose, manage, and prevent serotonergic toxicity.

Background Chronic kidney disease is increasing in prevalence. The association between low baseline estimated glomerular filtration rate (eGFR) and future myocardial infarction has not been comprehensively assessed. Methods A systematic review and meta-analysis of observational studies evaluating the risk for future myocardial infarction associated with eGFR 2 was completed. Data sources included PubMed, EMBASE, and the Cochrane Library. Included studies were required to have prospectively collected data, followed subjects for at least 6months, and reported baseline eGFR levels and the multivariable-adjusted relative risk for future myocardial infarction. A random effects model was used and subgroup analyses were conducted. Results 26 publications representing 41 observational cohorts were selected. In total, 1,986,850 participants with more than 35,752 documented myocardial infarctions (follow-up range: 9months to ~20years) were evaluated. eGFR 2 was associated with a relative risk of 1.52 (95% confidence interval 1.39–1.67; p 2 was associated with a relative risk of 1.21 (1.09–1.34; p =0.0002) for myocardial infarction. Significant heterogeneity existed among both eGFR groups. Subgroup analysis found a further increase in risk for myocardial infarction as eGFR declined from 30 to 60 to 2 (1.40, 95% confidence interval, 1.21–1.61 vs.1.94, 95% confidence interval, 1.51–2.50; p =0.03). Conclusions Decreased baseline eGFR is independently associated with increased future myocardial infarction, and the risk increases with advanced renal insufficiency. Clinicians should be wary of acute coronary syndromes in patients with CKD.

2005 Background: Next-Generation Sequencing (NGS) gene panels are often completed to guide therapeutic decisions for patients with advanced stage non-small cell lung cancer (NSCLC). Patients with highly-actionable gene variants may experience improved therapeutic treatments and reduced toxicities with use of targeted agents. Ensuring appropriate prescription of targeted therapies is therefore of high importance. We sought to identify barriers to targeted agent use within the Veterans Health Affairs’ (VHA) National Precision Oncology Program (NPOP). Methods: A retrospective evaluation examined the cohort of NSCLC patients who underwent NGS multi-gene panels through NPOP between July 2015 and February 2019. A level of evidence for drug actionability was assigned to each observed oncogenic gene variant using an artificial intelligence offering (IBM Watson for Genomics: WfG). WfG level 1 and 2A evidence was reviewed by NPOP staff to exclude gene variants that did not conform to NPOP level 1 and 2A definitions. Anti-neoplastic drug prescriptions and oncology provider notes were obtained for all included patients from the VHA Corporate Data Warehouse. Review of clinical notes of patients who did not receive targeted agents was performed to categorize the reason(s). Results: Of 1764 NSCLC patients who successfully underwent NGS gene panel testing, 156 (8.9%) received therapeutic level 1 (7.3%) or 2A (1.6%) options for targeted agents based on WfG evidence analysis. In total, 117 (6.6%) patients had NPOP level 1 and 2A gene variants, all within ALK, BRAF, EGFR, ERBB2, MET, and RET. Of these, 49 (41.2%) patients were not prescribed available targeted agents. The three most common reasons were: (1) treating provider did not comment on NGS results (30.7%), (2) patient did not carry a diagnosis of advanced stage disease (18.4%), and (3) patient had begun an alternative systemic therapy prior to completion of sequencing (16.3%). No patient was denied access to a level 1 or 2A targeted drug due to utilization-management review. Conclusions: A substantial minority of patients with advanced NSCLC bearing highly-actionable gene variants are not prescribed available targeted agents. Further provider- and pathologist-directed educational effort are needed, as well as implementation of health informatics systems to provide near real-time decision support for test ordering and interpretation.

e19295 Background: Immunotherapy (IO) has revolutionized the treatment paradigm for patients with advanced non-small cell lung cancer (NSCLC). Study objectives were to evaluate utilization of IO as first-line (1L) therapy and compare clinical characteristics between patients receiving IO and those receiving CT in 1L setting. Methods: Using the U.S. Department of Veterans Affairs corporate data warehouse, patients with stage IV NSCLC diagnosed 2012-2017 and initiated non-targeted systemic therapy within 120 days of diagnosis were selected. Unadjusted descriptive statistics were used to compare patient characteristics, inpatient and outpatient clinic visits, and prevalence of select adverse events (AE) between patients receiving IO monotherapy and CT. Kaplan-Meier and Cox regression approaches with and without propensity score matching (PSM) were used for overall survival (OS) analyses. OS was calculated from treatment initiation date to death or end of study period in June 2019. Results: 4609 patients were included in the analysis: 3.4% (n = 156) received IO monotherapy, 96% (n = 4426) received CT, and 0.6% (n = 27) received IO+CT (IO+CT not included in analysis). IO patients were older than CT patients (median age 69 vs. 66 years, p < 0.0001) and more frequently resided in the Midwest and West regions whereas CT patients were more likely to live in the Northeast and South (p = 0.0024). There were no significant differences in IO and CT by other demographic and clinical characteristics. Estimated median OS was 7.5 months (95% CI 7.2-7.7) for CT and 7.9 months (95% CI 5.3-12.6) for IO patients. The unadjusted HR for IO compared to CT patients was 0.81 (95% CI 0.67-0.98). With 1:4 PSM (144 and 559 patients matched in the IO and CT groups, respectively), the HR was 0.75 (95% CI 0.60-0.93). The mean number of outpatient visits for IO and CT patients were 47 and 36, respectively (p = 0.003). No difference in number of hospitalizations or length of hospital stays between the two groups was observed. Common AEs in the IO group were dyspnea (58%), colitis/enterocolitis (42%), and anemia (30%). Common AEs among CT patients were colitis/enterocolitis (36%), anemia (32%), and nausea/vomiting (31%). Conclusions: In a real-world 1L setting among veterans with NSCLC, improvement in OS was observed among patients receiving IO monotherapy compared to those receiving CT, and IO patients had a greater number of outpatient visits. Continued assessment of treatment patterns and impact of IO are needed as the use of IO continues to expand.

7075 Background: Tumor profiling identifies patients who are eligible for targeted anticancer therapies. Common tumor profiling approaches include targeted gene panel testing (TGPT), which tests for common mutations in select genes, and multigene panel sequencing (MGPS), which tests for a broad range of mutations in a comprehensive set of genes. Our objective was to determine the lifetime cost-effectiveness of MGPS and TGPT compared to no tumor profiling for Veterans with metastatic lung adenocarcinoma from the Veterans Health Administration’s (VHA) perspective. Methods: A decision analytic model was developed to simulate outcomes for a closed cohort of hypothetical Veterans with metastatic lung adenocarcinoma considering anticancer therapy. OncoKB genes with levels of evidence 1 and 2 for guiding therapy were included. Three profiling strategies were studied: TGPT ( ALK, EGFR, ROS1), MGPS ( ALK, BRAF, EGFR, HER2, MET, NTRK1, NTRK2, NTRK3, RET, ROS1), and no tumor profiling. We assumed 95% of patients with actionable mutations received targeted therapies. Non-targeted therapy options included chemotherapy and/or immunotherapy, and no anticancer therapy. Model inputs were derived from randomized trials (progression-free survival), VHA and Medicare (drug costs), published studies (non-drug cancer-related management costs, health care utilities), and VHA National Precision Oncology Program and cBioPortal for Cancer Genomics databases (mutation prevalence). Costs (2019 US$) and quality-adjusted life years (QALYs) were discounted at 3%/year. Base-case scenario, one-way sensitivity analyses, and probabilistic sensitivity analyses (PSA) using 1,000 Monte Carlo simulations were completed. Results: Base-case results and corresponding 95% credible intervals from the PSA indicated the cost/QALY gained was $309,399 ($280,371-$343,161) for TGPT and $324,707 ($296,086-$359,778) for MGPS compared to no tumor profiling. Of the 3 strategies, MGPS resulted in the highest number of QALYs. One-way sensitivity analyses revealed the cost/QALY estimates were most impacted by changes in health state utility on a targeted therapy (quality of life), costs of alectinib, and non-drug cancer-related costs in patients receiving targeted therapy. Compared to no tumor profiling, cost-effectiveness ratios for both profiling approaches surpassed the $150,000/QALY threshold in 100% of PSA simulations. Conclusions: Tumor profiling (TGPT or MGPS) can optimize anticancer therapy selection in patients with metastatic lung adenocarcinoma and improve quality-adjusted survival, but compared to no tumor profiling, is not cost-effective.

Metasurface is a new concept to manipulate the amplitude and phase of the incoming wave locally from the surface. Metasurface is composed of 2D elements so called nanoantennas, which show practical solution for manipulation of light unlike 3D metamaterials devices which are difficult to fabricate at nano scale level. Many of the devices are already designed using the concept of metasurfaces which include meta-lens, vortex plates, holography, and color filters. Color filters designed using metasurfaces attract attention of researchers because of their significant advantages over pigment based printing technology such as high contrast, low power, and ultra high resolution. Recently, a new trend is emerging to use all dielectric based metasurface filters, which are much more efficient compare to plasmonics color filters. These filters can be easily integrated with existing electronic circuitry, since these filters are designed using Si material. In this work, we propose polarization dependent widely tunable all dielectric color filters, whose basic constitute element is Si based cross shaped nanoantennas. These filters are designed using cross shaped nanoantennas with different arm lengths. Each arm of nanoantenna responds for different state of polarization of incoming light, which results in different color spectra. We illustrate a wide tunability of these filters in visible spectrum with numerical simulation.

Printing technology based on plasmonic structures has many advantages over pigment based color printing such as high resolution, ultra-compact size and low power consumption. However, due to high losses and broad resonance behavior of metals in the visible spectrum, it becomes challenging to produce well-defined colors. Here, we investigate cross-shaped dielectric nanoresonators which enable high quality resonance in the visible spectral regime and, hence, high quality colors. We numerically predict and experimentally demonstrate that the proposed all-dielectric nanostructures exhibit high quality colors with selective wavelengths, in particular, due to lower losses as compared to metal based plasmonic filters. This results in fundamental colors (RGB) with high hue and saturation. We further show that a large gamut of colors can be achieved by selecting the appropriate length and width of individual $Si$ nanoantennas. Moreover, the proposed all-dielectric metasurface based color filters can be integrated with the well matured fabrication technology of electronic devices., 18 pages, 3 figures

Designing color pixels using plasmonic nanostructures and metasurfaces has become a luring area of research in recent years. Here, we experimentally demonstrated the voltage tunability of a dynamic plasmonic color filter by using an aluminum grating integrated with the nematic liquid crystal (LC). Along with a typical substrate coated with rubbed polyimide film, the aluminum grating itself serves as a molecular alignment layer to form a twisted LC cell. This hybrid structure allows electrically controlled transmission color by applying the voltage. A significant spectral tunability of such a device has been demonstrated by applying the small voltage from 0 to 4 Vrms.