Florida-California Cancer Research, Education and Engagement (CaRE2) Health Equity Center: Structure, Innovations, and Initial Outcomes.

INTRODUCTION: The Florida-California Cancer Research, Education, and Engagement (CaRE2) Health Equity Center is a triad partnership committed to increasing institutional capacity for cancer disparity research, the diversity of the cancer workforce, and community empowerment. This article provides an overview of the structure, process innovations, and initial outcomes from the first 4 years of the CaRE2 triad partnership. METHODS: CaRE2 serves diverse populations in Florida and California using a "molecule to the community and back" model. We prioritize research on the complex intersection of biological, environmental, and social determinants health, working together with scientific and health disparities communities, sharing expertise across institutions, bidirectional training, and community outreach. Partnership progress and outcomes were assessed using mixed methods and four Program Steering Committee meetings. RESULTS: Research capacity was increased through development of a Living Repository of 81 cancer model systems from minority patients for novel cancer drug development. CaRE2 funded 15 scientific projects resulting in 38 publications. Workforce diversity entailed supporting 94 cancer trainees (92 URM) and 34 ESIs (32 URM) who coauthored 313 CaRE2-related publications and received 48 grants. Community empowerment was promoted via outreaching to more than 3000 individuals, training 145 community cancer advocates (including 28 Community Scientist Advocates), and publishing 10 community reports. CaRE2 members and trainees together have published 639 articles, received 61 grants, and 57 awards. CONCLUSION: The CaRE2 partnership has achieved its initial aims. Infrastructure for translational cancer research was expanded at one partner institution, and cancer disparities research was expanded at the two cancer centers.

NTRK1 Fusions identified by non-invasive plasma next-generation sequencing (NGS) across 9 cancer types.

BACKGROUND: Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored. METHODS: We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions. RESULTS: NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value. CONCLUSION: Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms.

Characterization of Thyroid Cancer among Hispanics in California, USA, from 2010 to 2020.

BACKGROUND: Previous studies on Hispanic thyroid cancer cases show sex disparities and an increased prevalence of large tumor sizes and nodal involvement. Here, we characterized Hispanic thyroid cancer cases in California. METHODS: We identified thyroid cancer cases from 2010 to 2020 using the California Cancer Registry by sex, race/ethnicity, histology, TNM stage, tumor size, lymph node involvement, and Charlson comorbidity score. The age-adjusted incidence rate (AAIR) and age-adjusted mortality rate (AAMR) for all causes of death were calculated. A Cox proportional hazards regression analysis was performed to evaluate the mortality risk from all causes of death by race. RESULTS: Overall, 56,838 thyroid cancer cases were identified, including 29.75% in Hispanics. Hispanics had the highest female-to-male incidence rate ratio (IRR 3.54) and the highest prevalence of T3/T4 tumor size (28.71%), the highest N1 nodal status (32.69%), and the highest AAMR (0.79 per 100,000 people). After adjusting for demographic and tumor covariates, compared to non-Hispanic White people, Hispanic ethnicity, with an HR of 1.22 (95% CI 1.18-1.25, p < 0.0001), remained a significant independent contributor to mortality risk. CONCLUSIONS: Hispanics had the greatest female-to-male IRR ratio, a greater prevalence of advanced disease features at diagnosis, along with the highest AAMR and increased mortality risk despite adjustments for demographic and tumor covariates. Further investigation into other risk factors is needed.

Influence of TP53 Comutation on the Tumor Immune Microenvironment and Clinical Outcomes With Immune Checkpoint Inhibitors in STK11-Mutant Non-Small-Cell Lung Cancer.

PURPOSE: Non-small-cell lung cancer (NSCLC) with STK11mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of STK11mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring TP53 comutations could have favorable outcomes to ICIs. PATIENTS AND METHODS: NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11mut NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for STK11mutTP53mut versus STK11mutTP53wt NSCLC. RESULTS: Overall, 12.6% of NSCLC tumors had a STK11mut with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of STK11mut (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in TP53mut NSCLC (P < .01). Compared with STK11mutTP53wt, tumors with STK11mutTP53mut had higher CD8+T cells and natural killer cells (P < .01), higher TMB (P < .001) and neoantigen load (P < .001), and increased expression of MYC and HIF-1A (P < .01), along with higher expression (P < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with STK11mutTP53mut. In the DFCI cohort, compared with the STK11mut TP53wt cohort, the STK11mutTP53mut tumors had higher objective response rates (42.9% v 16.7%; P = .04) and also had longer TTF (14.5 v 4.5 months, P adj = .054) with ICI. CONCLUSION: STK11mut NSCLC with TP53 comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches.

Complete response with pembrolizumab in recurrent squamous cell carcinoma of the oral tongue: A case report.

Immunotherapies such as immune checkpoint inhibitors have shown promising results in solid tumors associated with BRCA2, but there are no consistent predictors for who will respond to immunotherapy. More research is needed on the impact of this mutation in head and neck squamous cell carcinomas, particularly for recurrent/metastatic tumors. We report a case of stage IV oral squamous cell carcinoma associated with BRCA2 mutation that achieved complete remission with pembrolizumab treatment for relapsed disease.

Biopsy Method and Needle Size on Success of Next-Generation Sequencing in NSCLC: A Brief Report.

Introduction: Next-generation sequencing (NGS) is essential to the care of patients with NSCLC. Nevertheless, NGS is dependent on adequate material from biopsy. We evaluated the impact of biopsy method and needle gauge necessary for optimizing success in tissue NGS. Methods: A total of 1660 formalin-fixed, paraffin-embedded samples were submitted to Caris Life Sciences from 2007 to 2022 for tumor profiling. The results of NGS assays were linked with retrospective biopsy data for patients with lung cancer treated at USC/Norris Cancer Center to create a database with the following parameters: demographics, biopsy method, tumor location (lung mass versus lymph node versus metastasis), needle gauge, number of needle passes, complications, tumor volume, DNA content, and status of NGS. Fisher's exact test and analysis of variance were performed to determine the impact of biopsy method and needle gauge (G). Results: In total, 77 computed tomography (CT)-guided transthoracic core needle (CT-TTCN) biopsies, 74 endobronchial ultrasound (EBUS)-guided transbronchial needle aspirations (TBNAs), 27 bronchial forceps biopsies, and 107 surgical resections were included. Furthermore, 41 of 77 CT-TTCN biopsies (53.2%), 43 of 74 EBUS-TBNAs (58.1%), 22 of 27 bronchial forceps biopsies (81.5%), and 105 of 107 surgical resections (98.1%) underwent successful NGS assays. The probability of successful NGS completion for lung cancers was highest in surgical resections and bronchial forceps biopsies. Needle-based biopsies were more successful when a needle larger than 20G was used. Complication rates were higher for CT-TTCN biopsies compared with EBUS-TBNA (p < 0.0001). Overall, the DNA yield was significantly higher in EBUS-TBNA compared with CT-TTCN biopsies in primary lung sites (p = 0.0002). EBUS-TBNA was found to have higher success rates in NGS compared with CT-TTCN for both primary lung lesions (p = 0.023) and lymph node targets (p = 0.035). Conclusions: The less invasive EBUS-TBNAs had higher success rates in NGS than CT-TTCN biopsies and resulted in higher DNA concentrations. In CT-TTCN biopsies, use of 20G or smaller needles is associated with a higher risk of obtaining an inadequate specimen regardless of the number of passes taken. Surgical and bronchial forceps biopsies had highest success in achieving NGS.

Real world prognostic utility of platelet lymphocyte ratio and nutritional status in first-line immunotherapy response in stage IV non-small cell lung cancer.

BACKGROUND: Elevated platelet lymphocyte ratio (PLR) and low body mass index (BMI) are associated with inferior survival in non-small cell lung cancer (NSCLC) patients receiving immunotherapy (IO). We evaluated real-world prognostic utility of PLR, BMI, and albumin level in stage IV NSCLC patients receiving first line (1L) IO. METHODS: We identified 75 stage IV patients who received 1L IO therapy at USC Norris Comprehensive Cancer Center and Los Angeles General Medical Center from 2015 to 2022. The primary outcome was overall survival (OS) from time of IO with attention to pre-treatment BMI < 22, albumin < 3.5 g/dL, and PLR > 180. RESULTS: Median age was 66.5 years with 49 (65.3%) males. 25 (33.3%) had BMI < 22. 45/75 (60%) had PLR > 180. Patients with BMI < 22 had inferior OS (13.1 months (m) vs. 37.4 m in BMI > 28, p-value = 0.042) along with patients with albumin<3.5 g/dL (OS: 2.8 m vs. 14.6 m, p-value = 0.0027), and patients with PLR>180 (OS: 8.7 m vs. 23.0 m, p = 0.028). Composite BMI < 22, PLR > 180 had the worst OS, p-value = 0.0331. Multivariate analysis controlling for age, smoking, gender, PD-L1 tumor proportion score (TPS), and histology (adenocarcinoma, squamous, adenosquamous, and large cell) showed that BMI (HR: 0.8726, 95% CI: 0.7892-0.954) and PLR > 180 (HR: 2.48, 95% CI: 1.076-6.055) were significant in OS mortality risk. CONCLUSION: Patients with a composite of BMI < 22, albumin < 3.5 g/dL, and PLR > 180 had significantly worse OS. This highlights the importance of screening for poor nutritional status and high PLR to better inform stage IV NSCLC patients receiving IO therapy of their prognosis and supportive care. MICROABSTRACT: We evaluated real-world prognostic utility of platelet lymphocyte ratio (PLR), body mass index (BMI), and albumin level in 75 Stage IV NSCLC patients receiving first line IO. Patients with a composite of BMI < 22, albumin < 3.5 g/dL, and PLR > 180 had significantly worse OS. This highlights the importance of screening for poor nutritional status and high PLR to better inform stage IV NSCLC patients of their prognosis and to emphasize supportive care needs.

Impact of gender and mutational differences in hormone receptor expressing non-small cell lung cancer.

Background: The incidence of lung cancer in the US has been decreasing but a bigger decline has been observed in men despite similar declines in tobacco use between men and women. Multiple theories have been proposed, including exposure to exogenous estrogens. Our study seeks to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of non-small lung cancer (NSCLC). Methods: 3,256 NSCLC tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified and assessed for HR expression. Hormone receptor (HR+) was defined as ≥ 1% nuclear staining of estrogen receptor-alpha (ER-a) or progesterone receptor (PR) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n=2753) and Illumina NextSeq 592 gene panel (n=503). An adjusted p-value (q-value) <0.05 was determined significant. Results: HR+ was identified in 18.3% of NSCLC. HR+ occurred more commonly in women compared to men (19.6% vs 11.4%, p <0.0001, q <0.0001). EGFR mutations occurred more commonly in HR+ NSCLC than HR- NSCLC (20.2% vs. 14.6%, p = 0.002, q=0.007). Overall, men with EGFR mutations were affected by HR status with a higher prevalence in HR+ NSCLC while such differences were not seen in women. However, in women ages ≤45, there was a trend towards greater prevalence HR+ NSCLC (25.25% vs. 11.32%, q= 0.0942) and 10/25 (40.0%) of HR+ cases in young women were found to be EGFR mutated. KRAS mutations and ALK+ IHC expression occurred more in HR+ NSCLC whereas TP53 mutations occurred more in HR- NSCLC. Conclusions: Women were more likely to have HR+ NSCLC than men and EGFR and KRAS mutations occurred more commonly in HR+ NSCLC. Additional studies with more strict inclusion criteria for HR+ are warranted to see if there is benefit to targeting HR in these subgroups.

Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked.

INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab. METHODS: This is a randomized, phase II, multicenter study evaluating carboplatin, pemetrexed, bevacizumab with and without atezolizumab in 117 patients with stage IV nonsquamous NSCLC. Randomization is 2 to 1 favoring the atezolizumab containing arm. Eligible patients include: 1) those with tumors with sensitizing EGFR alterations in exons 19 or 21 or 2) patients who have never smoked and have wild-type tumors (ie, no EGFR, ALK or ROS1 alterations). Patients are defined as having never smoked if they have smoked less than 100 cigarettes in a lifetime. Patients with EGFR-mutated tumors must have disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate, duration of response, and time to response. CONCLUSION: This phase II trial is accruing patients at U.S. sites through the National Comprehensive Cancer Network (NCCN). The trial opened in August 2019 and accrual is expected to be completed in the Fall of 2024.

A pilot study of long-acting octreotide for symptomatic malignant ascites.

BACKGROUND: Effective, non-invasive, palliative strategies for symptomatic malignant ascites are unavailable. This trial explored whether octreotide, an inhibitor of vascular endothelial growth factor, a putative mediator of ascites, prolongs the interval to next paracentesis. METHODS: After a baseline paracentesis and a test of short-acting agent, patients with symptomatic ascites were randomly assigned to long-acting octreotide (Sandostatin LAR®) depot 30 mg intramuscularly every month versus 0.9% sodium chloride administered similarly. Patients were then monitored for recurrent, symptomatic ascites. RESULTS: Thirty-three patients were enrolled: 16 assigned to the octreotide and 17 to the control arm. The median time to next paracentesis was 28 and 14 days in the octreotide and placebo arm, respectively (p = 0.17). After adjustment for extracted ascites volume and abdominal girth change, no statistically significant difference between the groups was observed (hazard ratio = 0.52, with a 95% confidence interval of 0.21-1.28; p = 0.15, per Cox model). Octreotide-treated patients described less of abdominal bloating (p = 0.01), abdominal discomfort (p = 0.02), and shortness of breath (p = 0.007) at one month, although other quality of life symptoms were comparable between the arms. Long-acting octreotide was reasonably well tolerated. CONCLUSION: As prescribed in this trial, octreotide did not seem effective in prolonging the time to next paracentesis, although improvements in symptoms suggest that vascular endothelial growth factor inhibition merits further investigation.

Fluid biopsy for solid tumors: a patient's companion for lifelong characterization of their disease.

Cancer is currently diagnosed and treated based on the results of a tissue biopsy of the primary tumor or a metastasis using invasive techniques such as surgical resection or needle biopsy. New technology for retrieving cancer cells from the circulation, developed in the last 5 years, has made it possible to obtain a 'fluid biopsy' from the bloodstream without the need for an invasive procedure. This technological development makes it possible to diagnose and manage cancer from a blood test rather than from a traditional biopsy. It also allows the repeated sampling of cancer cells from a patient, making it possible, in a practical manner, to interrogate the disease repeatedly in order to understand the mechanisms by which cancer cells evolve within a given individual. The ability to obtain cancer cells repeatedly also has the potential to substantially advance drug development by enabling early ex vivo validation of both targets and early-stage compounds, as well as creating new efficiencies in the drug development process during clinical trials.

COVID-19 and the acceleration toward remote cancer care.

The disruption caused by the COVID-19 pandemic has disproportionately affected cancer patients' access to care. As a result, many specialists in the United States, including oncologists, have adopted telemedicine-a transition largely made possible by reforms to insurer reimbursement schemes. Years after the COVID-19 crisis, there will continue to be a steady demand for remote outpatient visits, particularly in oncology. However, in a health system heavily influenced by reimbursements, strategies to optimize remote oncology care will not be embraced without appropriate incentives. Here we propose that restructuring financial incentives in three areas of cancer care-anticancer drug delivery, wearable health monitoring, and digital data-sharing tools-has the potential to improve patient outcomes, reduce overall costs, and expand clinical trial access for patients in underresourced areas. As with telemedicine, it is time for policymakers to recognize this need and adjust the incentives, both for routine care and for clinical trials, to make it possible.

Evaluating Real World Mutational Differences Between Hispanics and Asians in NSCLC at a Large Academic Institution in Los Angeles.

INTRODUCTION: Hispanics living in the United States have higher rates of Epidermal Growth Factor Receptor (EGFR) mutations compared with Non-Hispanic Whites. While this higher incidence is like Asian patients living in the United States, the outcomes for Hispanic patients differ. We looked to compare the variances in mutational profiles between Hispanics and Asians in Los Angeles. PATIENTS AND METHODS: Three hundred ninety three non-small cell lung cancer (NSCLC) patients treated at Los Angeles County + University of Southern California (LAC + USC) Medical Center and Norris Comprehensive Cancer Center who received comprehensive genomic profiling (CGP) were evaluated from July 2017 to August 2020. CGP was done using tissue biopsies (n = 211) from Caris Life Sciences and liquid biopsies (n = 231) from Guardant Health. Multivariate logistic regression evaluated the role of race between Hispanics and Asians. RESULTS: In the Hispanic cohort (n = 90), 50.0% were male, median age of diagnosis was 62, 54.5% were non-smokers, and 85.5% had adenocarcinoma. In Asians (n = 142), 47.5% were male, median age of diagnosis was 65, 59.6% were non-smokers, and 83.8% had adenocarcinoma. Hispanic patients had greater prevalence of Kirsten rat sarcoma virus (KRAS) mutations (odds ratio [OR] 4.42, 95% confidence interval [95% CI]: 1.63-12.83) and lesser prevalence of EGFR mutations (OR 0.31, 95% CI: 0.16-0.59). There were a greater proportion of Hispanic smokers with KRAS mutations (14/41; 34.1%) than Asian smokers (4/58; 6.9%). CONCLUSION: We saw a greater percentage of Hispanics with KRAS mutations despite similar smoking percentages along with a greater percentage of Asians with EGFR mutations. This study shows that ethnic and racial backgrounds of the patient can influence the effects of potentially carcinogenic exposures leading to variances of mutation frequency of NSCLC among different ethnicities.

Characterization of mortality and high-risk characteristics of thyroid cancer in Filipinos using the California Cancer Registry.

Introduction: Filipinos are the third largest Asian American subgroup and have the highest incidence of thyroid cancer among all races. To better understand this racial/ethnic disparity in thyroid cancer affecting Filipinos we analyzed the California Cancer Registry (CCR) data in Filipino thyroid cancer cases from 1988 to 2018. Methods: 97,948 thyroid cancer cases in California from 1988 to 2018 (until 2015 for Asian subgroups) were evaluated. We examined the case distribution by sex, age at diagnosis, race/ethnicity including Asian ethnic subgroups, histology, TNM stage, tumor size, lymph node involvement, lymphovascular invasion, and multifocality. We also looked at treatment data including surgery and radiation including radioactive iodine therapy. We calculated age-adjusted mortality rates (AAMR) for each major racial group and each Asian ethnic subgroup. Binary logistic regression was used to determine the likelihood of high-risk characteristics and treatment when comparing Filipinos to other racial/ethnic groups. Kaplan-Meier Estimate was performed to evaluate thyroid cancer survival across all race/ethnicities. Multivariate Cox proportion hazards regression was performed to evaluate mortality risk from all causes of death by race. Results: There were 5,243 (5.35%) Filipino thyroid cancer cases in California from 1988 to 2018. Filipinos had the highest AAMR (1.22 deaths per 100,000) in 2015. Filipinos had a higher likelihood of Stage IV thyroid cancer compared with Non-Hispanic Whites, Non-Hispanic Blacks, Hispanics and nearly all Asian subgroups. Filipinos had a worse 5-year and 10-year overall survival (OS) than the combination of all other Asian/Pacific Islanders. Filipinos compared to Non-Hispanic Whites had significant mortality risk in overall and papillary thyroid cancer cases (Overall HR: 1.10, 95% CI 1.07-1.13, p < 0.0001, Papillary HR: 1.11, 95% CI 1.07-1.14, p < 0.0001) when adjusted for race/ethnicity, age, gender, socioeconomic status, and stage. When stratified by Charlson comorbidity score, Filipinos compared to Non-Hispanic Whites still had significant mortality risk (Charlson 0 HR: 1.07, 95% CI 1.02-1.11, p = 0.0017, Charlson 1+ HR: 1.07 95% CI 1.002-1.14, p = 0.0434). Conclusions: Filipino thyroid cancer patients have higher incidences of high-risk pathological features and greater AAMR and mortality risk. These findings warrant further investigation into better understanding the connection between the greater incidence of high-risk characteristics and increased mortality in Filipinos.

Molecular characterization of Kita-Kyushu lung cancer antigen (KK-LC-1) expressing carcinomas.

Cancer/testis antigens (CTAs) are strongly expressed in some solid tumors but minimally expressed in normal tissue, making them appealing therapeutic targets. KK-LC-1 (CXorf61) has cytoplasmic expression in gastric, breast, and lung cancer. We characterized the molecular subtypes of non-small cell lung cancer (NSCLC) expressing KK-LC-1 to inform rational clinical trials of T-cell receptor therapy (TCR-T) targeting KK-LC-1. 9790 NSCLC tumors that underwent whole transcriptome sequencing (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ) were analyzed. Tumors were split into quartiles based on KK-LC-1 expression and pathological and molecular differences were investigated. Adenocarcinoma had significantly higher KK-LC-1 expression than squamous cell carcinoma (median, 3.25 vs. 1.17 transcripts per million (TPM), p < 0.0001). Tumors with the highest quartile of KK-LC-1 expression had a greater proportion of tumors with high tumor mutation burden (TMB) (≥10 mutations per megabase; 44% vs. 28% in Q1, p < 0.001). Increased KK-LC-1 expression was associated with increased M1 macrophage abundance. Higher levels of KK-LC-1 expression were seen in pan-wild type and KRAS mutated tumors and associated with high TMB. TCR-T therapy directed against KK-LC-1 should be considered in patients whose clinical features reflect these characteristics.

Blood-Based Multi-Cancer Detection Using a Novel Variant Calling Assay (DEEPGENTM): Early Clinical Results.

This is an early clinical analysis of the DEEPGENTM platform for cancer detection. Newly diagnosed cancer patients and individuals with no known malignancy were included in a prospective open-label case-controlled study (NCT03517332). Plasma cfDNA that was extracted from peripheral blood was sequenced and data were processed using machine-learning algorithms to derive cancer prediction scores. A total of 260 cancer patients and 415 controls were included in the study. Overall, sensitivity for all cancers was 57% (95% CI: 52, 64) at 95% specificity, and 43% (95% CI: 37, 49) at 99% specificity. With 51% sensitivity and 95% specificity for all stage 1 cancers, the stage-specific sensitivities trended to improve with higher stages. Early results from this preliminary clinical, prospective evaluation of the DEEPGENTM liquid biopsy platform suggests the platform offers a clinically relevant ability to differentiate individuals with and without known cancer, even at early stages of cancer.

Impact of XPO1 mutations on survival outcomes in metastatic non-small cell lung cancer (NSCLC).

BACKGROUND: Nuclear protein transport is essential in guiding the traffic of important proteins and RNAs between the nucleus and cytoplasm. Export of proteins from the nucleus is mostly regulated by Exportin 1 (XPO1). In cancer, XPO1 is almost universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm. Currently, there are no studies evaluating XPO1 amplifications and mutations in NSCLC and the impact on outcomes. METHODS: Tumor samples were analyzed using next-generation sequencing (NGS) (NextSeq, 592 Genes), immunohistochemistry (IHC), and whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate. RESULTS: Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations and 24 had amplifications. XPO1 mutant tumors were more likely to have high TMB (79% vs. 52%, p = 0.007) and less likely to have high PD-L1 (32% vs. 68%, p = 0.03). KRAS co-mutations were seen in 19% (n = 5) and EGFR co-mutations were rare (n = 2). Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant. Comparison of survival between XPO1 mutant and WT showed a negative association with a hazard ratio (HR) of 1.932 (95% CI: 1.144-3.264 p = 0.012). XPO1 amplification was not associated with survival. CONCLUSIONS: XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted.

Characterization of KRAS Mutation Subtypes in Non-small Cell Lung Cancer.

KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS-mutated non-small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type.Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS-mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%).KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.

Trimodality vs Chemoradiation and Salvage Resection in cN2 Stage IIIA Non-Small Cell Lung Cancer.

To determine the overall survival (OS) in patients who underwent planned trimodality therapy (TMT) and those who underwent definitive concurrent chemoradiation (CRT), but later received salvage resection (SR) for stage IIIA (cN2) (AJCC 7th ed.) non-small cell lung cancer. National Cancer Database data set from 2004 to 2014 was queried. TMT was defined as multiagent CRT with dose >45 Gy, followed by lobectomy or pneumonectomy ≤90 days from end of CRT. SR was defined as multiagent CRT with dose >59 Gy and lobectomy or pneumonectomy performed >90 days from CRT completion. Propensity score weighting and propensity score matching methods were used to balance patient and tumor characteristics and to calculate hazard ratios. A total of 2025 (1899 TMT and 126 SR) patients were analyzed. TMT and SR groups shared similar characteristics. Surgery occurred at a median of 41 days (range 1-90) after CRT in the TMT group and 114 days (91-440) in the SR group. The 90-day mortality after surgery was 6.5% for TMT and 5% for SR (P = 0.43). The 3- and 5-year OS were 55.1% and 35.7% for TMT and 51.6% and 45.0% for SR (P = 0.92, 0.68), with no difference across unadjusted cohort and propensity-adjusted cohort. Patients with cN2 stage IIIA non-small cell lung cancer treated in the United States with definitive CRT followed by SR had similar OS as upfront TMT with similar postoperative mortality despite SR occurring >90 days after >59 Gy CRT. SR remains an option for medically appropriate patients after definitive dose CRT.

A Randomized Double-Blind Phase II Study of the Seneca Valley Virus (NTX-010) versus Placebo for Patients with Extensive-Stage SCLC (ES SCLC) Who Were Stable or Responding after at Least Four Cycles of Platinum-Based Chemotherapy: North Central Cancer Treatment Group (Alliance) N0923 Study.

INTRODUCTION: The Seneca Valley virus (NTX-010) is an oncolytic picornavirus with tropism for SCLC. This phase II double-blind, placebo-controlled trial evaluated NTX-010 in patients with extensive-stage (ES) SCLC after completion of first-line chemotherapy. METHODS: Patients with ES SCLC who did not progress after four or more cycles of platinum-based chemotherapy were randomized 1:1 to a single dose of NTX-010 or placebo within 12 weeks of chemotherapy. The primary end point was progression-free survival (PFS). A prespecified interim analysis for futility was performed after 40 events. Viral clearance and the development of neutralizing antibodies were followed. RESULTS: From January 15, 2010, to January 10, 2013, a total of 50 patients were randomized and received therapy on study (26 received NTX-010 and 24 received placebo). At the specified interim analysis, the median PFS was 1.7 months (95% confidence interval [CI]: 1.4-3.1 months) for the NTX-010 group versus 1.7 months (95% CI: 1.4-4.3 months) for the placebo group (hazard ratio = 1.03, p = 0.92), and the trial was terminated owing to futility. In the NTX-010 group, PFS was shorter in patients with detectable virus at days 7 and 14 versus in those in whom it was not detected after treatment (1.0 month [95% CI: 0.4-1.5 months] versus 1.8 months [95% CI: 1.3-5.5 months, p = 0.008] and 0.9 months [95% CI: 0.4-2.6 months] versus 1.3 months [95% CI: 1.0-5.3 months], respectively [p = 0.04]). CONCLUSIONS: Patients with ES SCLC did not benefit from NTX-010 treatment after chemotherapy with a platinum doublet. Persistence of NTX-010 in the blood 1 or 2 weeks after treatment was associated with a shorter PFS.