Mutations Associated With High-Grade irAEs in NSCLC Patients Receiving Immunotherapies.

OBJECTIVES: Compared to low-grade irAEs, high-grade irAEs are more often dose-limiting and can alter the long-term treatment options for a patient. Predicting the incidence of high-grade irAEs would help with treatment selection and therapeutic drug monitoring. MATERIALS AND METHODS: We performed a retrospective study of 430 stage III and IV patients with non-small cell lung cancer (NSCLC) who received an immune checkpoint inhibitor (ICI), either with or without chemotherapy, at a single comprehensive cancer center from 2015 to 2022. The study team retrieved sequencing data and complete clinical information, including detailed irAEs medical records. Fisher's exact test was used to determine the association between mutations and the presence or absence of high-grade irAEs. Patients were analyzed separately based on tumor subtypes and sequencing platforms. RESULTS: High-grade and low-grade irAEs occurred in 15.2% and 46.2% of patients, respectively. Respiratory and gastrointestinal irAEs were the 2 most common irAEs. The distribution of patients with or without irAEs was similar between ICI and ICI+chemotherapy-treated patients. By analyzing the mutation data, we identified 5 genes (MYC, TEK, FANCA, FAM123B, and MET) with mutations that were correlated with an increased risk of high-grade irAEs. For the adenocarcinoma subtype, mutations in TEK, MYC, FGF19, RET, and MET were associated with high-grade irAEs; while for the squamous subtype, ERBB2 mutations were associated with high-grade irAEs. CONCLUSION: This study is the first to demonstrate that specific tumor mutations correlate with the incidence of high-grade irAEs in patients with NSCLC treated with an ICI, providing molecular guidance for treatment selection and drug monitoring.

IASLC grading system predicts distant metastases for resected lung adenocarcinoma.

AIMS: The International Association for the Study of Lung Cancer (IASLC) has proposed a new histological grading system for invasive lung adenocarcinoma (LUAD). However, the efficacy of this grading system in predicting distant metastases in patients with LUAD remains unexplored. This study aims to assess the potential of the IASLC grading system in predicting the occurrence of brain and bone metastases in patients with resectable LUAD, thereby identifying individuals at high risk of post-surgery distant metastasis. METHODS: We retrospectively analysed clinical data and pathological reports of 174 patients with early-stage LUAD who underwent surgical resection between 2008 and 2015 at our cancer center. Patients were monitored for 5 years, and their bone and brain metastasis-free survival rates were determined. RESULTS: 28 out of 174 patients developed distant metastases in 5 years with a median overall survival of 60 months for metastasis-free patients and 38.3 months for patients with distant metastasis. Tumour grading of all samples was evaluated by both IASLC grading and predominant pattern-based grading systems. Receiver operating characteristic (ROC) curves were used to evaluate the predictive capabilities of the IASLC grading system and tumour stage for distant metastasis. Compared with the predominant pattern-based grading system, the IASLC grading system showed a better correlation with the incidence of distant metastasis and lymphovascular invasion. ROC analyses revealed that the IASLC grading system outperformed tumour stage in predicting distant metastasis. CONCLUSIONS: Our study indicates that the IASLC grading system is capable of predicting the incidence of distant metastasis among patients with early-stage invasive LUAD.

Tumor-intrinsic CDC42BPB confers resistance to anti-PD-1 immune checkpoint blockade in breast cancer.

Immune checkpoint blockade has been used to treat breast cancer, but the clinical responses remain relatively poor. We have used the CRISPR-Cas9 kinome knockout library consisting of 763 kinase genes to identify tumor-intrinsic kinases conferring resistance to anti-PD-1 immune checkpoint blockade. We have identified the CDC42BPB kinase as a potential target to overcome the resistance to anti-PD-1 immune checkpoint blockade immunotherapy. We found that CDC42BPB is highly expressed in breast cancer patients who are non-responsive to immunotherapy. Furthermore, a small-molecule pharmacological inhibitor, BDP5290, which targets CDC42BPB, synergized with anti-PD-1 and enhanced tumor cell killing by promoting T cell proliferation in both in vitro and in vivo assays. Moreover, anti-PD-1-resistant breast cancer cells showed higher expression of CDC42BPB, and its inhibition rendered the resistant cells more susceptible to T cell killing in the presence of anti-PD-1. We also found that CDC42BPB phosphorylated AURKA, which in turn upregulated PD-L1 through cMYC. Our results have revealed a robust link between tumor-intrinsic kinase and immunotherapy resistance and have provided a rationale for a unique combination therapy of CDC42BPB inhibition and anti-PD-1 immunotherapy for breast cancer.

Treatment Options for Brain Metastases.

OPINION STATEMENT: Therapies for brain metastasis continue to evolve as the life expectancies for patients have continued to prolong. Novel advances include the use of improved technology for radiation delivery, surgical guidance, and response assessment, along with systemic therapies that can pass through the blood brain barrier. With increasing complexity of treatments and the increased need for salvage treatments, multi-disciplinary management has become significantly more important.

Brain metastases from renal cell carcinoma: Effects of novel systemic agents on brain metastasis outcomes.

OBJECTIVE: The objective of this study was to examine survival outcomes in 136 patients with renal cell carcinoma with metastases to the brain who were treated with radiation combined with immunotherapy or tyrosine kinase inhibitor compared to those who were treated with radiation therapy alone. METHODS: The Wake Forest Gamma Knife prospective database was searched for all patients with renal cell carcinoma brain metastases. Outcome measurements included overall survival, determined via the Kaplan-Meier Method, and cumulative incidence of local and distant failure, determined using the Fine Gray competing risks analysis with death as a competing risk for the 136 patients included. RESULTS: Overall survival for the entire population at 6 months, 12 months, and 24 months was 67%, 47% and 30%, respectively. For the TKI (non-immunotherapy-treated) population (n = 37), overall survival was 75%, 61%, and 40% at 6 months, 12 months, and 24 months, respectively. For the immunotherapy-treated population (n = 35), overall survival was 85%, 64%, and 50% at 6 months, 12 months, and 24 months, respectively. Overall survival was significantly increased for patients who received radiation with either immunotherapy or TKI (p < 0.0001). CONCLUSION: Prior series of patients with brain metastases of multiple histologies have demonstrated an improvement in the local efficacy of stereotactic radiosurgery when combined with systemic agents. We found that patients treated with targeted agents and patients treated with immunotherapy demonstrated a trend towards improvement over patients treated in the era prior to the advent of either classes of novel therapies.

Delayed Imaging Changes 18 Months or Longer After Stereotactic Radiosurgery for Brain Metastases: Necrosis or Progression.

OBJECTIVE: Imaging changes after stereotactic radiosurgery (SRS) can occur for years after treatment, although the available data on the incidence of tumor progression and adverse radiation effects (ARE) are generally limited to the first 2 years after treatment. METHODS: A single-institution retrospective review was conducted of patients who had >18 months of imaging follow-up available. Patients who had ≥1 metastatic brain lesions treated with Gamma Knife SRS were assessed for the time to radiographic progression. Those with progression ≥18 months after the initial treatment were included in the present study. The lesions that progressed were characterized as either ARE or tumor progression based on the tissue diagnosis or imaging characteristics over time. RESULTS: The cumulative incidence of delayed imaging radiographic progression was 35% at 5 years after the initial SRS. The cumulative incidence curves of the time to radiographic progression for lesions determined to be ARE and lesions determined to be tumor progression were not significantly different statistically. The cumulative incidence of delayed ARE and delayed tumor progression was 17% and 16% at 5 years, respectively. Multivariate analysis indicated that the number of metastatic brain lesions present at the initial SRS was the only factor associated with late radiographic progression. CONCLUSIONS: The timing of late radiographic progression does not differ between ARE and tumor progression. The number of metastatic brain lesions at the initial SRS is a risk factor for late radiographic progression.

Use of comprehensive genomic profiling for biomarker discovery for the management of non-small cell lung cancer brain metastases.

Background: Clinical biomarkers for brain metastases remain elusive. Increased availability of genomic profiling has brought discovery of these biomarkers to the forefront of research interests. Method: In this single institution retrospective series, 130 patients presenting with brain metastasis secondary to Non-Small Cell Lung Cancer (NSCLC) underwent comprehensive genomic profiling conducted using next generation circulating tumor deoxyribonucleic acid (DNA) (Guardant Health, Redwood City, CA). A total of 77 genetic mutation identified and correlated with nine clinical outcomes using appropriate statistical tests (general linear models, Mantel-Haenzel Chi Square test, and Cox proportional hazard regression models). For each outcome, a genetic signature composite score was created by summing the total genes wherein genes predictive of a clinically unfavorable outcome assigned a positive score, and genes with favorable clinical outcome assigned negative score. Results: Seventy-two genes appeared in at least one gene signature including: 14 genes had only unfavorable associations, 36 genes had only favorable associations, and 22 genes had mixed effects. Statistically significant associated signatures were found for the clinical endpoints of brain metastasis velocity, time to distant brain failure, lowest radiosurgery dose, extent of extracranial metastatic disease, concurrent diagnosis of brain metastasis and NSCLC, number of brain metastases at diagnosis as well as distant brain failure. Some genes were solely associated with multiple favorable or unfavorable outcomes. Conclusion: Genetic signatures were derived that showed strong associations with different clinical outcomes in NSCLC brain metastases patients. While these data remain to be validated, they may have prognostic and/or therapeutic impact in the future. Statement of translation relevance: Using Liquid biopsy in NSCLC brain metastases patients, the genetic signatures identified in this series are associated with multiple clinical outcomes particularly these ones that lead to early or more numerous metastases. These findings can be reverse-translated in laboratory studies to determine if they are part of the genetic pathway leading to brain metastasis formation.

Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial.

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

Single-cell sequencing reveals the landscape of the human brain metastatic microenvironment.

Brain metastases is the most common intracranial tumor and account for approximately 20% of all systematic cancer cases. It is a leading cause of death in advanced-stage cancer, resulting in a five-year overall survival rate below 10%. Therefore, there is a critical need to identify effective biomarkers that can support frequent surveillance and promote efficient drug guidance in brain metastasis. Recently, the remarkable breakthroughs in single-cell RNA-sequencing (scRNA-seq) technology have advanced our insights into the tumor microenvironment (TME) at single-cell resolution, which offers the potential to unravel the metastasis-related cellular crosstalk and provides the potential for improving therapeutic effects mediated by multifaceted cellular interactions within TME. In this study, we have applied scRNA-seq and profiled 10,896 cells collected from five brain tumor tissue samples originating from breast and lung cancers. Our analysis reveals the presence of various intratumoral components, including tumor cells, fibroblasts, myeloid cells, stromal cells expressing neural stem cell markers, as well as minor populations of oligodendrocytes and T cells. Interestingly, distinct cellular compositions are observed across different samples, indicating the influence of diverse cellular interactions on the infiltration patterns within the TME. Importantly, we identify tumor-associated fibroblasts in both our in-house dataset and external scRNA-seq datasets. These fibroblasts exhibit high expression of type I collagen genes, dominate cell-cell interactions within the TME via the type I collagen signaling axis, and facilitate the remodeling of the TME to a collagen-I-rich extracellular matrix similar to the original TME at primary sites. Additionally, we observe M1 activation in native microglial cells and infiltrated macrophages, which may contribute to a proinflammatory TME and the upregulation of collagen type I expression in fibroblasts. Furthermore, tumor cell-specific receptors exhibit a significant association with patient survival in both brain metastasis and native glioblastoma cases. Taken together, our comprehensive analyses identify type I collagen-secreting tumor-associated fibroblasts as key mediators in metastatic brain tumors and uncover tumor receptors that are potentially associated with patient survival. These discoveries provide potential biomarkers for effective therapeutic targets and intervention strategies.

Fertilización asistida con óvulos propios en mujeres mayores de 40 años: indicaciones y resultados

Las mujeres posponen su maternidad por el deseo de superación personal y profesional. Se conoce que la cantidad y calidad de los óvulos por ciclo dependen de la edad de la paciente. Las tasas de éxito en tratamientos de reproducción asistida disminuyen con la edad, especialmente después de los 40 años. Se observan tasas más altas de nacidos vivos en mujeres más jóvenes y las tasas disminuyen significativamente en mujeres mayores debido a la disminución de la fertilidad y el aumento de abortos espontáneos. Por ello, la edad es crucial al evaluar la posibilidad de un embarazo exitoso mediante tratamientos de reproducción asistida (TRA). Las indicaciones para realizar fertilización in vitro (FIV) con óvulos propios en mujeres mayores de 40 años incluyen iniciar lo más pronto procedimientos de alta complejidad, buena evaluación de la reserva ovárica con análisis de la hormona antimülleriana y conteo de folículos antrales para realizar asesoramiento genético, proponer FIV-inyección intracitoplasmática de espermatozoides (ICSI) antes de los 44 años, generar expectativas realistas y realizar consentimiento informado, con estadisticas propias. En la REDLARA, de todos los procedimientos de FIV-ICSI, el 34% de las pacientes tienen más de 40 años; se prefiere transferir blastocistos con prueba genética preimplantacional de aneuploidías (PGT-A) para seleccionar embriones euploides. Las tasas de éxito son bajas, inclusive cuando son tasas de embarazo por transferencia de un embrión en el grupo de mujeres ≥ 40 años (18,2% sin PGT, 42,7% con PGT en el IMRCRP). Se recomienda acumular óvulos o embriones realizando múltiples estimulaciones ováricas. Se debe optar por transferir un solo embrión para evitar complicaciones obstétricas con embarazos múltiples en pacientes ≥ 40 años, por el alto riesgo debido a la edad.

Women postpone motherhood because of their desire for personal and professional improvement. It is known that the quantity and quality of oocytes per cycle depends on the patient's age. Success rates in assisted reproduction treatments decrease with age, especially after 40 years of age. Higher live birth rates are observed in younger women, and rates decrease significantly in older women due to decreased fertility and increased miscarriages. Therefore, age is crucial when assessing the possibility of a successful pregnancy through assisted reproductive treatments (ART). The indications to perform in vitro fertilization (IVF) with own ovules in women older than 40 years include starting as soon as possible highly complex procedures, good evaluation of ovarian reserve with antimüllerian hormone analysis (AMH) and antral follicle count (AFC) for genetic counseling, proposing IVF-intracytoplasmatic sperm injection (ICSI) before the age of 44 years, generating realistic expectations and informed consent, with own statistics. At REDLARA, of all IVF-ICSI procedures, 34% of patients are over 40 years old; preference is given to transfer blastocysts with preimplantation genetic testing for aneuploidy (PGT-A) to select euploid embryos. Success rates are low, even when they are pregnancy rates per embryo transfer in the group of women ≥ 40 years (18.2% without PGT, 42.7% with PGT in IMRCRP). It is recommended to bank ovules or embryos by performing multiple ovarian stimulations. A single embryo transfer should be chosen to avoid obstetric complications with multiple pregnancies in patients ≤ 40 years, because of the high risk due to age.

c-Met Mediated Cytokine Network Promotes Brain Metastasis of Breast Cancer by Remodeling Neutrophil Activities.

The brain is one of the most common metastatic sites among breast cancer patients, especially in those who have Her2-positive or triple-negative tumors. The brain microenvironment has been considered immune privileged, and the exact mechanisms of how immune cells in the brain microenvironment contribute to brain metastasis remain elusive. In this study, we found that neutrophils are recruited and influenced by c-Met high brain metastatic cells in the metastatic sites, and depletion of neutrophils significantly suppressed brain metastasis in animal models. Overexpression of c-Met in tumor cells enhances the secretion of a group of cytokines, including CXCL1/2, G-CSF, and GM-CSF, which play critical roles in neutrophil attraction, granulopoiesis, and homeostasis. Meanwhile, our transcriptomic analysis demonstrated that conditioned media from c-Met high cells significantly induced the secretion of lipocalin 2 (LCN2) from neutrophils, which in turn promotes the self-renewal of cancer stem cells. Our study unveiled the molecular and pathogenic mechanisms of how crosstalk between innate immune cells and tumor cells facilitates tumor progression in the brain, which provides novel therapeutic targets for treating brain metastasis.

Prognostic Mutational Signatures of NSCLC Patients treated with chemotherapy, immunotherapy and chemoimmunotherapy.

Different types of therapy are currently being used to treat non-small cell lung cancer (NSCLC) depending on the stage of tumor and the presence of potentially druggable mutations. However, few biomarkers are available to guide clinicians in selecting the most effective therapy for all patients with various genetic backgrounds. To examine whether patients' mutation profiles are associated with the response to a specific treatment, we collected comprehensive clinical characteristics and sequencing data from 524 patients with stage III and IV NSCLC treated at Atrium Health Wake Forest Baptist. Overall survival based Cox-proportional hazard regression models were applied to identify mutations that were "beneficial" (HR < 1) or "detrimental" (HR > 1) for patients treated with chemotherapy (chemo), immune checkpoint inhibitor (ICI) and chemo+ICI combination therapy (Chemo+ICI) followed by the generation of mutation composite scores (MCS) for each treatment. We also found that MCS is highly treatment specific that MCS derived from one treatment group failed to predict the response in others. Receiver operating characteristics (ROC) analyses showed a superior predictive power of MCS compared to TMB and PD-L1 status for immune therapy-treated patients. Mutation interaction analysis also identified novel co-occurring and mutually exclusive mutations in each treatment group. Our work highlights how patients' sequencing data facilitates the clinical selection of optimized treatment strategies.

Five-year survivors from brain metastases treated with stereotactic radiosurgery: Biology, improving treatments, or just plain luck?

Background: Improvements in therapies have led to an increasing number of long-term survivors of brain metastases. The present series compares a population of 5-year survivors of brain metastases to a generalized brain metastases population to assess for factors attributable to long-term survival. Methods: A single institution retrospective review was performed to identify 5-year survivors of brain metastases who received stereotactic radiosurgery (SRS). A historical control population of 737 patients with brain metastases was used to assess similarities and differences between the long-term survivor population and the general population treated with SRS. Results: A total of 98 patients with brain metastases were found to have survived over 60 months. No differences between long-term survivors and controls were identified with regards to the age at first SRS (P = .19), primary cancer distribution (P = .80), and the number of metastases at first SRS (P = .90). Cumulative incidence of neurologic death at 6, 8 and 10 years for the long-term survivor cohort was 4.8%, 16%, and 16% respectively. In the historical controls, cumulative incidence of neurologic death reached a plateau at 40% after 4.9 years. A significant difference in the distribution of burden of disease at the time of the first SRS was found between the 5-year survivors and the control (P = .0049). 58% of 5-year survivors showed no evidence of clinical disease at the last follow-up. Conclusion: Five-year survivors of brain metastases represent a diverse histologic population, suggesting a small population of oligometastatic and indolent cancers exist for each cancer type.

Modulation of oxidative phosphorylation and mitochondrial biogenesis by cigarette smoke influence the response to immune therapy in NSCLC patients.

The treatment regimen of non-small cell lung cancer (NSCLC) has drastically changed owing to the superior anti-cancer effects generated by the immune-checkpoint blockade (ICB). However, only a subset of patients experience benefit after receiving ICBs. Therefore, it is of paramount importance to increase the response rate by elucidating the underlying molecular mechanisms and identifying novel therapeutic targets to enhance the efficacy of IBCs in non-responders. We analyzed the progression-free survival (PFS) and overall survival (OS) of 295 NSCLC patients who received anti-PD-1 therapy by segregating them with multiple clinical factors including sex, age, race, smoking history, BMI, tumor grade and subtype. We also identified key signaling pathways and mutations that are enriched in patients with distinct responses to ICB by gene set enrichment analysis (GSEA) and mutational analyses. We found that former and current smokers have a higher response rate to anti-PD-1 treatment than non-smokers. GSEA results revealed that oxidative phosphorylation (OXPHOS) and mitochondrial related pathways are significantly enriched in both responders and smokers, suggesting a potential role of cellular metabolism in regulating immune response to ICB. We also demonstrated that all-trans retinoic acid (ATRA) which enhances mitochondrial function significantly enhanced the efficacy of anti-PD-1 treatment in vivo. Our clinical and bioinformatics based analyses revealed a connection between smoking induced metabolic switch and the response to immunotherapy, which can be the basis for developing novel combination therapies that are beneficial to never smoked NSCLC patients.

Collagen deposition within brain metastases is associated with leptomeningeal failure after cavity-directed radiosurgery.

Background: Leptomeningeal failure (LMF) represents a devastating progression of disease following resection of brain metastases (BrM). We sought to identify a biomarker at time of BrM resection that predicts for LMF using mass spectrometry-based proteomic analysis of resected BrM and to translate this finding with histochemical assays. Methods: We retrospectively reviewed 39 patients with proteomic data available from resected BrM. We performed an unsupervised analysis with false discovery rate adjustment (FDR) to compare proteomic signature of BrM from patients that developed LMF versus those that did not. Based on proteomic analysis, we applied trichrome stain to a total of 55 patients who specifically underwent resection and adjuvant radiosurgery. We used competing risks regression to assess predictors of LMF. Results: Of 39 patients with proteomic data, FDR revealed type I collagen-alpha-1 (COL1A1, P = .045) was associated with LMF. The degree of trichrome stain in each block correlated with COL1A1 expression (ß = 1.849, P = .001). In a cohort of 55 patients, a higher degree of trichrome staining was associated with an increased hazard of LMF in resected BrM (Hazard Ratio 1.58, 95% CI 1.11-2.26, P = .01). Conclusion: The degree of trichrome staining correlated with COL1A1 and portended a higher risk of LMF in patients with resected brain metastases treated with adjuvant radiosurgery. Collagen deposition and degree of fibrosis may be able to serve as a biomarker for LMF.

Team-Based Hospice Referrals: A Potential Quality Metric for Lung Cancer in the Immunotherapy Era.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can lead to durable responses in patients with lung cancer but may delay transitions to hospice at the end of life (EOL). We aimed to test the association of continuity of care with EOL outcomes in the ICI era. METHODS: We collected retrospective data on all patients with lung cancer who started ICI treatment at a single comprehensive cancer center in the United States (1/1/14-5/1/18) and subsequently died. We defined a hospice referral as having continuity of care if placed by a provider from the patient's multidisciplinary cancer team (e.g., a medical oncologist, palliative care specialist, intensivist, and hospitalist). RESULTS: In this cohort of 143 patients, 58% had a team-based hospice referral which was associated with a lower risk of death in the hospital. The most common reason patients declined hospice at EOL was an unwillingness to discontinue cancer-directed therapy. As compared to a similar historical cohort of patients treated with chemotherapy alone (2008-2010), there was a similar rate of hospice referral (68% vs 74%) but higher rates of new systemic therapy initiated within 30 days of death (17% vs 6%, p .001) and last dose within 14 days of death (13% vs 5%, p .005). CONCLUSIONS: Future studies should test the continuity of care at EOL as a new quality metric for advanced NSCLC.

Long term survivors of stereotactic radiosurgery for brain metastases: do distant brain failures reach a plateau and what factors are associated with a brain metastasis velocity of zero?

PURPOSE: Life expectancy continues to increase for patients with brain metastases treated with stereotactic radiosurgery (SRS). The present study sought to retrospectively analyze brain metastasis patients who have survived 2 years or more, and assess for what factors may predict for a final brain metastasis velocity (BMV) of zero. METHODS: This was a single-institution retrospective study of 300 patients treated with SRS from 2001 to 2019 for brain metastases who survived greater than 2 years after first SRS. Final BMV is calculated by summing all metastases through the observed time divided by the total time in years. A BMV of zero is defined as at least 2 years of imaging follow-up without distant brain failure (DBF). RESULTS: Median age at first SRS is 61 (IQR: 53, 70). Kaplan-Meier estimated median overall survival is 4.9 years and time to DBF is 1.5 years (95% CI 1.2, 2.0). Twenty-eight (9.3%) patients underwent subsequent WBRT. One hundred and one (33.7%) patients never had any further brain metastases (BMV = 0) at a median follow-up time of 3.3 years. Median BMV is 0.4 (IQR: 0, 1.4). Distant brain failures reach a plateau at 4 years where the cumulative incidence of DBF is 82%. 70% of first time DBFs have occurred by 2 years. Factors significantly associated with a BMV of zero include fewer brain metastases at first SRS (HR 1.1; p = 0.0004) and Caucasian race (HR 1.5; p = 0.03). CONCLUSION: Approximately one third of brain metastasis patients who live beyond 2 years after initial SRS have a BMV of zero. DBFs appear to reach a plateau at 4 years. Factors significantly associated with a BMV of zero include Caucasian race and having had a single brain metastasis at first SRS.

Upfront immunotherapy leads to lower brain metastasis velocity in patients undergoing stereotactic radiosurgery for brain metastases.

Background: While immunotherapy has been shown to improve survival and decrease neurologic death in patients with brain metastases, it remains unclear whether this improvement is due to prevention of new metastasis to the brain. Method: We performed a retrospective review of patients presenting with brain metastases simultaneously with the first diagnosis of metastatic disease and were treated with upfront immunotherapy as part of their treatment regimen and stereotactic radiosurgery (SRS) to the brain metastases. We compared this cohort with a historical control population (prior to the immunotherapy era) who were treated with pre-immunotherapy standard of care systemic therapy and with SRS to the brain metastases. Results: Median overall survival time was improved in the patients receiving upfront immunotherapy compared to the historical cohort (48 months vs 8.4 months, p=0.001). Median time to distant brain failure was statistically equivalent (p=0.3) between the upfront immunotherapy cohort and historical control cohort (10.3 vs 12.6 months). Brain metastasis velocity was lower in the upfront immunotherapy cohort (median 3.72 metastases per year) than in the historical controls (median 9.48 metastases per year, p=0.001). Cumulative incidence of neurologic death at one year was 12% in the upfront immunotherapy cohort and 28% in the historical control cohort (p=0.1). Conclusions: Upfront immunotherapy appears to improve overall survival and decrease BMV compared to historical controls. While these data remain to be validated, they suggest that brain metastasis patients may benefit from concurrent immunotherapy with SRS.

Military exposures and lung cancer in United States veterans.

Lung cancer screening begins at age 50, with yearly low dose computed tomography (LDCT) scans until age 80, for patients determined to be high risk due to tobacco smoking. Veterans serving from World War II to the Gulf War are now at the age where LDCT is recommended. This recommendation from the United States Preventative Service Task Force includes patients who have a 20-pack year tobacco history and currently smoke or quit within the last 15 years. This recommendation does not consider additional risk factors such as exposures to lung carcinogens. We discuss unique operational and occupational exposures encountered while serving in the armed forces, which may potentially increase the risk of lung cancers in the Veteran population. The additional risk of lung cancer due to military exposure history is unclear and more work is needed to identify and quantify risk at an individual level. Increasing awareness at the provider level regarding the carcinogenic exposures encountered may allow a larger population of Veterans, not meeting traditional LDCT criteria, to benefit from lung cancer screening.