5-Hydroxymethylcytosine in Cell-Free DNA Predicts Immunotherapy Response in Lung Cancer.

Immune checkpoint inhibitors (ICIs) drastically improve therapeutic outcomes for lung cancer, but accurately predicting individual patient responses to ICIs remains a challenge. We performed the genome-wide profiling of 5-hydroxymethylcytosine (5hmC) in 85 plasma cell-free DNA (cfDNA) samples from lung cancer patients and developed a 5hmC signature that was significantly associated with progression-free survival (PFS). We built a 5hmC predictive model to quantify the 5hmC level and validated the model in the validation, test, and control sets. Low weighted predictive scores (wp-scores) were significantly associated with a longer PFS compared to high wp-scores in the validation [median 7.6 versus 1.8 months; p = 0.0012; hazard ratio (HR) 0.12; 95% confidence interval (CI), 0.03-0.54] and test (median 14.9 versus 3.3 months; p = 0.00074; HR 0.10; 95% CI, 0.02-0.50) sets. Objective response rates in patients with a low or high wp-score were 75.0% (95% CI, 42.8-94.5%) versus 0.0% (95% CI, 0.0-60.2%) in the validation set (p = 0.019) and 80.0% (95% CI, 44.4-97.5%) versus 0.0% (95% CI, 0.0-36.9%) in the test set (p = 0.0011). The wp-scores were also significantly associated with PFS in patients receiving single-agent ICI treatment (p < 0.05). In addition, the 5hmC predictive signature demonstrated superior predictive capability to tumor programmed death-ligand 1 and specificity to ICI treatment response prediction. Moreover, we identified novel 5hmC-associated genes and signaling pathways integral to ICI treatment response in lung cancer. This study provides proof-of-concept evidence that the cfDNA 5hmC signature is a robust biomarker for predicting ICI treatment response in lung cancer.

Cell-Free DNA 5-Hydroxymethylcytosine Signatures for Lung Cancer Prognosis.

Accurate prognostic markers are essential for guiding effective lung cancer treatment strategies. The level of 5-hydroxymethylcytosine (5hmC) in tissue is independently associated with overall survival (OS) in lung cancer patients. We explored the prognostic value of cell-free DNA (cfDNA) 5hmC through genome-wide analysis of 5hmC in plasma samples from 97 lung cancer patients. In both training and validation sets, we discovered a cfDNA 5hmC signature significantly associated with OS in lung cancer patients. We built a 5hmC prognostic model and calculated the weighted predictive scores (wp-score) for each sample. Low wp-scores were significantly associated with longer OS compared to high wp-scores in the training [median 22.9 versus 8.2 months; p = 1.30 × 10-10; hazard ratio (HR) 0.04; 95% confidence interval (CI), 0.00-0.16] and validation (median 18.8 versus 5.2 months; p = 0.00059; HR 0.22; 95% CI: 0.09-0.57) sets. The 5hmC signature independently predicted prognosis and outperformed age, sex, smoking, and TNM stage for predicting lung cancer outcomes. Our findings reveal critical genes and signaling pathways with aberrant 5hmC levels, enhancing our understanding of lung cancer pathophysiology. The study underscores the potential of cfDNA 5hmC as a superior prognostic tool for guiding more personalized therapeutic strategies for lung cancer patients.

A Phase 2 Study of In Situ Oncolytic Virus Therapy and Stereotactic Body Radiation Therapy Followed by Pembrolizumab in Metastatic Non-Small Cell Lung Cancer.

PURPOSE: A phase 2 study of stereotactic body radiation therapy (SBRT) and in situ oncolytic virus therapy in metastatic non-small cell lung cancer (mNSCLC) followed by pembrolizumab (STOMP) was designed to explore the dual approach in enhancing single pembrolizumab with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mNSCLC. METHODS AND MATERIALS: STOMP is a single-arm, open-label phase 2 study. Patients with mNSCLC received intratumoral injections of ADV/HSV-tk (5 × 1011 vp) and SBRT (30 Gy in 5 fractions) followed by pembrolizumab 200 mg IV every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was overall response rate (ORR) (complete response [CR] and partial response [PR]). Secondary endpoints included clinical benefit rate (CBR) (CR, PR and stable disease [SD]), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 28 patients were enrolled, of whom 27 were evaluated for response. The ORR was 33.3%, including 2 CR (7.4%) and 7 PR (25.9%). CBR was 70.4%. Six of eight (75.0%) patients who were immune checkpoint inhibitor (ICI) refractory derived clinical benefits. Responders had durable responses with median PFS, and OS not reached. The entire cohort had a median PFS of 7.4 months (95% CI, 5.1-9.6 months), and median OS of 18.1 months (95% CI, 15.4-20.9 months). The combination was well tolerated, with grade 3 or higher toxicity in 6 (21.4%) patients. CONCLUSIONS: The dual approach of in situ ADV/HSV-tk plus valacyclovir gene therapy and SBRT as a chemotherapy-sparing strategy to enhance the antitumor effect of pembrolizumab is a well-tolerated encouraging treatment in patients with mNSCLC.

Incidence and outcome of immune checkpoint-induced pneumonitis in oncology patients with history of pulmonary disease.

Background: Immune checkpoint-induced pneumonitis (ICIP) is one of the most fatal adverse events caused by immune checkpoint inhibitors (ICI) and accounts for 35% of anti-PD-[L]1-related deaths. Risk factors including thoracic radiation and use of EGFR tyrosine kinase inhibitors have been identified as contributors to ICIP development. However, there has been very limited information on obstructive pulmonary disease as a risk factor. Objective: The purpose of this study is to evaluate the incidence and management of ICIP in a cohort of patients with pre-existing obstructive pulmonary disease. Methods: This retrospective, descriptive study, includes data from 139 patients between January 1, 2017 and August 31, 2022. Patients included were adult patients 18 years or older, received at least 2 cycles of an immune checkpoint inhibitor, and had a history of an obstructive pulmonary disorder prior to administration. Patients were excluded if they had literature-established risk factors for pneumonitis. Results: The incidence of ICIP was 7.19% (10 out of 139 patients). From a management perspective, 90% of patients had immunotherapy held, 40% received oral steroids, and 70% received intravenous steroids at the time of ICIP identification. After receiving treatment for the initial episode of ICIP, 6 patients restarted immunotherapy and 3 (50%) subsequently experienced a recurrent episode. One patient experienced grade 4 ICIP event and subsequently died from respiratory failure attributed to ICIP. Conclusion: These findings indicate that a pre-existing history of an obstructive pulmonary disorder may be a risk factor for the development of ICIP and subsequent recurrence of ICIP when rechallenged.

Lung adenocarcinoma in a patient with Lynch syndrome: a case report and literature review.

This article presents a case of a 62-year-old Vietnamese woman with a history of Lynch syndrome (LS), who developed lung adenocarcinoma with EGFR L858R mutation. LS is an autosomal dominant cancer predisposition syndrome caused by a pathogenic germline variant in DNA mismatch repair genes, often leading to microsatellite instability. While LS is primarily associated with gastrointestinal, endometrial, ovarian, and urologic tract cancers, lung cancer accounts for less than 1% of LS-related cancers, with only six cases of LS-related lung cancer previously reported in the literature. The patient underwent multiple lines of treatment for her lung adenocarcinoma, including tyrosine kinase inhibitors, stereotactic body radiation therapy, pemetrexed and pembrolizumab, amivantamab, and fam-trastuzumab deruxtecan, but all resulted in only a partial response followed by a progressive disease. This case highlights the complex interplay of genetic cancer predisposition syndromes and the development of spontaneous driver mutations in the disease course and the subsequent management of tumors arising in these patients.

Treatment at Twilight: An Analysis of Therapy Patterns and Outcomes in Adults 80 Years and Older With Advanced or Metastatic NSCLC.

Introduction: The aim of this study is to evaluate treatment patterns, survival outcomes, and factors influencing systemic treatment decisions in adults 80 years and older with NSCLC. Methods: This was a retrospective National Cancer Database study evaluating outcomes in adults aged 80 years and older with advanced NSCLC. Patients were analyzed on the basis of systemic therapy, including none, chemotherapy or immunotherapy (IO) alone, and chemotherapy plus IO (chemotherapy + IO). Median overall survival (OS) was compared using Kaplan-Meier methodology. Hazard ratio with 95% confidence interval (CI) was used to assess differences in outcomes, and OR with 95% CI was used to assess factors contributing to systemic therapy provision. Results: Patients 80 years and older (OR = 1.135 [95% CI: 1.127-1.142], p = 0.000), females (OR = 1.129 [95% CI: 1.085-1.175], p < 0.001), blacks (OR = 1.272 [95% CI: 1.179-1.372], p < 0.001), non-Hispanic whites (OR = 1.210 [95% CI: 1.075-1.362], p = 0.002), and those with increasing Charlson-Deyo Comorbidity Index score (p < 0.001) were less likely to receive systemic therapy. Median OS for no therapy, IO alone, chemotherapy alone, and chemotherapy plus IO was 2.63 (95% CI: 2.57-2.69), 10.68 (95% CI: 9.96-11.39), 12.35 (95% CI: 11.98-12.72), and 14.03 (95% CI: 13.87-14.88) months, respectively. In chemotherapy alone, mean OS was 1.12 months (95% CI: 0.55-1.70) (p < 0.001) longer with multiagent versus single agent. There was no difference between IO plus single agent versus IO plus multiagent chemotherapy (0.67 mo [95% CI -1.18 to 2.54], p = 1.00). Conclusions: Age, comorbidities, patient race, and sex affected systemic therapy provision. Multiagent chemotherapy and chemotherapy plus IO significantly improved survival; with the latter, survival was similar with IO plus single or multiagent chemotherapy.

Climate Change and Cancer Care-Feeling the Heat.

This Viewpoint describes how climate change and air pollution markedly affect cancer incidence, care delivery, and patient outcomes.

Multiplying Brown Spots.

PURPOSE: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a paraneoplastic syndrome affecting the eye that is a sign of poor prognosis of underlying malignancy.This is the first documented case to show serial and sustained improvement of BDUMP following immunotherapy in the setting of primary non-small cell carcinoma of the lung. OBSERVATIONS: A 65-year-old man reported a gradual decrease in vision and floaters in the right eye after cataract surgery. Fundus examination demonstrated diffuse multiple brown subretinal lesions bilaterally. Next generation sequencing of melanocytic tissue of the patient described in this case revealed a specific RB1 c.411A>T (p.Glu137Asp) variant with an allele frequency of 44.8%, consistent with heterozygosity. Plasma samples from the patient and a control patient with no history of cancer and/or paraneoplastic syndrome were cultured with neonatal melanocytes, which revealed a greater than 180% increase in proliferation of normal neonatal melanocytes compared to the control. Pembrolizumab therapy was initiated which resulted in shrinkage and stabilization of the lesions documented in serial diagnostic testing. CONCLUSIONS: In conclusion, we report a cytologically and serologically confirmed case of BDUMP in a patient with a primary non-small cell carcinoma of the lung. Next generation sequencing of melanocytic tissue of the patient described in this case revealed a specific RB1c.411A>T (p.Glu137Asp) variant with an allele frequency of 44.8%, consistent with heterozygosity. Furthermore, we show documented serial improvement in the patient's ocular and systemic disease with treatment. This case as one of the longest surviving confirmed cases of a patient with BDUMP.

Lung Cancer Screening Eligibility and Referral Practices in Texas Organizations Serving People with Substance Use Disorders.

For people at elevated risk for lung cancer, lung cancer screening (LCS) reduces lung cancer mortality. People with non-nicotine substance use disorders (SUDs) have elevated rates of smoking compared with the general population, highlighting them as a priority population for LCS consideration. Although research has shown LCS is underutilized, there is little literature to inform whether organizations that serve individuals with SUDs have existing clinical protocols surrounding LCS. In the current study, we examine the LCS eligibility and referral practices among these organizations. We conducted a statewide needs assessment survey in 2021 to discern how tobacco use was being addressed at Texas organizations that provide treatment or services to individuals with SUDs. Respondents were asked to report on their center's LCS eligibility and referral practices. The analytic sample consists of 125 respondents who represented 23 federally qualified health centers, 29 global local mental health authorities (LMHAs), 12 substance use treatment programs in LMHAs, and 61 standalone substance use treatment centers. Very few respondents indicated that healthcare providers at their center made referrals to LCS for patients (8.8%); a few respondents indicated that their healthcare providers assessed patients' eligibility for LCS but did not make referrals (3.2%). Intervention and implementation efforts are needed in these and other SUD healthcare settings to bolster organizational capacity and ensure that patients are being navigated to lung cancer screening at multiple touch points across the care continuum.

A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer.

PURPOSE: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. PATIENTS AND METHODS: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. RESULTS: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. CONCLUSIONS: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

Metastatic pulmonary carcinoids with EML4-ALK fusion response to ALK inhibitors: two case reports and review of literature.

Background: Pulmonary carcinoids (PC), including typical (TC) and atypical carcinoids (AC), are low-grade neuroendocrine tumors (NETs) which account for 1-5% of all lung tumors. Due to the low prevalence of PC and extreme rarity of anaplastic lymphoma kinase (ALK) rearrangements in patients with PC, the advances in targeted therapy development in PC are still limited and there is no standard treatment. Even though in patients with PC harboring ALK rearrangements there is a room for a success in targeted therapy. To our knowledge, case 1 was the first report to detect ALK gene p.I1171N mutation after taking alectinib and sensitive to ceritinib in patients with atypical carcinoid. Case Description: Herein, we report the cases of 2 non-smoking patients, 51 year-old female with tumor in left lower lobe and 49 year-old female with tumor in right upper lobe, both with metastatic PC who harbored EML4-ALK fusion and were sensitive to small-molecule ALK inhibitors. The first patient initially received alectinib, then therapy was switched to ceritinib after developing drug resistance due to the missense mutation of ALK gene p.I1171N mutation in exon 22 detected by next-generation sequencing (NGS), and finally died of intracranial disease progression. The second patient also received alectinib, and her treatment is currently ongoing with good effect and tolerance. After conducting comprehensive review of literature, we found that 14 lung NETs with ALK rearrangements have been reported to date. The clinical outcome was partial response for 6 NETs patients and 5 patients exhibited stable disease after treatment with ALK inhibitors. Conclusions: According to the effectiveness of ALK inhibitors in our cases and previous articles, we recommend alectinib for the first-line treatment of metastatic PC with EML4-ALK fusion and highlight the need for molecular profiling of metastatic lung NETs patients and that ALK inhibitors are feasible in the treatment for metastatic lung NETs patients with ALK rearrangements. Finally, further studies to assess the real prevalence of ALK gene fusions and their spectrum of sensitivity to different ALK inhibitors are needed in larger cohorts.

Molecular Signatures of KRAS-Mutated Lung Adenocarcinoma: Analysis of Concomitant EGFR, ALK, STK11, and PD-L1 Status.

Background: KRAS mutations are the most common oncogenic driver mutations of non-small cell lung cancer (NSCLC) in the Western world. Mutations of the KRAS gene are most prevalent in the patient population of current and former cigarette smokers. With the recent pivotal approval of a targeted inhibitor therapy for patients with KRAS p.G12C mutated and pretreated NSCLC, analysis of the heterogeneity of KRAS mutations and concomitant molecular alterations in patients with these tumors at all clinical stages is indicated. Methods: In this retrospective analysis, patient pathology records were reviewed for all cases receiving a pathologic diagnosis of NSCLC within our hospital system. All data were collected with IRB approval. Cases of indeterminate tumor type favoring a non-lung primary, as well as non-adenocarcinoma NSCLC (eg, squamous) were excluded from the cohort. In this hospital system, molecular testing for KRAS mutations is part of a molecular biomarker panel that is reflex ordered at initial diagnosis by the pathologist and may be performed as a single gene test or as a solid organ cancer hotspot panel by next generation sequencing. For each patient, KRAS mutational status and specific KRAS mutations, if present, were collated. Additional information assessed for this study included patient demographics (age, gender, and smoking history), tumor staging if available, PD-L1 expression levels by immunohistochemistry (IHC), and the presence of other genetic alterations (EGFR, ALK, and STK11). Results: Between January 1, 2017 and January 1, 2019, there were 276 patients diagnosed with NSCLC of all stages who had KRAS mutational analysis performed in our hospital system and who met the criteria for inclusion into the study cohort. A KRAS driver mutation was detected in 29% of these patients. The most frequently identified KRAS mutation was p.G12C (38%), followed by p.G12D (21%) and p.G12V (13%). KRAS-mutated lung adenocarcinoma was significantly associated with current or former patient smoking status in this cohort (29/202 (14%) smokers and 1/74 (1%) non-smokers; P = .0006). PD-L1 expression of at least 1% by IHC was present in 43% of KRAS-mutated lung adenocarcinomas and 45% of non-KRAS-mutated adenocarcinomas. In this study, KRAS mutations were not found to co-occur with gene alterations in EGFR, ALK, or STK11. In 48% of cases, at least one genetic alteration (KRAS, ALK, EGFR, or STK11) was identified. Conclusions: In this study cohort, KRAS-mutated lung adenocarcinoma demonstrated significant mutational heterogeneity, which is consistent with previously published studies. KRAS mutational status was also significantly associated with a current or former smoking history. Notably, p.G12C was the most frequently identified KRAS mutation in this cohort, with a frequency of 38%. This finding is particularly relevant given the recent approval of a KRAS p.G12C-specific targeted inhibitor therapy and the continued development of additional KRAS targeted therapies that may prove effective in treating NSCLC. These findings also highlight the necessity of considering molecular testing for KRAS mutations in patients with NSCLC and a smoking history, as this population most frequently harbors KRAS mutations and may benefit from these emerging targeted therapies.

Three-year outcomes of uveal melanoma treated with intra-operative ultrasound-guided iodine-125 brachytherapy using custom-built eye plaques.

Purpose: The aim of this study was to demonstrate that uveal melanoma (UM) treated with eye plaque brachytherapy (EPB) with intra-operative ultrasound (IOUS) guidance results in increased local control. Material and methods: A retrospective study was conducted among 212 patients with 214 UM tumors treated by iodine-125 EPB with IOUS guidance from 2013 to 2019. 85 Gy was prescribed to tumor apical height or 5 mm from inner sclera, whichever was greater. Lesions were treated to 95% of 85 Gy at 2 mm margin from tumor edge. Local failure (LF), distant metastasis (DM), and radiation-related toxicity were recorded. Results: Median tumor apical height was 3.3 mm. COMS stage was 90 small (42.1%), 81 medium (37.9%), and 43 large (20.1%). Most patients had gene expression profile (GEP) class available, with 119 (55.6%), 30 (14.0%), 55 (25.7%) cases classified as 1A, 1B, and 2, respectively. Median dose at apex for tumor height > 5 mm and ≤ 5 mm was 85.0 Gy and 120.6 Gy, respectively. Outcomes data for 180 patients with over 12 months follow-up were reported. Mean follow-up was 37.3 months. Rates of LF and DM were 0.0% and 12.2%, respectively. Actuarial estimates of 5-year DM for class 1A, 1B, and 2 tumors were 2.5%, 0.0%, and 57.8%, respectively. 87 patients (48.3%) developed radiation-related toxicities. Conclusions: The excellent local control rate amongst lesions ranging across all sizes and GEP classes emphasizes the importance of image-guided brachytherapy with IOUS. We report favorable 5-year DM rates compared to established rates. Acceptable rate and severity of radiation-related toxicities were observed.

Contemporary trends in management of uveal melanoma.

Purpose: In the management of uveal melanoma, eye plaque brachytherapy (EPBT) has replaced enucleation as the standard of care for small size tumors that require treatment, and for medium size tumors. In the modern era, EPBT is being utilized more frequently for certain large tumors as well. While there is prospective randomized evidence to support utilization of EPBT for tumors of appropriate dimensions, it is unclear what the actual practice patterns are across the United States. The purpose of this publication was to look at contemporary trends in the management of uveal melanoma across the United States to determine whether practices are appropriately adopting EPBT, and to investigate demographic and socio-economic factors that might be associated with deviations from this standard of care. Material and methods: The National Cancer Database was queried (2004-2015) for patients with uveal melanoma. Data regarding tumor characteristics and treatment were collected. Two-sided Pearson χ2 test was used to compare categorical frequencies between patients who received globe preserving treatments vs. those who received enucleation. Multivariable logistic regression modeling was used to determine characteristics predictive for receiving enucleation. Results: The enucleation rate for small/medium tumors (≤ 10 mm apical height and ≤ 16 mm basal diameter) decreased from 20% in 2004 to 10% in 2015. The EPBT rate for large tumors increased from 30% in 2004 to 45% in 2015. Numerous demographic and socio-economic factors were found to be associated with higher rates of enucleation. Conclusions: The overall trend across the nation is a decreased enucleation rate for small/medium tumors, and an increased EPBT rate for large tumors. A fraction of patients who should be candidates for EPBT are instead receiving enucleation, and in this study, we have shown that certain adverse demographic factors are associated with this.

Comparison of Tumor Size and Gene Expression at Presentation in Uveal Melanoma Patients before and during the COVID-19 Pandemic.

Introduction: The aim of this study was to compare the clinical and gene expression variables of uveal melanoma patients presenting before and after the start of the COVID-19 pandemic as surrogate markers in order to assess the pandemic's potential impact on care. Methods: We conducted a retrospective chart review of uveal melanoma patients at Retina Consultants of Texas and assessed tumor size, staging, and gene expression data during two time periods: May 2019 to February 2020 (Group 1: Before the COVID-19 pandemic declaration by the WHO in March 2020) and May 2020 to March 2021 (Group 2: After the start of the COVID-19 pandemic). Results: A total of 80 patients with uveal melanoma were studied (Group 1: 40 [50%] and Group 2: 40 [50%]). There was no statistically significant difference in the tumor thickness (p = 0.768), largest base dimension (p = 0.758), Collaborative Ocular Melanoma Study size class (p = 0.762), and American Joint Committee on Cancer stages (p = 0.872) between the two groups. Additionally, there was no difference in the tumors' gene expression data including gene expression profile class (p = 0.587) and PRAME expressivity (p = 0.861) between the two groups. Discussion/Conclusion: The COVID-19 pandemic had no effect on the presentation of uveal melanoma patients across all tumor characteristics including size, staging, and gene expression data, suggesting there was not a significant diagnostic delay in care for uveal melanoma patients at our center due to the pandemic.

Understanding Factors Associated With Anaplastic Lymphoma Kinase Testing Delays in Patients With Non-Small Cell Lung Cancer in a Large Real-World Oncology Database.

CONTEXT.­: With multiple therapeutic options available for patients with advanced non-small cell lung cancer, the timely ordering and return of results to determine therapy are of critical importance. OBJECTIVE.­: To assess factors impacting anaplastic lymphoma kinase (ALK) test ordering and time to result delivery. DESIGN.­: A retrospective study using a de-identified electronic health record database was performed. Postdiagnosis ALK tests (n = 14 657) were analyzed from 14 197 patients with advanced non-small cell lung cancer diagnosed between January 2015 and May 2019. Time from non-small cell lung cancer diagnosis to ALK sample receipt in the laboratory was a surrogate for test order time. Test ordering was considered delayed if order time was more than 20 days. Turnaround time from sample received to test result was calculated and considered delayed if more than 10 days. Multivariable logistic regression was used to assess factors associated with order time and turnaround time delays. RESULTS.­: Median ALK test order time was 15 days, and 36.4% (5342) of all 14 657 orders were delayed. Factors associated with delays were non-fluorescence in situ hybridization testing, send-out laboratories, testing prior to 2018, nonadenocarcinoma histology, and smoking history. Median turnaround time was 9 days, and 40.3% (5906) of all 14 657 test results were delayed. Non-fluorescence in situ hybridization testing, tissue sample, and orders combining ALK with other biomarkers were associated with delayed ALK result reporting. CONCLUSIONS.­: This study provides a snapshot of real-world ALK test ordering and reporting time in US community practices. Multiple factors impacted both test ordering time and return of results, revealing opportunities for improvement. It is imperative that patients eligible for targeted therapy be identified in a timely fashion.

Impact of Infections in Patients Receiving Pembrolizumab-Based Therapies for Non-Small Cell Lung Cancer.

Background: Immune checkpoint inhibitor (ICI) therapy has significantly improved outcomes across a range of malignancies. While infections are a well-known contributor to morbidity and mortality amongst patients receiving systemic chemotherapy regimens, little is known about the impact of infections on patients receiving ICI therapy. This study aims to assess incidence, risk factors, and outcomes in patients who develop infections while on pembrolizumab-based therapies for non-small cell lung cancer (NSCLC). Methods: Patients receiving pembrolizumab for stage III/IV NSCLC from 1/1/2017-8/1/2021 across seven hospitals were identified. Incidence and type of infection were characterized. Covariates including baseline demographics, treatment information, treatment toxicities, and immunosuppressive use were collected and compared between infected and non-infected patients. Outcomes included the rate of infections, all-cause hospital admissions, median number of treatment cycles, overall survival (OS), and progression free survival (PFS). Univariable and multivariable analysis with reported odds ratio (OR) and 95% confidence intervals (CI) were utilized to evaluate infection risks. OS and PFS were analyzed by Kaplan−Meier analysis and tested by log-rank test. p-value < 0.05 was considered statistically significant. Results: There were 243 NSCLC patients that met the inclusion criteria. Of these, 111 (45.7%) had one documented infection, and 36 (14.8%) had two or more. Compared to non-infected patients, infected patients had significantly more all-cause Emergency Department (ED) [37 (33.3%) vs. 26 (19.7%), p = 0.016], hospital [87 (78.4%) vs. 53 (40.1%), p < 0.001], and ICU visits [26 (23.4%) vs. 5 (3.8%), p < 0.001], and had poorer median OS (11.53 [95% CI 6.4−16.7] vs. 21.03 [95% CI: 14.7−24.2] months, p = 0.033). On multivariable analysis, anti-infective therapy (OR 3.32, [95% CI: 1.26−8.76], p = 0.015) and ECOG of >1 (OR 5.79, [95% CI 1.72−19.47], p = 0.005) at ICI initiation conferred an increased risk for infections. At last evaluation, 74 (66.7%) infected and 70 (53.0%) non-infected patients died (p = 0.041). Conclusion: Infections occurred in nearly half of patients receiving pembrolizumab-based therapies for NSCLC. Infected patients had frequent hospitalizations, treatment delays, and poorer survival. ECOG status and anti-infective use at ICI initiation conferred a higher infection risk. Infection prevention and control strategies are needed to ameliorate the risk for infections in patients receiving ICIs.

A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer.

The inducible nitric oxide signaling (iNOS) pathway is associated with poor prognosis in triple-negative breast cancer (TNBC). Prior studies using in vivo models showed that inhibition of the iNOS signaling pathway using the pan-NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) reduced tumor growth and enhanced survival in patients with TNBC. Here, we report a first-in-class phase 1/2 trial of L-NMMA combined with taxane for treating patients with chemorefractory, locally advanced breast cancer (LABC) or metastatic TNBC. We also examined immune cell correlates of chemotherapy response. 35 patients with metastatic TNBC were recruited: 15 in the phase 1 trial and 24 in the phase 2 trial (including 4 recommended phase 2 dose patients from the phase 1 trial). The overall response rate was 45.8% (11 of 24): 81.8% (9 of 11) for patients with LABC and 15.4% (2 of 13) for patients with metastatic TNBC. Among the patients with LABC, three patients had a pathological complete response at surgery (27.3%). Grade ≥3 toxicity was noted in 21% of patients; however, no adverse events were attributed to L-NMMA. Immune cells analyzed by CyTOF indicated that chemotherapy nonresponders showed greater expression of markers associated with M2 macrophage polarization and increased concentrations of circulating IL-6 and IL-10 cytokines. In contrast, chemotherapy responders showed an increase in CD15+ neutrophils in blood, as well as a decrease in arginase (a marker of protumor N2 neutrophils) in tumor biopsies obtained at the end of treatment. L-NMMA combined with taxane warrants further investigation in larger clinical studies of patients with breast cancer.

DMSA-SPECT: A Novel Approach to Nephron Sparing SBRT for Renal Cell Carcinoma.

PURPOSE: Stereotactic body radiation therapy (SBRT) treatment planning for renal cell carcinoma requires accurate delineation of tumor from normal tissue due to the radiosensitivity of normal renal cortical tissue. Tc-99m dimercapto succinic acid (DMSA) renal imaging is a functional imaging technique that precisely differentiates normal renal cortical tissue from tumor. There are no prior publications reporting using this imaging modality for SBRT treatment planning. METHODS AND MATERIALS: A 59-year-old female with stage IV renal cell carcinoma progressed on systemic therapy and was dispositioned to primary cytoreduction with SBRT. She had baseline renal dysfunction and her tumor was 9 cm without clear delineation from normal tissue on conventional imaging. DMSA-single-photon emission computerized tomography (SPECT)/computed tomography (CT) was used for treatment planning. RESULTS: DMSA-SPECT/CT precisely delineated normal renal cortical tissue from tumor. Three months after treatment, labs were stable and DMSA-SPECT/CT was unchanged. The treated lesion had markedly decreased positron emission tomography avidity. CONCLUSIONS: DMSA-SPECT or SPECT/CT can be incorporated into radiation therapy planning for renal lesions to improve target delineation and better preserve renal function.