Advances and future directions in ROS1 fusion-positive lung cancer.

ROS1 gene fusions are an established oncogenic driver comprising 1%-2% of non-small cell lung cancer (NSCLC). Successful targeting of ROS1 fusion oncoprotein with oral small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment landscape of metastatic ROS1 fusion-positive (ROS1+) NSCLC and transformed outcomes for patients. The preferred Food and Drug Administration-approved first-line therapies include crizotinib, entrectinib, and repotrectinib, and currently, selection amongst these options requires consideration of the systemic and CNS efficacy, tolerability, and access to therapy. Of note, resistance to ROS1 TKIs invariably develops, limiting the clinical benefit of these agents and leading to disease relapse. Progress in understanding the molecular mechanisms of resistance has enabled the development of numerous next-generation ROS1 TKIs, which achieve broader coverage of ROS1 resistance mutations and superior CNS penetration than first-generation TKIs, as well as other therapeutic strategies to address TKI resistance. The approach to subsequent therapy depends on the pace and pattern of progressive disease on the initial ROS1 TKI and, if known, the mechanisms of TKI resistance. Herein, we describe a practical approach for the selection of initial and subsequent therapies for metastatic ROS1+ NSCLC based on these clinical considerations. Additionally, we explore the evolving evidence for the optimal treatment of earlier-stage, non-metastatic ROS1+ NSCLC, while, in parallel, highlighting future research directions with the goal of continuing to build on the tremendous progress in the management of ROS1+ NSCLC and ultimately improving the longevity and well-being of people living with this disease.

Lung Cancer Survivorship: Physical, Social, Emotional, and Medical Needs of NSCLC Survivors.

BACKGROUND: Newer therapies prolong survival for patients with lung cancer. Beyond extending survival, the needs of lung cancer (LC) survivors are poorly described. METHODS: We conducted a single-institution needs assessment survey of LC survivors alive ≥1 year from diagnosis. Needs were rated on a 5-point Likert scale for 4 domains (physical, social, emotional, and medical). Multiple regression models identified demographic or treatment characteristics associated with more needs in each category. A subset analysis of survivors with metastatic LC was performed. RESULTS: Of 360 patients approached, 235 surveys were completed. Among completed survey respondents, the median age was 69 years; most were female (62%), married (71%), and White (74%); and 41% had stage IV cancer. Finding support resources (34%) was the most common medical need. Fatigue (70%), sleep disturbance (60%), memory and concentration (57.5%), weakness (54%), and trouble breathing (51%) were physical needs affecting more than half of respondents. The most common social need was managing daily activities (42%). Emotional needs were highly prevalent, with 79% of respondents reporting a fear of recurrence and 74.5% reporting living with uncertainty. Multiple regression analysis identified that receipt of multiple lines of systemic therapy and lower household income were associated with higher physical and social needs. Younger age was associated with having a greater number of social and emotional needs. Similar results were found in the subset of survivors with metastatic disease at diagnosis. CONCLUSIONS: The needs of LC survivors are diverse across multiple domains. Several clinical and demographic factors are independently associated with higher numbers of patient-reported needs. Our study identifies critical gaps in survivorship care for LC survivors with all stages of disease and highlights areas of future intervention.

PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage.

The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.

Outpatient Embedded Palliative Care for Patients with Advanced Thoracic Malignancy: A Retrospective Cohort Study.

Although cancer care is often contextualized in terms of survival, there are other important cancer care outcomes, such as quality of life and cost of care. The ASCO Value Framework assesses the value of cancer therapies not only in terms of survival but also with consideration of quality of life and financial cost. Early palliative care for patients with advanced cancer is associated with improved quality of life, mood, symptoms, and overall survival for patients, as well as cost savings. While palliative care has been shown to have numerous benefits, the impact of real-world implementation of outpatient embedded palliative care on value-based metrics is not fully understood. We sought to describe the association between outpatient embedded palliative care in a multidisciplinary thoracic oncology clinic and inpatient value-based metrics. We performed a retrospective cohort study of 215 patients being treated for advanced thoracic malignancies with non-curative intent. We evaluated the association between outpatient embedded palliative care and inpatient clinical outcomes including emergency room visits, hospitalizations, intensive care unit admissions, hospital charges, as well as hospital quality metrics including 30-day readmissions, admissions within 30 days of death, inpatient mortality, and inpatient hospital charges. Outpatient embedded palliative care was associated with lower hospital charges per day (USD 3807 vs. USD 4695, p = 0.024). Furthermore, patients who received outpatient embedded palliative care had lower hospital admissions within 30 days of death (O.R. 0.45; 95% CI 0.29, 0.68; p < 0.001) and a lower inpatient mortality rate (IRR 0.67; 95% CI 0.48, 0.95; p = 0.024). Our study further supports that outpatient palliative care is a high-value intervention and alternative models of palliative care, including one embedded into a multidisciplinary thoracic oncology clinic, is associated with improved value-based metrics.

Patient and Caregiver Experience With the Hope and Prognostic Uncertainty of Immunotherapy: A Qualitative Study.

PURPOSE: Immunotherapy has improved survival for patients with melanoma and non-small cell lung cancer (NSCLC). Yet, as responses vary widely, immunotherapy also introduces challenges in prognostic communication. In this study, we sought to explore how patients and caregivers learned about the goal of immunotherapy and their experience of living with uncertainty. MATERIALS AND METHODS: We conducted a qualitative study of patients with stage III or IV melanoma or stage IV NSCLC within 12 weeks of initiating or 12 months of discontinuing immunotherapy, and their caregivers. We conducted in-depth interviews with participants to explore how they learned about immunotherapy from oncology clinicians and how they experienced uncertainty. We used a framework approach to analyze interview transcripts and synthesized concepts into themes. RESULTS: Forty-two patients and 10 caregivers participated; median age was 67 years and most were male (68%), white (95%), married (61%), and had melanoma (62%). We identified four themes: (1) the oncology team shaped participants' hopeful expectations of immunotherapy, including as a potential cure among those with melanoma; (2) distress related to prognostic uncertainty particularly affected patients who experienced toxicity or progressive disease; (3) patients who did not have long-term responses experienced overwhelming disappointment; and (4) some patients and caregivers had conflicting preferences for prognostic information. Participants provided suggestions to improve education and underscored unmet psychosocial needs. CONCLUSION: Patients and caregivers held optimistic expectations of immunotherapy, which resulted in heightened disappointment among the subset with progression or toxicity. Clinicians should elicit information preferences of both patients and caregivers, as these may be disparate. Our results highlight the need to optimize prognostic communication and support for living with uncertainty among patients receiving immunotherapy.

Learning About and Living With Toxicity: A Qualitative Study of Patients Receiving Immune Checkpoint Inhibitors For Melanoma or Lung Cancer and Their Caregivers.

Background/Objective: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for melanoma and lung cancer and are in widespread use. This study aims to describe how patients and caregivers learn about ICI toxicities and their perceptions and experiences of toxicity. Methods: We conducted a qualitative study of 42 patients with advanced non-small cell lung cancer (NSCLC; n = 16) or melanoma (n = 26) who were initiating or discontinuing an ICI and their caregivers (n = 9). We conducted in-depth interviews to explore patients' and caregivers' experiences learning about and living with ICI side effects. We audio-recorded the first oncology visit after enrollment. We used a framework approach to code interview and visit transcripts and synthesized codes into themes. Results: The median age of patients was 67; 68% were male. Themes of participant interviews and clinician-patient dialogue included: i) Patients initiating an ICI received extensive information about side effects, which some patients found overwhelming or scary and difficult to absorb; ii) Patients who were deterred by fear of toxicity ultimately proceeded with treatment because of oncologist encouragement or the sense of no alternative; iii) participants found hope in the association between toxicity and ICI efficacy; iv) caregivers helped patients navigate the deluge of information and uncertainty related to ICIs. Participants suggested ways to improve ICI side effect education, such as incorporating patient stories. Conclusion: Patients perceived that ICI toxicity counseling was overwhelming yet were encouraged by oncologists' reassurance that serious side effects were manageable and by the framing of toxicity as a sign of efficacy. We identified opportunities to improve communication of ICI risks and benefits.

Unmet Needs, Quality of Life, and Financial Toxicity Among Survivors of Lung Cancer.

Importance: Despite a growing population of survivors of lung cancer, there is limited understanding of the survivorship journey. Survivors of lung cancer experience unmet physical, social, emotional, and medical needs regardless of stage at diagnosis or treatment modalities. Objective: To investigate the association of unmet needs with quality of life (QOL) and financial toxicity (FT) among survivors of lung cancer. Design, Setting, and Participants: This survey study was conducted at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center thoracic oncology clinics between December 1, 2020, and September 30, 2021, to assess needs (physical, social, emotional, and medical), QOL, and FT among survivors of lung cancer. Patients had non-small cell lung cancer of any stage and were alive longer than 1 year from diagnosis. A cross-sectional survey was administered, which consisted of an adapted needs survey developed by the Mayo Survey Research Center, the Comprehensive Score for Financial Toxicity measure, and the European Organization for Research and Treatment of Cancer QLQ-C30 QOL scale. Demographic and clinical information was obtained through retrospective medical record review. Data analysis was performed between May 9 and December 8, 2022. Main Outcomes and Measures: Separate multiple linear regression models, treating QOL and FT as dependent variables, were performed to assess the adjusted association of total number of unmet needs and type of unmet need (physical, emotional, social, or medical) with QOL and FT. Results: Of the 360 survivors of lung cancer approached, 232 completed the survey and were included in this study. These 232 respondents had a median age of 69 (IQR, 60.5-75.0) years. Most respondents were women (144 [62.1%]), were married (165 [71.1%]), and had stage III or IV lung cancer (140 [60.3%]). Race and ethnicity was reported as Black (33 [14.2%]), White (172 [74.1%]), or other race or ethnicity (27 [11.6%]). A higher number of total unmet needs was associated with lower QOL (ß [SE], -1.37 [0.18]; P < .001) and higher FT (ß [SE], -0.33 [0.45]; P < .001). In the context of needs domains, greater unmet physical needs (ß [SE], -1.24 [0.54]; P = .02), social needs (ß [SE], -3.60 [1.34]; P = .01), and medical needs (ß [SE], -2.66 [0.98]; P = .01) were associated with lower QOL, whereas only greater social needs was associated with higher FT (ß [SE], -3.40 [0.53]; P < .001). Conclusions and Relevance: The findings of this survey study suggest that among survivors of lung cancer, unmet needs were associated with lower QOL and higher FT. Future studies evaluating targeted interventions to address these unmet needs may improve QOL and FT among survivors of lung cancer.

Primary Resistance to Larotrectinib in a Patient With Squamous NSCLC With Subclonal NTRK1 Fusion: Case Report.

The NTRK genes encode the TRK proteins. NTRK fusions lead to constitutively active, ligand-independent downstream signaling. NTRK fusions are implicated in up to 1% of all solid tumors and 0.2% of NSCLC. Larotrectinib, a highly selective small molecule inhibitor of all three TRK proteins, has a response rate of 75% across a wide range of solid tumors. Mechanisms of primary resistance to larotrectinib are not well understood. We report a case of a 75-year-old male with minimal smoking history with NTRK fusion-positive metastatic squamous NSCLC with primary resistance to larotrectinib. We suggest subclonal NTRK fusion as a possible mechanism contributing to primary resistance to larotrectinib.

Financial toxicity in lung cancer.

In the United States, lung cancer is the third most common cancer and the overall leading cause of cancer death. Due to advances in immunotherapy and targeted therapy, 5-year survival is increasing. The growing population of patients with lung cancer and cancer survivors highlights the importance of comprehensive cancer care, including recognizing and addressing financial toxicity. Financial toxicity is a term used to contextualize the negative effects of the costs of cancer treatment in terms of patient quality of life. The American Society of Clinical Oncology (ASCO) Value Framework places emphasis on high-value care as it evaluates cancer treatments "based on clinical benefit, side effects, and improvements in patient symptoms or quality of life in the context of cost". Prior studies have shown that risk factors for financial toxicity in patients with lung cancer include lower household income or savings, inability to afford basic necessities, higher than anticipated out of pocket expenses, and taking sick leave. Among lung cancer survivors, patients experience increased unemployment and lower wages compared to the general population underscoring the lasting effects of financial toxicity. Financial toxicity is associated with increased psychosocial distress and decreased quality of life, and bankruptcy is an independent predictor of mortality in patients with cancer. Despite the negative implications of financial toxicity on patients, standardized screening practices and evidence-based interventions are lacking. The "COmphrensive Score for financial Toxicity (COST)" tool has been validated for assessing financial toxicity with correlation with health-related quality of life. Further research is needed to understand the utility of incorporating routine screening for financial toxicity into clinical practice and the efficacy of interventions. Understanding the relationship between financial toxicity and quality of life and survival is critical to providing high-value cancer care and survivorship care.

Disparities in Telemedicine Success and Their Association With Adverse Outcomes in Patients With Thoracic Cancer During the COVID-19 Pandemic.

Importance: Disparities in access to telemedicine were identified at the onset of the COVID-19 pandemic, but the consequences of these disparities are not well characterized. Objective: To investigate factors associated with successfully accessing and completing telemedicine visits and the association between telemedicine visit success and clinical outcomes among patients with thoracic cancer. Design, Setting, and Participants: This retrospective cohort study included patients who attended outpatient visits at the thoracic oncology division of Johns Hopkins Medical Institute in Baltimore, Maryland, from March 1 to July 17, 2020. Main Outcomes and Measures: Associations of age, sex, race, ethnicity, insurance status, marital status, zip code, type of cancer, cancer stage, and type of therapy with telemedicine visit success (defined as completed visits with synchronous audio-video connection) and of visit success status with changes in therapy and odds of emergency department and urgent care visits, hospitalizations, and death were assessed using χ2 and Fisher exact tests and are reported as odds ratios (ORs). Results: A total of 720 patients and 1940 visits with complete data were included in the analysis; the median patient age was 65.7 years (range, 54.7-76.7 years), and 384 (53.33%) were male. Of the 1940 visits, 679 (35.00%) were in person and 1261 (65.00%) were telemedicine. Of the telemedicine visits, 717 (56.86%) were successful and 544 (43.14%) were unsuccessful. Patients who were Black (OR, 0.62; 95% CI, 0.41-0.95), had Medicaid (OR, 0.38; 95% CI, 0.18-0.81), or were from a zip code with an elevated risk of cancer mortality (OR, 0.51; 95% CI, 0.29-0.90) were less likely to have successful telemedicine visits than to have unsuccessful visits. Patients with at least 1 unsuccessful telemedicine visit had higher likelihood of an emergency department (OR, 2.73; 95% CI, 1.42-5.22) or urgent care (OR, 4.50; 95% CI, 2.41-8.41) visit or hospitalization (OR, 2.37; 95% CI, 1.17-4.80). Similarly, patients who had no successful telemedicine visits and for whom more than 1 telemedicine visit was scheduled had a higher likelihood of an emergency department (OR, 3.43; 95% CI 1.80-6.52) or urgent care (OR, 4.24; 95% CI 2.24-8.03) visit or hospitalization (OR, 4.19; 95% CI 2.17-8.10). Patients with all successful telemedicine visits (OR, 0.52; 95% CI, 0.30-0.90) or only 1, unsuccessful visit (OR, 0.32; 95% CI, 0.13-0.75) had lower odds of death compared with patients seen in-person only. Starting a new therapy was associated with lower odds of having a telemedicine visit vs an in-person visit (OR, 0.49; 95% CI, 0.37-0.64) and higher odds of a successful telemedicine visit vs an unsuccessful telemedicine visit (OR, 1.90; 95% CI, 1.28-2.82). Conclusions and Relevance: In this cohort study, patients with thoracic cancer who were Black, had Medicaid, or were from a zip code with a high risk of cancer mortality had increased odds of unsuccessful telemedicine visits compared with their counterparts and unsuccessful telemedicine visits were associated with worse clinical outcomes compared with successful visits. These findings suggest that more work is needed to improve telemedicine access for disadvantaged patients.

Peripheral Plasma Cells Associated with Mortality Benefit in Severe COVID-19: A Marker of Disease Resolution.

BACKGROUND: Cytokines seen in severe coronavirus disease 2019 (COVID-19) are associated with proliferation, differentiation, and survival of plasma cells. Plasma cells are not routinely found in peripheral blood, though may produce virus-neutralizing antibodies in COVID-19 later in the course of an infection. METHODS: Using the Johns Hopkins COVID-19 Precision Medicine Analytics Platform Registry, we identified hospitalized adult patients with confirmed severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and stratified by presence of plasma cells and World Health Organization (WHO) disease severity. To identify plasma cells, we employed a sensitive flow cytometric screening method for highly fluorescent lymphocytes and confirmed these microscopically. Cox regression models were used to evaluate time to death and time to clinical improvement by the presence of plasma cells in patients with severe disease. RESULTS: Of 2301 hospitalized patients with confirmed infection, 371 had plasma cells identified. Patients with plasma cells were more likely to have severe disease, though 86.6% developed plasma cells after onset of severe disease. In patients with severe disease, after adjusting for age, sex, body mass index, race, and other covariates associated with disease severity, patients with plasma cells had a reduced hazard of death (adjusted hazard ratio: 0.57; 95% confidence interval: 0.38-0.87; P value: .008). There was no significant association with the presence of plasma cells and time to clinical improvement. CONCLUSIONS: Patients with severe disease who have detectable plasma cells in the peripheral blood have improved mortality despite adjusting for known covariates associated with disease severity in COVID-19. Further investigation is warranted to understand the role of plasma cells in the immune response to COVID-19.

Adipose Tissue Mast Cells Promote Human Adipose Beiging in Response to Cold.

In a recent study, repeated cold application induced beiging in subcutaneous white adipose tissue (SC WAT) of humans independent of body mass index. To identify factors that promote or inhibit beiging, we performed multiplex analysis of gene expression with the Nanostring nCounter system (the probe set contained genes for specific immune cell markers, cytokines, and chemokines) on the SC WAT from lean subjects. Multiple correlations analysis identified mast cell tryptase and CCL26, a chemokine for mast cells, as genes whose change correlated positively with the change in UCP1 in SC WAT, leading to the hypothesis that mast cells promote SC WAT beiging in response to cold. We quantified mast cell recruitment into SC WAT and degranulation. Mast cells increased in number in SC WAT in lean subjects, and there was an increase in the number of degranulated mast cells in both lean subjects and subjects with obesity. We determined that norepinephrine stimulated mast cell degranulation and histamine release in vitro. In conclusion, cold stimulated adipose tissue mast cell recruitment in lean subjects and mast cell degranulation in SC WAT of all research participants independent of baseline body mass index, suggesting that mast cells promote adipose beiging through the release of histamine or other products.

Melanocortin 1 Receptor: Structure, Function, and Regulation.

The melanocortin 1 receptor (MC1R) is a melanocytic Gs protein coupled receptor that regulates skin pigmentation, UV responses, and melanoma risk. It is a highly polymorphic gene, and loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and sub-optimal DNA repair. MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin, the negative agonist agouti signaling protein, and the neutral antagonist ß-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis which functions to limit UV penetration into the skin and enhances nucleotide excision repair (NER), the genomic stability pathway responsible for clearing UV photolesions from DNA to avoid mutagenesis. Herein we review MC1R structure and function and summarize our laboratory's findings on the molecular mechanisms by which MC1R signaling impacts NER.

Defining the Contribution of MC1R Physiological Ligands to ATR Phosphorylation at Ser435, a Predictor of DNA Repair in Melanocytes.

The melanocortin 1 receptor (MC1R), a GS-coupled receptor that signals through cAMP and protein kinase A (PKA), regulates pigmentation, adaptive tanning, and melanoma resistance. MC1R-cAMP signaling promotes PKA-mediated phosphorylation of ataxia telangiectasia and rad3-related (ATR) at Ser435 (ATR-pS435), a modification that enhances nucleotide excision repair (NER) by facilitating recruitment of the XPA protein to sites of UV-induced DNA damage. High-throughput methods were developed to quantify ATR-pS435, measure XPA-photodamage interactions, and assess NER function. We report that melanocyte-stimulating hormone (α-MSH) or ACTH induce ATR-pS435, enhance XPA's association with UV-damaged DNA and optimize melanocytic NER. In contrast, MC1R antagonists agouti signaling protein (ASIP) or human ß-defensin 3 (HBD3) interfere with ATR-pS435 generation, impair the XPA-DNA interaction, and reduce DNA repair. Although ASIP and HBD3 each blocked α-MSH-mediated induction of the signaling pathway, only ASIP depleted basal ATR-pS435. Our findings confirm that ASIP diminishes agonist-independent MC1R basal signaling whereas HBD3 is a neutral MC1R antagonist that blocks activation by melanocortins. Furthermore, our data suggest that ATR-pS435 may be a useful biomarker for the DNA repair-deficient MC1R phenotype.