Natural history of SCLC patients treated in third-line and beyond: A retrospective real world study.

OBJECTIVES: To describe treatment patterns and estimate outcomes among real-world small cell lung cancer (SCLC) patients in the US who received three or more lines of therapy. MATERIALS AND METHODS: We conducted a retrospective analysis of adult patients with SCLC who received a front-line platinum-based regimen and two additional lines of therapy (ie., a cohort of at least three lines of therapy). De-identified patients were selected from a United States Flatiron Health oncology database of electronic health records. Treatment patterns were captured by line of therapy. Outcomes evaluated by line of therapy included real-world overall survival (rwOS), real-world progression free survival (rwPFS), real-world response rate (rwRR) and real-world duration of response (rwDOR). RESULTS: The analysis included 326 3L SCLC patients, of which 103 (32 %) received 4L treatment, and 38 % (39/103) of 4L treated received 5L of therapy. Among the 3L cohort, the average age was 67 years, 49 % were male, and nearly all had a history of smoking (96 %). In the 3L setting, the median rwOS was 5.3 months (95 % Confidence Interval (CI): 4.5, 6.0), median rwPFS was 2.5 months (95 % CI: 2.1, 2.7), rwRR was 19.3 % (95 % CI: 15.2, 24.0) and median DOR was 3.4 months (95 % CI: 2.8, 4.4). No differences were seen in outcomes between the overall cohort and a subgroup of patients treated with front-line platinum-based regimen with an anti-programmed cell death ligand 1 (PD-L1) agent (atezolizumab or durvalumab), in each respective line of therapy. CONCLUSION: Results from this large, real-world study of US patients with SCLC in the 3L setting and beyond highlight the poor treatment outcomes in advanced SCLC patients with existing therapies and underscore the dire need for new therapies for SCLC patients.

Symptoms and Experiences with Small Cell Lung Cancer: A Mixed Methods Study of Patients and Caregivers.

INTRODUCTION: Understanding of the patient-perceived symptom burden of small cell lung cancer (SCLC) is limited. The objective of this study was to explore patients' experiences with SCLC, identify which treatment-/disease-related symptoms have the greatest impact on their well-being, and gain caregiver perspectives. METHODS: A noninterventional, cross-sectional, multimodal, mixed methods study was conducted from April-June 2021. Adult patients with SCLC and unpaid caregivers were eligible to participate. Patients' experiences, captured via 5-day video diaries and follow-up interviews, were scored 1-10 on how bothersome the patients perceived each symptom/symptomatic adverse event. Patients indicated if they believed a symptom was disease or treatment related. Caregivers participated in an online community board. RESULTS: The study included nine patients (five with extensive-stage [ES] disease, four with limited-stage [LS] disease) and nine caregivers. Except for one patient/caregiver pairing, patients and caregivers were unmatched. The most common impactful symptoms in patients with ES-SCLC were shortness of breath, fatigue, coughing, chest pain, and nausea/vomiting; in LS-SCLC, these were fatigue and shortness of breath. Among patients with ES disease, SCLC had a high impact on physical (leisure/hobbies, work, sleep, ability to do household chores and errands/responsibilities outside home), social (family dynamics, extrafamilial social interaction), and emotional (mental health) aspects. Patients with LS-SCLC faced the long-term physical effects of treatment, financial implications, and emotional toll of an uncertain prognosis. SCLC had a high personal and psychologic burden among caregivers, whose duties consumed much of their time. Caregivers observed similar symptoms and impacts of SCLC as those reported by patients. CONCLUSIONS: This study provides valuable insight into patient- and caregiver-perceived burden of SCLC and can inform the design of prospective studies. Clinicians should seek to understand patients' opinions and priorities before making treatment decisions.

A Real-World Evaluation of Atezolizumab Plus Platinum-Etoposide Chemotherapy in Patients With Extensive-Stage SCLC in Canada.

INTRODUCTION: The real-world data evaluating treatment outcomes of atezolizumab plus carboplatin-etoposide chemotherapy (atezolizumab) for extensive-stage SCLC (ESCLC) are lacking. Our objective was to evaluate real-world outcomes of ESCLC treated with atezolizumab. METHODS: A retrospective analysis of provincial patients with ESCLC who started first-line (1L) systemic treatment was conducted. We primarily evaluated the progression-free survival (PFS) and overall survival (OS) outcomes in association with atezolizumab compared with platinum-etoposide chemotherapy (chemotherapy) while adjusting for relevant demographic and clinical factors. Adverse events (AEs) during 1L were evaluated. RESULTS: A total of 67 patients were identified. Of the 34 patients who received atezolizumab, 24% had Eastern Cooperative Oncology Group performance status greater than or equal to 2, approximately 50% were more than or equal to 65 years, 21% received cisplatin-etoposide chemotherapy before atezolizumab, and 12% had thoracic radiation (tRT).Within the atezolizumab versus chemotherapy group, the median PFS equals to 6.0 versus 4.3 months (p = 0.03) whereas OS = 12.8 versus 7.1 months (p = 0.01). Relative to chemotherapy, the hazard ratio (95% confidence interval) for PFS was 0.53 (0.28-1.02) and OS was 0.42 (0.20-0.88) with atezolizumab. tRT compared with no tRT receipt correlated with reduced death risk (hazard ratio [95% confidence interval] = 0.33 [0.13-0.88]).AE-related treatment withdrawal with atezolizumab was 32% and 15% with chemotherapy (p = 0.02). Within the tRT subgroup, 25% versus 20% in atezolizumab versus chemotherapy group, respectively, discontinued 1L owing to AE. CONCLUSIONS: This is the first real-world study revealing comparable survival with that in the IMpower133 trial. Treatment discontinuation from AEs was higher with atezolizumab among Canadian patients with ESCLC. Our data suggest safe use of tRT and chemoimmunotherapy, but its efficacy for ESCLC warrants further study.

Effectiveness and Safety of First-Line Pembrolizumab in Older Adults with PD-L1 Positive Non-Small Cell Lung Cancer: A Retrospective Cohort Study of the Alberta Immunotherapy Database.

The emergence of immunotherapy revolutionized the treatment of non-small-cell-lung cancer (NSCLC), with multiple landmark clinical trials establishing the efficacy of these agents. However, many patients who receive immunotherapy in clinical practice would be considered clinical trial ineligible. One such population that is often under-represented in clinical trials is older adults. In the current study, we evaluated clinical and safety outcomes in this population. Overall, older adults (>70 years of age) and younger adults had comparable clinical outcomes with an equivalent objective response rate (ORR), time to treatment failure (TTF), and median overall survival (p = 0.67, p = 0.98, and p = 0.91, respectively). Furthermore, the safety outcomes were equivalent between the cohorts with similar rates of immune-related adverse events (irAEs), irAE-related hospitalizations, and all-cause hospitalization (p = 0.99, p = 0.63, and p = 0.74, respectively). While older age was not found to impact overall survival, multivariant analysis revealed that a poor Eastern Cooperative Oncology Group (ECOG) status, low body-mass-index (BMI), and poor/intermediate lung immune prognostic index (LIPI) were all associated with worse survival. In conclusion, age does not impact the efficacy or safety of pembrolizumab in NSCLC, and therefore advanced age should not be a deterrent for treating these patients with pembrolizumab. Physicians and care providers can thus focus on other factors that may influence therapeutic outcomes.

Retrospective Real-World Outcomes for Patients With ALK-Rearranged Lung Cancer Receiving ALK Receptor Tyrosine Kinase Inhibitors.

INTRODUCTION: This study explored the use, safety, and efficacy of initial use of an ALK-inhibiting targeted therapy (ALK tyrosine kinase inhibitor [TKI]) in patients with ALK-rearranged NSCLC in a population-based, real-world clinical population within the province of Alberta, Canada. METHODS: Demographic, clinical, treatment, and outcome data of the patients with advanced or metastatic ALK-rearranged NSCLC receiving their first ALK TKI between 2014 and 2019 were included in the analysis. RESULTS: A total of 92 patients with ALK-rearranged NSCLC treated with ALK TKI (78% crizotinib, 22% alectinib) were identified. In the ALK-rearranged cohort, 1-year survival rate was 73% and median overall survival (OS) and progression-free survival (PFS) were 48.5 months and 17.0 months, respectively. An objective response rate of 49% was observed, and adverse events were reported in 70% of the patients, primarily of low grade (84%). Case-matched comparison to patients with ALK-wildtype disease treated with cytotoxic chemotherapy revealed the benefit of ALK TKI in the context of an ALK rearrangement (ALK-rearranged versus ALK-wildtype) (median post-treatment initiation OS: 46.8 versus 14.2 mo, p < 0.001). Outcomes, measured from the time of ALK TKI initiation, differed by Eastern Cooperative Oncology Group (ECOG) (ECOG < 2 versus ECOG ≥ 2) (median OS: not reached versus 6.8 mo, p < 0.001; median PFS 17.6 versus 7.4 mo, p = 0.02), disease presentation (relapsed versus de novo) (median PFS: 30.8 versus 15.0 mo, p = 0.04), and brain metastasis onset (brain metastases development during ALK TKI versus baseline brain metastases) (not reached versus 12.8 mo, p = 0.04). CONCLUSIONS: Clinical trials have firmly established that ALK TKIs are safe, well tolerated, and effective; these findings reveal that their impact in a real-world setting is just as profound. The availability and use of ALK TKI therapies contribute to the impressive gains in survival experienced by contemporary patients with ALK-rearranged disease, rendering patients with this oncodriven form of NSCLC among the longest surviving patients with lung cancer.

Real-World Treatment Patterns, Clinical Outcomes, and Health Care Resource Utilization in Extensive-Stage Small Cell Lung Cancer in Canada.

The prognosis for extensive-stage small cell lung cancer (ES-SCLC) is poor. Real-world evidence can highlight the unmet clinical need within this population. We conducted a population-based cohort study of ES-SCLC patients diagnosed in a large Canadian province (2010-2018) using electronic medical records and administrative claims data. In all, 1941 ES-SCLC patients were included, of which 476 (25%) were recurrent cases. Median age at diagnosis was 70 years (range: 39-94) and 50.2% were men. Of the 1941 ES-SCLC patients, 29.5% received chemotherapy and radiotherapy, 17.0% chemotherapy alone, 8.7% radiotherapy alone, and 44.8% received best supportive care. Chemotherapy was initiated by 46.5%, 8.5%, and 1.4% of first-, second-, and third-line patients, with lower uptake for recurrent cases. Median survival from first-, second-, and third-line chemotherapy was 7.82 months (95% CI: 7.50-8.22), 5.72 months (95% CI: 4.90-6.87), and 3.83 months (95% CI: 2.99-4.60). Among patients who received first-line therapy, the 2-year and 5-year survival was 7.3% (95% CI: 5.7-9.2) and 2.9% (95% CI: 1.8-4.5). In conclusion, initiation of first-line treatment in ES-SCLC was low with significant attrition in subsequent lines. These results underscore the need for effective front-line treatments and highlight the potential for novel therapies to improve patient outcomes.

CXCR4 expression in lung carcinogenesis: Evaluating gender-specific differences in survival outcomes based on CXCR4 expression in early stage non-small cell lung cancer patients.

INTRODUCTION: Evidence suggests that the expression of certain cytokine receptors increases with lung cancer evolution. Overexpression of the cytokine receptor CXCR4 is associated with poor outcomes in stage IV non-small cell lung cancer (NSCLC), with shorter survival in females with high CXCR4 expression. This study quantifies CXCR4 expression in early stage disease and evaluates its association with gender-specific recurrence-free (RFS) and overall survival (OS) in resected stage I-III NSCLC patients. METHODS: Patient characteristics and clinical outcomes were obtained from the Glans-Look Lung Cancer (G-LLC) database for early stage NSCLC patients diagnosed between 2003-2006 at the Tom Baker Cancer Centre (TBCC). CXCR4 expression was quantified on tissue microarrays (TMA). Median RFS and OS were evaluated by gender using Kaplan-Meier analyses. CXCR4 expression and outcome data were analyzed using Cox proportional hazards (PH) and multi-state models (MSM). RESULTS: 176 stage I-III NSCLC patients were identified. CXCR4 expression was lower in early stage NSCLC patients, with a mean CXCR4 expression of 1729 (SD 1083) compared to 2640 (SD 1541) in stage IV patients. On Kaplan-Meier, median RFS by gender was similar (male 52.8 months vs. female 54.5 months) as was median OS (male 80.9 months vs. female 89.0 months), and there was no significant difference in RFS (p = 0.60) or OS (p = 0.30) by gender and CXCR4 groups over follow-up. By multivariable analysis, CXCR4 expression was not prognostic for RFS (Hazard Ratio (HR) = 1.00, p = 0.73) or OS (HR = 1.00, p = 0.44), and no gender difference was observed. CONCLUSIONS: CXCR4 expression increases with stage progression in NSCLC but is not prognostic in early stage NSCLC patients of either gender. Mechanisms by which CXCR4 expression increases during lung carcinogenesis warrant further exploration and testing in clinical trials.

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults.

The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approved in Canada for the treatment of solid tumours harbouring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. These NTRK gene fusions are oncogenic drivers found in most tumour types at a low frequency (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., secretory carcinoma of the salivary gland and of the breast). They are generally mutually exclusive of other common oncogenic drivers. Larotrectinib and entrectinib have demonstrated impressive overall response rates and tolerability in Phase I/II trials in patients with TRK fusion cancer with no other effective treatment options. Given the low frequency of TRK fusion cancer and the heterogeneous molecular testing landscape in Canada, identifying and optimally managing such patients represents a new challenge. We provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor. We focus on five tumour types: thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, and salivary gland carcinoma. Based on the probability of the tumour harbouring an NTRK gene fusion, we also suggest a tumour-agnostic consensus for NTRK gene fusion testing and treatment. We recommend considering a TRK inhibitor in all patients with TRK fusion cancer with no other effective treatment options.

Population-based Treatment Patterns and Outcomes for Stage III Non-Small Cell Lung Cancer Patients: A Real-world Evidence Study.

BACKGROUND: Most patients with stage III non-small cell lung cancer (NSCLC) develop metastases and succumb to their cancer. Approaches to the treatment of stage III disease can be highly variable. Understanding current treatment patterns can inform the optimal integration of emerging therapies. In this study, we describe contemporary treatment patterns and outcomes for a population-based cohort of stage III NSCLC patients from a large Canadian province. METHODS: On the basis of the provincial cancer registry, all adult patients diagnosed with stage III NSCLC from April 1, 2010 to March 31, 2015 were identified. Analyses of these patients' existing electronic medical records and administrative claims data were conducted to describe patient characteristics, treatment patterns, and survival outcomes. RESULTS: In total, we screened 6438 patients diagnosed with NSCLC, of whom 1151 (17.9%) had stage III disease. Among them, 61.2% were stage IIIA, 36.4% were stage IIIB, and 2.4% were unspecified. Median age at diagnosis was 70 (22 to 94) years and 50.2% were men. In this cohort, a significant proportion of patients received only palliative radiotherapy (35.6%), palliative chemotherapy (8.8%), or best supportive care (24.8%) as initial treatment. Conversely, relatively few underwent concurrent chemoradiotherapy (11.7%) or trimodality therapy (1.7%). Surgery±adjuvant treatments were performed in 14.8% of stage III patients. Median overall survival was 13.2 months (95% confidence interval [CI], 12.2-14.0) among stage III patients. Patients who received initial curative treatment had statistically significant better survival compared with those who received noncurative treatment (P<0.001); median overall survival 29.8 months (95% CI, 22.3-34.6) and 8.9 months (95% CI, 7.6-11.6), respectively. CONCLUSIONS: In a population-based setting that includes community, regional, and tertiary cancer centers, use of concurrent chemoradiotherapy and trimodality therapy in stage III NSCLC was low despite evidence supporting the potential benefits of these strategies.

The prevalence and prognostic significance of estrogen receptor beta expression in non-small cell lung cancer.

BACKGROUND: Estrogen receptor beta (ERß) is the predominant estrogen receptor (ER) expressed in non-small cell lung cancer (NSCLC); however, due to methodological disparities among prior studies, the prognostic value of ERß expression in NSCLC remains unclear. Our objective was to apply improved detection and analysis techniques to assess the prognostic value of ERß expression in NSCLC. METHODS: A tissue microarray (TMA) was used which contained resected and biopsy specimens from 299 patients diagnosed at a single center with stages I-IV NSCLC. Sections of this array were stained using high-sensitivity fluorescence immunohistochemistry, with the well-validated PPG5/10 monoclonal antibody. Digital images of the stained array slides were analyzed using software-based image analysis, which reported ERß expression as a continuous variable in different subcellular domains. RESULTS: There were no differences in ERß expression between male and female patients. High expression of ERß was not a prognostic factor, but was significantly associated with stage IV disease in both tumor and stroma (P<0.001). In multivariable analysis, a high nuclear/cytoplasmic (N/C) ratio of ERß expression was significantly associated with shorter overall survival, based on expression in the tumor [hazard ratio (HR): 1.65; 95% confidence interval (CI): 1.25-2.19; P<0.001] and in the stroma (HR: 1.57; 95% CI: 1.16-2.12; P=0.003). CONCLUSIONS: These results suggest that subcellular localization of ERß, but not absolute expression, is a prognostic factor in NSCLC.

Correction: Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. This has now been corrected in both the PDF and HTML versions of the Article.

The Population-based Impact of Adjuvant Chemotherapy on Outcomes in T2N0M0 Non-Small Cell Lung Cancer.

OBJECTIVES: The value of adjuvant chemotherapy in T2N0M0 non-small-cell lung cancer (NSCLC) is unclear. Some current guidelines suggest adjuvant chemotherapy be considered for patients with tumors ≥4 cm. Prior population-based evaluations lacked lung cancer-specific survival (LCSS) and health insurance status. The authors aimed to identify predictors of adjuvant chemotherapy use and assess its real-world benefit in T2N0M0 NSCLC. MATERIALS AND METHODS: The authors included patients who underwent surgery for T2N0M0 NSCLC in a large Canadian province with universal health care between 2004 and 2015, grouping cases by adjuvant chemotherapy receipt. They identified predictors of chemotherapy use with logistic regression and correlates of overall survival (OS) and LCSS using Cox regression. RESULTS: The authors analyzed 967 patients. The median age was 68 years (interquartile range, 61 to 74), 455 (47%) were men, and 164 (17%) received adjuvant chemotherapy. Sex, tumor location, and laterality were similar between groups. Younger age, lower Charlson comorbidity score, large cell histology, and tumor size ≥4 cm were associated with a higher likelihood of chemotherapy receipt (all P<0.05). In the entire cohort and in the ≥4 and ≥5 cm subgroups, chemotherapy improved OS but not LCSS on univariate analysis. Chemotherapy was not associated with OS or LCSS in multivariate analysis (OS hazard ratio [HR], 0.925; 95% confidence interval [0.693-1.236], P=0.598, 0.725 [0.454-1.157], P=0.177 in the ≥4 cm group; LCSS HR, 1.196 [0.843-1.695], P=0.316, 0.917 [0.533-1.577], P=0.754 in the ≥4 cm group). CONCLUSION: Adjuvant chemotherapy was not associated with improved survival in this population-based T2N0M0 NSCLC cohort, even for ≥4 or ≥5 cm tumors, suggesting that it has a limited role in real-world practice.

The Lung Immune Prognostic Index Discriminates Survival Outcomes in Patients with Solid Tumors Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of several solid tumor types. However, as patient outcomes are heterogeneous, clinical tools to aid in prognostication are needed. The Lung Immune Prognostic Index (LIPI) correlates with outcomes in patients with non-small cell lung cancer (NSCLC) treated with ICI, but its applicability beyond NSCLC is poorly defined. We sought to determine whether LIPI is associated with overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in a pooled, real-world, retrospective cohort of patients with solid tumors treated with ICI. Of the total pooled cohort (N = 578), 47.2%, 38.2% and 14.5% of patients were stratified into good, intermediate and poor LIPI group, respectively. Median OS were 22.8 (95% CI 17.4-29.5), 7.8 (95% CI 6.6-9.6), and 2.5 months (95% CI 1.4-3.4) (p < 0.0001). Median PFS were 9.9 (95% CI 7.2-11.5), 3.6 (95% CI 2.7-4.3), and 1.4 months (95% CI 1.2-2.2) (p < 0.0001). ORR was also associated with LIPI group (p < 0.001). Intermediate and poor LIPI were independently prognostic of OS compared to good LIPI, with hazard ratios (HR) of 1.8 (95% CI 1.4-2.3, p < 0.001) and 3.6 (95% CI 2.5-5.1, p < 0.001), respectively. These data are the first to suggest that in a real-world setting, the prognostic value of LIPI may be tumor agnostic.

Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells.

BACKGROUND: Up to 40% of lung adenocarcinoma have been reported to lack ataxia-telangiectasia mutated (ATM) protein expression. We asked whether ATM-deficient lung cancer cell lines are sensitive to poly-ADP ribose polymerase (PARP) inhibitors and determined the mechanism of action of olaparib in ATM-deficient A549 cells. METHODS: We analysed drug sensitivity data for olaparib and talazoparib in lung adenocarcinoma cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) project. We deleted ATM from A549 lung adenocarcinoma cells using CRISPR/Cas9 and determined the effects of olaparib and the ATM/Rad3-related (ATR) inhibitor VE-821 on cell viability. RESULTS: IC50 values for both olaparib and talazoparib positively correlated with ATM mRNA levels and gene amplification status in lung adenocarcinoma cell lines. ATM mutation was associated with a significant decrease in the IC50 for olaparib while a similar trend was observed for talazoparib. A549 cells with deletion of ATM were sensitive to ionising radiation and olaparib. Olaparib induced phosphorylation of DNA damage markers and reversible G2 arrest in ATM-deficient cells, while the combination of olaparib and VE-821 induced cell death. CONCLUSIONS: Patients with tumours characterised by ATM-deficiency may benefit from treatment with a PARP inhibitor in combination with an ATR inhibitor.

Factors associated with early mortality in non-small cell lung cancer patients following systemic anti-cancer therapy: A 10 year population-based study.

OBJECTIVES: To investigate how clinical, demographic and treatment-related factors in non-small cell lung cancer (NSCLC) patients impact the risk of mortality in the 30 days following receipt of systemic anti-cancer therapies (SACT), and undertake a comprehensive review of the treatment decisions and experiences of a real-world population. MATERIALS AND METHODS: We reviewed NSCLC patients receiving SACT from 2005 to 2014, and captured in the Glans-Look Lung Cancer Database, which contains demographic, clinical, pathological, treatment and outcome data. The 30-day post-SACT mortality rate was calculated, and regimen changes in the last 14 days of life were identified. Univariate analysis and multivariate logistic regression were used to identify demographic, tumor and treatment-related factors that correlated with mortality risk. RESULTS: 1044 patients receiving ≥ 1 cycle of SACT in 2005-2014 were identified. 233 (22.3%) deaths occurred ≤ 30 days following SACT receipt; 32 (13.7%) of which had new SACT regimens ≤ 14 days prior to death. Risk of 30-day mortality and regimen changes at the end of life increased in association with being male [OR: 1.48 (1.12-1.95), p = 0.005], advanced disease at diagnosis [OR: 1.85 (1.19-2.88), p = 0.006], palliative-intent treatment [OR: 6.75 (3.88-11.77), p < 0.001], and use of EGFR-targeting agents [OR: 4.5 (3.27-6.18) p < 0.001]. Risk of early mortality decreased for never-smokers [OR: 0.62 (0.41-0.95), p = 0.028], and those receiving SACT in more recent years (2010-2014) [OR: 0.65 (0.49-0.86), p = 0.002]. CONCLUSION: Our findings identified several factors that affected the risk of early mortality in NSCLC patients following SACT. These results from a representative population provide insights regarding the benefits and risks of SACT and can serve to inform clinical and palliative best practices.

Impact of number versus location of metastases on survival in stage IV M1b non-small cell lung cancer.

BACKGROUND: To assess the impact of location versus number of extra-pulmonary metastatic sites (EPMS) on survival in stage IV non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Retrospective analysis was conducted on patients diagnosed during 1999-2013 with stage IV, M1b (AJCC 7th edition) NSCLC using the large, institutional Glans-Look Database, which contains patient demographic, clinical, pathological, treatment, and outcome information. We assessed the impact of location and number of EPMS and identified correlates of overall survival using the Kaplan-Meier method and Cox regression. RESULTS: We identified a total of 2065 NSCLC patients with EPMS. Median age was 67 (IQR 58-75) years, 52% were men, and 78% were current or former smokers. 60% had one EPMS, and 40% had two or more EPMS. Among those with only one EPMS, most frequent organ involvement included bone (40%), brain (32%), and liver (13%). Median overall survival (mOS) was worst in those with liver metastasis and best in those with adrenal metastasis (2.0 vs. 5.2 months, p = 0.015). However, outcomes based on site of organ involvement were not significantly different in multivariable analysis. Compared to patients with one EPMS, individuals with two or more EPMS experienced worse outcomes (mOS ≤ 2.9 vs. 3.9 months, p < 0.001), and were associated with worse prognosis in Cox regression analysis (HR 1.5, 95% CI 1.3-1.7, p < 0.001). CONCLUSIONS: Number rather than location of EPMS is a prognostic factor in patients with stage IV M1b NSCLC. This information is relevant for accurate prognostication, stratification of participants in future clinical trials, and timely and appropriate advanced care planning.

Associations of objectively assessed physical activity and sedentary time with health-related quality of life among lung cancer survivors: A quantile regression approach.

OBJECTIVES: No studies have examined objectively assessed physical activity, sedentary time, and patient-reported outcomes among lung cancer survivors. The objective of this study was to determine associations of objectively assessed moderate-to-vigorous intensity physical activity (MVPA) and sedentary time with health-related quality of life (HRQoL) and fatigue among lung cancer survivors. MATERIALS AND METHOD: Lung cancer survivors in Southern Alberta (N = 540) were invited to complete a mailed survey that assessed HRQoL [Functional Assessment of Cancer Therapy-Lung (FACT-L)], physical and functional well-being [Trial Outcome Index (TOI)], and fatigue [Fatigue Scale (FS)]. Physical activity and sedentary time data was collected using an Actigraph® GT3X+ accelerometer that was worn on the hip for seven consecutive days. Quantile regression was used to examine associations of HRQoL and fatigue with physical activity and sedentary time at the 25th, 50th, and 75th HRQoL and fatigue percentiles. RESULTS: A total of 127 lung cancer survivors participated for a 24% response rate (Mean age = 71 years; Mean time since diagnosis = 75 months). Total MVPA minutes was positively associated with fewer fatigue symptoms at the 25th percentile (ß = 0.16, p = 0.046). Total sedentary time was inversely associated with HRQoL at the 75th percentile (ß = -0.07, p = 0.014) and inversely associated with fatigue symptoms at the 50th percentile (ß = -0.04, p = 0.009). Total sedentary time was also inversely associated with physical and functional well-being scores at the 25th (ß = -0.07, p = 0.045), 50th (ß = -0.07, p = 0.004) and 75th (ß = -0.04, p = 0.035) percentiles. CONCLUSION: Across the HRQoL, fatigue, and physical and functional well-being distributions, sedentary time was inversely associated with HRQoL, fatigue, and physical and functional well-being in lung cancer survivors. Small associations were observed between MVPA and fatigue, but no associations emerged with HRQoL or physical and functional well-being.

Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC.

Ataxia-telangiectasia mutated (ATM) is critical in maintaining genomic integrity. In response to DNA double-strand breaks, ATM phosphorylates downstream proteins involved in cell-cycle checkpoint arrest, DNA repair, and apoptosis. Here we investigate the frequency, and influence of ATM deficiency on outcome, in early-resected non-small cell lung cancer (NSCLC). Tissue microarrays, containing 165 formalin-fixed, paraffin-embedded resected NSCLC tumours from patients diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, between 2003 and 2006, were analyzed for ATM expression using quantitative fluorescence immunohistochemistry. Both malignant cell-specific ATM expression and the ratio of ATM expression within malignant tumour cells compared to that in the surrounding tumour stroma, defined as the ATM expression index (ATM-EI), were measured and correlated with clinical outcome. ATM loss was identified in 21.8% of patients, and was unaffected by clinical pathological variables. Patients with low ATM-EI tumours had worse survival outcomes compared to those with high ATM-EI (p < 0.01). This effect was pronounced in stage II/III patients, even after adjusting for other clinical co-variates (p < 0.001). Additionally, we provide evidence that ATM-deficient patients may derive greater benefit from guideline-recommended adjuvant chemotherapy following surgical resection. Taken together, these results indicate that ATM loss seems to be an early event in NSCLC carcinogenesis and is an independent prognostic factor associated with worse survival in stage II/III patients.

ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.

The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor.