Comparative analyses of overall survival in patients with anaplastic lymphoma kinase-positive and matched wild-type advanced nonsmall cell lung cancer.

BACKGROUND: The purpose of this study was to investigate the overall survival (OS) of patients with advanced ALK-positive nonsmall cell lung cancer (NSCLC) who were managed in the pre-ALK inhibitor era and to compare their survival with that of a matched case cohort of ALK wild-type (WT) patients. METHODS: Data from 1166 patients who had stage IIIB/IV NSCLC with nonsquamous histology were collected from the NSCLC database of Seoul National University Hospital between 2003 and 2009. ALK fluorescence in situ hybridization (FISH) was used to analyze 262 patients who either had the WT epidermal growth factor receptor (EGFR) or were nonresponders to previous EGFR tyrosine kinase inhibitor (TKI) therapy. Overall survival (OS) was compared between 3 groups: 1) ALK-positive patients, 2) EGFR mutation-positive patients, and 3) ALK-WT/EGFR-WT patients. Progression-free survival (PFS) after first-line chemotherapy and EGFR TKIs also was analyzed. RESULTS: Twenty-three patients were ALK-positive according to FISH analysis and did not receive ALK inhibitors during follow-up. The median OS for ALK-positive patients, EGFR mutation-positive patients, and WT/WT patients was 12.2 months, 29.6 months, and 19.3 months, respectively (vs EGFR mutation-positive patients, P = .001; vs WT/WT, P = .127). The PFS after first-line chemotherapy for the 3 groups was not different. However, the PFS for patients who received EGFR TKIs was shorter in ALK-positive patients compared with the other 2 groups (vs EGFR mutation-positive patients, P < .001; vs WT/WT, P < .021). CONCLUSIONS: In the pre-ALK inhibitor era, ALK-positive patients experienced the shortest survival, although it did not differ statistically from that of WT/WT patients. Although their responses to platinum-based chemotherapy were not different from comparator groups, ALK-positive patients were even more resistant to EGFR TKI treatment than WT/WT patients.

Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.

BACKGROUND: ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period. METHODS: We examined overall survival in patients with advanced, ALK-positive NSCLC who enrolled in the phase 1 clinical trial of crizotinib, focusing on the cohort of 82 patients who had enrolled through Feb 10, 2010. For comparators, we identified 36 ALK-positive patients from trial sites who were not given crizotinib (ALK-positive controls), 67 patients without ALK rearrangement but positive for EGFR mutation, and 253 wild-type patients lacking either ALK rearrangement or EGFR mutation. To assess differences in overall survival, we assessed subsets of clinically comparable ALK-positive and ALK-negative patients. FINDINGS: Among 82 ALK-positive patients who were given crizotinib, median overall survival from initiation of crizotinib has not been reached (95% CI 17 months to not reached); 1-year overall survival was 74% (95% CI 63-82), and 2-year overall survival was 54% (40-66). Overall survival did not differ based on age, sex, smoking history, or ethnic origin. Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls given any second-line therapy (median overall survival not reached [95% CI 14 months to not reached] vs 6 months [4-17], 1-year overall survival 70% [95% CI 50-83] vs 44% [23-64], and 2-year overall survival 55% [33-72] vs 12% [2-30]; hazard ratio 0·36, 95% CI 0·17-0·75; p=0·004). Survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy (median overall survival not reached [95% CI 17 months to not reached] vs 24 months [15-34], 1-year overall survival 71% [95% CI 58-81] vs 74% [61-83], and 2-year overall survival 57% [40-71] vs 52% [38-65]; p=0·786), whereas survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (median overall survival 20 months [95% CI 13-26] vs 15 months [13-17]; p=0·244). INTERPRETATION: In patients with advanced, ALK-positive NSCLC, crizotinib therapy is associated with improved survival compared with that of crizotinib-naive controls. ALK rearrangement is not a favourable prognostic factor in advanced NSCLC. FUNDING: Pfizer Inc, V Foundation for Cancer Research.

A Novel Wearable Device for Continuous Temperature Monitoring & Fever Detection.

Objective: Continuous temperature monitoring in high-risk patients can enable healthcare providers to remotely track patients' temperatures, promptly detect fevers and timely intervene to improve clinical outcomes. We evaluated if a novel wearable, continuous temperature monitor (Verily Patch) can reliably estimate body temperature and early detect fevers in an outpatient setting in patients at a high risk of febrile neutropenia (FN) who recently underwent chemotherapy and autologous stem cell transplantation (ASCT). Methods: 86 patients at a high risk for FN were prospectively enrolled at Mayo Clinic, MN. Patients wore the device in their axilla region for 7 days post ASCT and recorded self-measured oral temperatures every 3 hours. Patients were also followed using clinical standard-of-care procedures with daily oral temperature assessment. The clinic- and patient-assessed oral temperatures were used to develop and evaluate Verily Patch's body temperature and early fever detection algorithms using a K-fold cross-validation approach. Results: The Verily Patch reliably measured body temperatures with an error of 0.35 ± 0.88°F in comparison to clinic- and patient-assessed oral temperatures. The sensitivity and specificity of the patch in detecting clinic-assessed fever episodes was 90.2% and 87.8%. The patch detected 14.3 times the number of clinic-assessed fever episodes with a median lead time of 4.3 hours. Conclusion: Patient self-monitoring of temperature and fever incidents suffers from low accuracy and is impractical for extended periods of time. Continuous temperature monitoring by a wearable device (such as Verily Patch) has the potential to overcome these challenges resulting in better patient clinical outcomes and more cost-effective care.

Comparative analysis of machine learning approaches to classify tumor mutation burden in lung adenocarcinoma using histopathology images.

Both histologic subtypes and tumor mutation burden (TMB) represent important biomarkers in lung cancer, with implications for patient prognosis and treatment decisions. Typically, TMB is evaluated by comprehensive genomic profiling but this requires use of finite tissue specimens and costly, time-consuming laboratory processes. Histologic subtype classification represents an established component of lung adenocarcinoma histopathology, but can be challenging and is associated with substantial inter-pathologist variability. Here we developed a deep learning system to both classify histologic patterns in lung adenocarcinoma and predict TMB status using de-identified Hematoxylin and Eosin (H&E) stained whole slide images. We first trained a convolutional neural network to map histologic features across whole slide images of lung cancer resection specimens. On evaluation using an external data source, this model achieved patch-level area under the receiver operating characteristic curve (AUC) of 0.78-0.98 across nine histologic features. We then integrated the output of this model with clinico-demographic data to develop an interpretable model for TMB classification. The resulting end-to-end system was evaluated on 172 held out cases from TCGA, achieving an AUC of 0.71 (95% CI 0.63-0.80). The benefit of using histologic features in predicting TMB is highlighted by the significant improvement this approach offers over using the clinical features alone (AUC of 0.63 [95% CI 0.53-0.72], p = 0.002). Furthermore, we found that our histologic subtype-based approach achieved performance similar to that of a weakly supervised approach (AUC of 0.72 [95% CI 0.64-0.80]). Together these results underscore that incorporating histologic patterns in biomarker prediction for lung cancer provides informative signals, and that interpretable approaches utilizing these patterns perform comparably with less interpretable, weakly supervised approaches.

PD-L1 Expression by Two Complementary Diagnostic Assays and mRNA In Situ Hybridization in Small Cell Lung Cancer.

INTRODUCTION: Therapeutic antibodies to immune checkpoints show promising results. Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, blocks the cancer immunity cycle by binding the PD-L1 receptor (programmed death 1). We investigated PD-L1 protein expression and messenger RNA (mRNA) levels in SCLC. METHODS: PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC) with SP142 and Dako 28-8 PD-L1 antibodies and in situ hybridization in primary tumor tissue microarrays in both tumor cells and tumor-infiltrating immune cells (TIICs) obtained from a limited-disease SCLC cohort of 98 patients. An additional cohort of 96 tumor specimens from patients with extensive-disease SCLC was assessed for PD-L1 protein expression in tumor cells with Dako 28-8 antibody only. RESULTS: The overall prevalence of PD-L1 protein expression in tumor cells was 16.5%. In the limited-disease cohort, the prevalences of PD-L1 protein expression in tumor cells with SP142 and Dako 28-8 were 14.7% and 19.4% (tumor proportion score cutoff ≥1%) and PD-L1 mRNA ISH expression was positive in 15.5% of tumor samples. Increased PD-L1 protein/mRNA expression was associated with the presence of more TIICs (p < 0.05). The extensive-disease cohort demonstrated a 14.9% positivity of PD-L1 protein expression in tumor cells with Dako 28-8 antibody. CONCLUSIONS: A subset of SCLCs is characterized by positive PD-L1 and/or mRNA expression in tumor cells. Higher PD-L1 and mRNA expression correlate with more infiltration of TIICs. The prevalence of PD-L1 in SCLC is lower than that published for NSCLC. The predictive role of PD-L1 expression in SCLC treatment remains to be established.

Sexual activity and substance use among adolescents by category of physical activity plus team sports participation.

OBJECTIVE: To determine whether being both vigorously active and a team sports participant or being vigorously physically active but not a team member is associated with substance use and sexual risk behaviors. DESIGN: Cross-sectional, using data from the 1999 national Youth Risk Behavior Survey. PARTICIPANTS: A nationally representative sample of 15 349 US high school students. MAIN OUTCOME MEASURES: Sexual risk behaviors and substance use among those who were both physically active and team sports participants, physically active but not on a sports team, physically nonactive but on a sports team, and physically nonactive and not on a sports team by sex and race/ethnicity. RESULTS: Nationwide, 41.9% of the students were both physically active and participants on a sports team, 22.1% were physically active but not sports team members, 12.6% were physically nonactive sports team members, and 22.3% were physically nonactive and not sports team members. More female (mean [SD], 29.3% [2.2%]) than male students (15.3% [1.9%]) were nonactive, and more male students were both physically active and participants in team sports (48.9% [3.4%]) than were female students (34.8% [3.2%]). Black students were more likely to be physically nonactive in both the team and nonteam categories than were students overall. Relative to nonactive nonteam female students, physically active female students on sports teams were less likely to be substance users or engage in sexual risk behaviors than were active nonteam and nonactive team female students. Other associations were specific to racial/ethnic subgroups. CONCLUSION: Overall, being both physically active and a team sports participant was associated with a lower prevalence of several health risk behaviors.

Detection of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer and related issues in ALK inhibitor therapy: a literature review.

Anaplastic lymphoma kinase (ALK) encodes a receptor tyrosine kinase, and ALK gene rearrangement (ALK+) is implicated in the oncogenesis of non-small cell lung carcinomas (NSCLCs), especially adenocarcinomas. The ALK inhibitor crizotinib was approved in August 2011 by the US Food and Drug Administration (FDA) for treating late-stage NSCLCs that are ALK+, with a companion fluorescent in situ hybridization (FISH) test using the Vysis ALK Break Apart FISH Probe Kit. This review covers pertinent issues in ALK testing, including approaches to select target patients for the test, pros and cons of different detection methods, and mechanisms as well as monitoring of acquired crizotinib resistance in ALK+ NSCLCs.

Immunohistochemical screening for anaplastic lymphoma kinase (ALK) rearrangement in advanced non-small cell lung cancer patients.

Fluorescence in situ hybridization (FISH) is currently used to detect non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK) gene rearrangement, who are candidates for ALK inhibitor therapy. However, FISH may not be a practical method for screening for ALK-positive patients in a large population due to its cost and difficulty in interpretation. We investigated the role of immunohistochemistry (IHC) to screen for ALK rearrangement in advanced NSCLC. We identified 1,166 stage IIIB or IV NSCLC patients with non-squamous histology from the Seoul National University Hospital NSCLC database. To enrich ALK-positive cases, we selected 262 patients who were either EGFR wild-type or non-responders to previous EGFR tyrosine kinase inhibitors (TKI). ALK IHC and ALK FISH were performed on formalin-fixed, paraffin-embedded tissue. ALK protein was expressed in 28 (10.7%) tumors in 262 patients. ALK FISH was positive in 25 (9.5%) cases. All patients with IHC score of 3 (n=9) were FISH-positive and all patients with score of 0 (n=234) were FISH-negative. Among patients with IHC scores of 1 and 2, five (83.3%, 5/6) and eleven (84.6%, 11/13) were FISH-positive, respectively. The sensitivity and specificity of ALK IHC with intensity score of 1 or more were 100% and 98.7%, respectively. IHC can be a useful test for screening ALK FISH-positive cases in advanced NSCLC. FISH testing should be considered for advanced NSCLC patients with tumors showing mild to moderate staining for ALK by IHC to confirm ALK translocation.

Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma.

INTRODUCTION: The EML4-anaplastic lymphoma kinase (ALK) translocation is a recognized oncogenic driver in non-small cell lung cancer. We investigated immunohistochemistry (IHC) screening with fluorescence in situ hybridization (FISH) confirmation for ALK detection and estimated the prevalence of ALK positivity in our patient cohort of never-smokers, together with differences in clinical outcomes and prognostic factors for patients with ALK-positive and ALK-negative tumors. METHODS: We designed a three-phase study (training, validation, and testing) in 300 never-smokers with lung adenocarcinoma from the observational Mayo Clinic Lung Cancer Cohort. Tumor samples were tested using IHC and FISH, and concordance between the methods was assessed. Clinical outcomes were assessed via 5-year progression- or recurrence-free survival from diagnosis. Prognostic factors for ALK-positive tumors and metastases were also investigated. RESULTS: ALK-positive patients were significantly (p < 0.05) younger and had higher grade tumors than ALK-negative patients. ALK positivity was 12.2% by IHC and confirmed at 8.2% of tumors by FISH, with complete concordance between IHC 3+/0 and FISH+/- assessments, respectively. Five-year risk of progression or recurrence was doubled for patients with ALK-positive compared with ALK-negative tumors; ALK-positive tumors also appeared to be associated with a higher risk of brain and liver metastases. CONCLUSIONS: Our findings suggest that ALK positivity is associated with a significantly poor outcome in nonsmoking-related adenocarcinoma and that ALK-positive tumors may be associated with an increased risk of brain and liver metastases compared with ALK-negative disease. Consequently, an unmet medical need exists in ALK-positive lung cancer patients, and effective ALK-specific therapies are needed.

Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH.

INTRODUCTION: Accurate, cost-effective methods for testing anaplastic lymphoma kinase gene rearrangement (ALK+) are needed to select patients with non-small cell lung carcinoma for ALK-inhibitor therapy. Fluorescent in situ hybridization (FISH) is used to detect ALK+, but it is expensive and not routinely available. We explored the potential of an immunohistochemistry (IHC) scoring system as an affordable, accessible approach. METHODS: One hundred one samples were obtained from an enriched cohort of never-smokers with adenocarcinoma from the Mayo Clinic Lung Cancer Cohort. IHC was performed using the ALK1 monoclonal antibody with ADVANCE detection system (Dako) and FISH with dual-color, break-apart probe (Abbott Molecular) on formalin-fixed, paraffin-embedded tissue. RESULTS: Cases were assessed as IHC score 0 (no staining; n = 69), 1+ (faint cytoplasmic staining, n = 21), 2+ (moderate, smooth cytoplasmic staining; n = 3), or 3+ (intense, granular cytoplasmic staining in ≥10% of tumor cells; n = 8). All IHC 3+ cases were FISH+, whereas 1 of 3 IHC 2+ and 1 of 21 IHC 1+ cases were FISH+. All 69 IHC 0 cases were FISH-. Considering FISH a gold-standard reference in this study, sensitivity and specificity of IHC were 90 and 97.8%, respectively, when 2+ and 3+ were regarded as IHC positive and 0 and 1+ as IHC negative. CONCLUSIONS: IHC scoring correlates with FISH and may be a useful algorithm in testing ALK+ by FISH in non-small cell lung carcinoma, similar to human epidermal growth factor-2 testing in breast cancer. Further study is needed to validate this approach.

Initial treatment and changes in adjuvant endocrine therapy for early stage breast cancer.

Clinical trials have shown that aromatase inhibitors (AIs) are an important advance in the treatment of early stage breast cancer (ESBC), but practice patterns and the impact of treatment side effects of endocrine therapy in the community setting have not been extensively explored. This retrospective chart review describes practice patterns among patients receiving adjuvant endocrine therapy for ESBC. Charts of 200 patients with confirmed stage I-IIIA breast cancer were reviewed. Patients received first-line treatment with tamoxifen (n=96) or AIs (n=104). Fifty-one patients completed a structured interview regarding symptom burden during therapy. Time to discontinuation or switching from first-line therapy did not vary by drug class (tamoxifen vs. AI). Musculoskeletal symptoms predicted time to switching among AI patients. Tamoxifen patients who switched to AIs tended to do so following clinical guidelines for use of AIs. Interview results showed that more anastrozole than tamoxifen patients cited side effects as the reason for switching.