Christopher S. Lathan

A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.

The Effect of Race on Invasive Staging and Surgery in Non–Small-Cell Lung Cancer

PURPOSE Black patients with early-stage non-small-cell lung cancer (NSCLC) have worse overall survival than white patients. Decreased likelihood of resection has been implicated. To isolate the effect of decision making from access to care, we used receipt of surgical staging as a proxy for access and willingness to undergo invasive procedures, and examined treatments and outcomes by race. PATIENTS AND METHODS We examined registry and claims data of Medicare-eligible patients with nonmetastatic NSCLC in areas monitored by the Surveillance, Epidemiology, and End Results program from 1991 to 2001. Patients who obtained invasive staging, defined as bronchoscopy, mediastinoscopy, or thoracoscopy, were included. Logistic regression and Cox modeling calculated the odds of having staging and surgery, and survival outcomes. RESULTS A total of 14,224 patients underwent staging, and 6,972 had surgery for lung cancer. Black patients were less likely to undergo staging (odds ratio [OR] = 0.75; 95% CI, 0.67 to 0.83), and once staged, were still less likely to have surgery than whites (OR = 0.55; 95% CI, 0.47 to 0.64). Survival for blacks and whites was equivalent after resection (hazard ratio = 1.02; P = .06). Staged black patients were less likely to receive a recommendation for surgery when it was not clearly contraindicated (67.0% v 71.4%; P < .05), and were more likely to decline surgery (3.4% v 2.0%; P < .05). CONCLUSION Black patients obtain surgery for lung cancer less often than whites, even after access to care has been demonstrated. They are more likely not to have surgery recommended, and more likely to refuse surgery. Additional research should focus on the physician-patient encounter as a potential source of racial disparities.

Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer.

Crystal structure and detailed analysis of different EGFR mutants explain why some mutations in exon 20 make lung cancers resistant to EGFR inhibitors and others make them more sensitive. A Crystal Clear Cause of Drug Resistance Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used to treat a variety of cancers, including non–small cell lung cancer. EGFR mutations have a wide range of effects on the success of TKI treatment in this cancer type, with some sensitizing the tumors to TKI inhibitors and others making them resistant to targeted therapy. For example, most of the mutations in exon 20, a relatively common mutation site, prevent cancer cells from responding to EGFR inhibitors. Here, Yasuda and co-workers determined the crystal structure of EGFR with an exon 20 mutation and used a combination of kinetic studies and structural analysis to elucidate the mechanism for these mutants’ differential sensitivity to TKIs. The findings of Yasuda et al. clarify the reasons for the drug resistance of most exon 20 mutations and show the mechanism for the rare mutation in the same exon that increases tumors’ sensitivity to treatment. In addition to explaining which of the mutants are resistant to targeted inhibition of EGFR and the reasons for this phenomenon, this work could help with the development of future therapeutics. By taking advantage of the crystal structure and detailed insights into the function of mutant EGFR, researchers may be able to design drugs that exploit the unique structural features of resistant mutants and specifically target them for treatment. Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non–small cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (~10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, and afatinib). The basis of this primary resistance is poorly understood. We studied a broad subset of exon 20 insertion mutations, comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients, and found that most are resistant to EGFR TKIs. The crystal structure of a representative TKI-insensitive mutant (D770_N771insNPG) reveals an unaltered adenosine triphosphate–binding pocket, and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation. Unlike EGFR-L858R, D770_N771insNPG activates EGFR without increasing its affinity for EGFR TKIs. Unexpectedly, we find that EGFR-A763_Y764insFQEA is highly sensitive to EGFR TKIs in vitro, and patients whose NSCLCs harbor this mutation respond to erlotinib. Analysis of the A763_Y764insFQEA mutant indicates that the inserted residues shift the register of the C helix in the N-terminal direction, altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R. Our studies reveal intricate differences between EGFR mutations, their biology, and their response to EGFR TKIs.

Support of cancer patients' spiritual needs and associations with medical care costs at the end of life

Although spiritual care is associated with less aggressive medical care at the end of life (EOL), it remains infrequent. It is unclear if the omission of spiritual care impacts EOL costs.

Clinicopathologic Features and Long-Term Outcomes of NUT Midline Carcinoma

Purpose: NUT midline carcinoma (NMC) is a poorly differentiated squamous cancer characterized by rearrangement of the NUT gene. Research advances have provided opportunities for targeted therapy in NMC, yet the clinical features of this rare disease have not been systematically characterized. We report on a large population of such patients to identify the disease characteristics and treatments, correlate them with outcome, and to consider clinical recommendations. Experimental Design: A clinical database was established using retrospective demographic and outcomes data available on all known cases of NMC. Questionnaires were completed by treating physicians. Pathologic, demographic, and clinical variables were assessed for 63 patients, the largest cohort of patients with NMC studied to date. Outcome data from 54 patients were available for survival analyses. Results: The diagnosis of NMC has increased annually since 2007. Since 2009, there has been an observed increase in the age at diagnosis (P < 0.05). Geographic distribution of patients with NMC has been concentrated in the United States (n = 41, 65%). The median overall survival for patients with NMC was 6.7 months. The 2-year progression-free survival (PFS) was 9% with a 95% confidence interval (CI) of 1% to 17% [1-year PFS 15% (5–24%) and 2-year overall survival (OS) was 19% with a 95% CI of 7%–31% (1-year OS: 30% (27–34%)]. Multivariate analysis suggested that extent of surgical resection and initial radiotherapy were independent predictors of PFS and OS. Notably, no chemotherapeutic regimen was associated with improved outcome. Conclusions: NMC portends a poor prognosis among all squamous cell neoplasms and seems to be frequently unrecognized. The finding that conventional chemotherapy has been inadequate indicates a pressing need for the development of targeted therapeutics. Intensive local therapies such as gross total resection and radiotherapy might be associated with enhanced survival. Clin Cancer Res; 18(20); 5773–9. ©2012 AACR.

Integrating Multiple Social Statuses in Health Disparities Research: The Case of Lung Cancer

OBJECTIVE To illustrate the complex patterns that emerge when race/ethnicity, socioeconomic status (SES), and gender are considered simultaneously in health care disparities research and to outline the needed research to understand them by using disparities in lung cancer risks, treatment, and outcomes as an example. PRINCIPAL FINDINGS SES, gender, and race/ethnicity are social categories that are robust predictors of variations in health and health services utilization. These are usually considered separately, but intersectionality theory indicates that the impact of each depends on the others. Each reflects historically and culturally contingent variations in social, economic, and political status. Distinct patterns of risk and resilience emerge at the intersections of multiple social categories and shape the experience of health, health care access, utilization, quality, and outcomes where these categories intersect. Intersectional approaches call for greater attention to understand social processes at multiple levels of society and require the collection of relevant data and utilization of appropriate analytic approaches to understand how multiple risk factors and resources combine to affect the distribution of disease and its management. CONCLUSIONS Understanding how race/ethnicity, gender, and SES are interactive, interdependent, and social identities can provide new knowledge to enhance our efforts to effectively address health disparities.

Racial composition of hospitals: effects on surgery for early-stage non-small-cell lung cancer.

PURPOSE Black patients undergo potentially curative surgery for early-stage lung cancer at a lower rate when compared with white patients. Our study examines the relationship between the percentage of black patients treated at a hospital to determine whether it affects the likelihood of obtaining cancer-directed surgery for patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS We examined claims data of Medicare-eligible patients with nonmetastatic NSCLC living in areas monitored by the Surveillance, Epidemiology, and End Results program between 1991 and 2001. Hospitals were categorized by the percentage of black patients seen: <or= 8%, more than 8% to 29%, and >or= 30%. Logistic regression with clustering analysis was used to calculate the odds of undergoing surgical resection. RESULTS Among 9,688 patients with NSCLC, 59% of white patients were seen at a hospital that had <or= 8% black patients, whereas 60% of black patients were seen in hospitals that had >or= 30% black patients. Regression analysis revealed that hospital racial composition of 30% or greater black patients had a significant negative effect on the likelihood of undergoing surgery for all patients (odds ratio [OR] = 0.71; 95% CI, 0.57 to 0.87), with black race (OR = 0.69; 95% CI, 0.56 to 0.85) and being seen at a low-volume hospital (OR = 0.64; 95% CI, 0.0.49 to 0.83) having a significant negative impact on likelihood of undergoing surgery. CONCLUSION Our study results indicate that patient and hospital characteristics are significant predictors of undergoing surgery for Medicare beneficiaries with localized lung cancer. Further examination of the role of the patient-, provider-, and hospital-level factors, in association with the decision to pursue surgical treatment of localized lung cancers, is needed.

Association of Financial Strain With Symptom Burden and Quality of Life for Patients With Lung or Colorectal Cancer

PURPOSE To measure the association between patient financial strain and symptom burden and quality of life (QOL) for patients with new diagnoses of lung or colorectal cancer. PATIENTS AND METHODS Patients participating in the Cancer Care Outcomes Research and Surveillance study were interviewed about their financial reserves, QOL, and symptom burden at 4 months of diagnosis and, for survivors, at 12 months of diagnosis. We assessed the association of patient-reported financial reserves with patient-reported outcomes including the Brief Pain Inventory, symptom burden on the basis of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, and QOL on the basis of the EuroQoL-5 Dimension scale. Multivariable linear regression models were fit for each outcome and cancer type, adjusting for age, race/ethnicity, sex, income, insurance, stage at diagnosis, and comorbidity. RESULTS Among patients with lung and colorectal cancer, 40% and 33%, respectively, reported limited financial reserves (≤ 2 months). Relative to patients with more than 12 months of financial reserves, those with limited financial reserves reported significantly increased pain (adjusted mean difference, 5.03 [95% CI, 3.29 to 7.22] and 3.45 [95% CI, 1.25 to 5.66], respectively, for lung and colorectal), greater symptom burden (5.25 [95% CI, 3.29 to .22] and 5.31 [95% CI, 3.58 to 7.04]), and poorer QOL (4.70 [95% CI, 2.82 to 6.58] and 5.22 [95% CI, 3.61 to 6.82]). With decreasing financial reserves, a clear dose-response relationship was present across all measures of well-being. These associations were also manifest for survivors reporting outcomes again at 1 year and persisted after adjustment for stage, comorbidity, insurance, and other clinical attributes. CONCLUSION Patients with cancer and limited financial reserves are more likely to have higher symptom burden and decreased QOL. Assessment of financial reserves may help identify patients who need intensive support.

Pathologic characteristics of NUT midline carcinoma arising in the mediastinum.

NUT midline carcinomas (NMCs) comprise a group of highly aggressive tumors that have been reported primarily in the head, neck, and mediastinum of younger individuals. These tumors overexpress the nuclear protein in the testis (NUT), most commonly due to a chromosomal translocation that fuses the NUT gene on chromosome 15 with the BRD4 gene on chromosome 19. Although the earliest recognized cases were described in the thymus or mediastinum, an extensive survey for NMCs among malignant thymic or other mediastinal neoplasms has not been reported. We examined NUT expression in 114 cases of poorly differentiated carcinomas or unclassified mediastinal malignancies using a clinically validated NUT-specific monoclonal antibody. Four of 114 (3.5%) cases showed nuclear NUT expression. A NUT translocation was confirmed by fluorescence in situ hybridization in 3 of these cases. These tumors arose in 2 men and 2 women with a median age of 50 years (range, 28 to 68 y). Three of the tumors were originally diagnosed as undifferentiated epithelioid or round cell malignant neoplasms; 1 tumor contained focal squamous differentiation and was originally diagnosed as a poorly differentiated squamous carcinoma of probable thymic origin. We find that the incidence of NMC within the mediastinum, particularly among undifferentiated tumors, is similar to that reported at other anatomic sites. NMC should be considered in the differential diagnosis of any poorly differentiated epithelioid mediastinal tumor, regardless of age.

Getting back to equal: The influence of insurance status on racial disparities in the treatment of African American men with high-risk prostate cancer.

OBJECTIVES Treating high-risk prostate cancer (CaP) with definitive therapy improves survival. We evaluated whether having health insurance reduces racial disparities in the use of definitive therapy for high-risk CaP. MATERIALS AND METHODS The Surveillance, Epidemiology, and End Results Program was used to identify 70,006 men with localized high-risk CaP (prostate-specific antigen level > 20 ng/ml or Gleason score 8-10 or stage > cT3a) diagnosed from 2007 to 2010. We used multivariable logistic regression to analyze the 64,277 patients with complete data to determine the factors associated with receipt of definitive therapy. RESULTS Compared with white men, African American (AA) men were significantly less likely to receive definitive treatment (adjusted odds ratio [AOR] = 0.60; 95% CI: 0.56-0.64; P < 0.001) after adjusting for sociodemographics and known CaP prognostic factors. There was a significant interaction between race and insurance status (P interaction = 0.01) such that insurance coverage was associated with a reduction in racial disparity between AA and white patients regarding receipt of definitive therapy. Specifically, the AOR for definitive treatment for AA vs. white was 0.38 (95% CI: 0.27-0.54, P < 0.001) among uninsured men, whereas the AOR was 0.62 (95% CI: 0.57-0.66, P < 0.001) among insured men. CONCLUSIONS AA men with high-risk CaP were significantly less likely to receive potentially life-saving definitive treatment when compared with white men. Having health insurance was associated with a reduction in this racial treatment disparity, suggesting that expansion of health insurance coverage may help reduce racial disparities in the management of aggressive cancers.