Distinct Clinical Course of EGFR-Mutant Resected Lung Cancers: Results of Testing of 1118 Surgical Specimens and Effects of Adjuvant Gefitinib and Erlotinib

Background:EGFR and KRAS mutations are mutually exclusive and predict outcomes with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in patients with stage IV lung cancers. The clinical significance of these mutations in patients with resected stage I–III lung cancers is unclear.Methods:At our institution, resection specimens from patients with stage I–III lung adenocarcinomas are tested for the presence of EGFR or KRAS mutations during routine pathology analysis such that the results are available before consideration of adjuvant therapy. In a cohort of 1118 patients tested over 8 years, overall survival was analyzed using multivariate analysis to control for potential confounders, including age, sex, stage, and smoking history. The impact of adjuvant erlotinib or gefitinib was examined in an independent data set of patients exclusively with EGFR mutation, in which date of recurrence was recorded.Results:In the overall population, we identified 227 KRAS (25%) and 222 EGFR (20%) mutations. Patients with EGFR-mutant lung cancers had a lower risk of death compared with those without EGFR mutations, overall survival (OS) HR 0.51 (95% confidence interval [CI]: 0.34–0.76, p < 0.001). Patients with KRAS-mutant lung cancers had similar outcomes compared with individuals with KRAS wild-type tumors, OS HR 1.17 (95% CI: 0.87–1.57, p = 0.30). A separate data set includes only patients with EGFR-mutant lung cancers identified over 10 years (n = 286). In patients with resected lung cancers and EGFR mutation, treatment with adjuvant erlotinib or gefitinib was associated with a lower risk of recurrence or death, disease-free survival HR 0.43 (95% CI: 0.26–0.72, p = 0.001), and a trend toward improved OS.Conclusions:Patients with resected stage I–III lung cancers and EGFR mutation have a lower risk of death compared with patients without EGFR mutation. This may be because of treatment with EGFR TKIs. Patients with, and without KRAS mutation have similar OS. These data support reflex testing of resected lung adenocarcinomas for EGFR mutation to provide prognostic information and identify patients for enrollment on prospective clinical trials of adjuvant EGFR TKIs

Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab

Background: Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear. Findings: We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors. Conclusion: The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy

Structure and mechanism of activity-based inhibition of the EGF-Receptor by Mig6

Mig6 is a feedback inhibitor that directly binds, inhibits and drives internalization of ErbB-family receptors. Mig6 selectivity targets activated receptors. Here we find that the EGF receptor phosphorylates Mig6 on Tyr394, and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Tyr395, by Src. Crystal structures of human EGFR–Mig6 complexes reveal the structural basis for enhanced phosphorylation of primed Mig6 and show how Mig6 rearranges after phosphorylation by EGFR to effectively irreversibly inhibit the same receptor that catalyzed its phosphorylation. This dual phosphorylation site allows Mig6 to inactivate EGFR in a manner that requires activation of the target receptor and can be modulated by Src. Loss of Mig6 is a driving event in human cancer; analysis of 1057 gliomas reveals frequent focal deletions of ERRFI, the gene that encodes Mig6, in EGFR-amplified glioblastomas

Intergenerational learning about keeping health: a qualitative regional Australian study

First published online: December 11, 2012Understanding the conditions under which families try to influence members’ health-related practices can provide information to build concepts adding to models of health promotion. This paper reports on an exploratory qualitative study examining the influences of intergenerational relationships in shaping beliefs, knowledge and practices about health and illness in a regional Australian city. We conducted semi-structured interviews with 27 adults with family members of other generations living in the city, all of whom had experience of asthma. We found that overall people’s experience of health and illness, particularly in childhood, was taken for granted and not reflected upon. It was in the face of serious illness or death of a family member that objective knowledge about health and illness was sought and integrated within the family leading, in most cases, to significant lifestyle changes or ‘doing things differently’. We drew on Bourdieu’s concept of the three forms of theoretical knowledge in analysing our findings. We found the concept of knowledge as ‘primary taken-for-granted experience’, and the concept of praxeological knowledge as the knowledge created by the dialectical relationships between an individual subject and objectives structures were helpful. To influence individual health practices, we need to acknowledge how the family context confirms the taken-for-granted health practices of an individual and the family circumstances that might lead families to seek objective knowledge and make lifestyle changes to promote health.Judy Taylor, Kay Price, Annette Braunack-Mayer, Matthew T. Haren and Robyn McDermot

The Structure of Co-Occurring Bullying Experiences and Associations with Suicidal Behaviors in Korean Adolescents.

OBJECTIVE:This study had two main goals: to examine the structure of co-occurring peer bullying experiences among adolescents in South Korea from the perspective of victims and to determine the effects of bullying on suicidal behavior, including suicidal ideation and suicide attempts, among adolescents. METHOD:This study used data gathered from 4,410 treatment-seeking adolescents at their initial visits to 31 local mental health centers in Gyeonggi Province, South Korea. The structure of peer bullying was examined using latent class analysis (LCA) to classify participants' relevant experiences. Then, a binomial logistic regression adjusted by propensity scores was conducted to identify relationships between experiences of being bullied and suicidal behaviors. RESULTS:The LCA of experiences with bullying revealed two distinct classes of bullying: physical and non-physical. Adolescents who experienced physical bullying were 3.05 times more likely to attempt suicide than those who were not bullied. Victims of (non-physical) cyber bullying were 2.94 times more likely to attempt suicide than were those who were not bullied. CONCLUSIONS:Both physical and non-physical bullying were associated with suicide attempts, with similar effect sizes. Schools and mental health professionals should be more attentive than they currently are to non-physical bullying

Scree plot of AIC and BIC.

<p>Scree plot of AIC and BIC.</p

LCA classes and bullying types.

<p>LCA classes and bullying types.</p

Integrated genomic approaches identify upregulation of SCRN1 as a novel mechanism associated with acquired resistance to erlotinib in PC9 cells harboring oncogenic EGFR mutation

Therapies targeting the tyrosine kinase activity of Epidermal Growth Factor Receptor (EGFR) have been proven to be effective in treating a subset of non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. Inevitably these patients develop resistance to the EGFR-targeted tyrosine kinase inhibitors (TKIs). Here, we performed integrated genomic analyses using an in vitro system to uncover alternative genomic mechanisms responsible for acquired resistance to EGFR-TKIs. Specifically, we identified 80 genes whose expression is significantly increased in the erlotinib-resistant clones. RNAi-based systematic synthetic lethal screening of these candidate genes revealed that suppression of one upregulated transcript, SCRN1, a secernin family member, restores sensitivity to erlotinib by enhancing inhibition of PI3K/AKT signaling pathway. Furthermore, immunohistochemical analysis revealed increased levels of SCRN1 in 5 of 11 lung tumor specimens from EGFR-TKIs resistant patients. Taken together, we propose that upregulation of SCRN1 is an additional mechanism associated with acquired resistance to EGFR-TKIs and that its suppression serves as a novel therapeutic strategy to overcome drug resistance in these patients.

Applying the Socio-ecological Model to Improving Fruit and Vegetable Intake Among Low-Income African Americans

Despite the growing body of literature that provides evidence of the health benefits of a diet high in fruits and vegetables, most Americans eat much less than the recommended amounts of this food group. Among those who are least likely to meet the USDA guidelines for the recommended daily servings of fruits and vegetables are non-Hispanic Blacks and individuals with lower incomes. The purpose of this literature review is to examine the dietary behaviors, focusing on fruit and vegetable intake, of low-income African Americans from a socio-ecological perspective, and to offer rationale for and guidance on integrating socio-ecological concepts into health promoting programs intended to improve dietary behaviors among this population. Based on the 12 descriptive studies retrieved in the review, dietary behaviors and fruit and vegetable intake among African Americans are the result of a complex interplay of personal, cultural, and environmental factors that can be categorized and described using the five levels of influence conceptualized by the socio-ecological model: Intrapersonal level (taste preferences, habits, and nutritional knowledge and skills), Interpersonal level/social environment (processes whereby culture, social traditions, and role expectations impact eating practices; and patterns within peer groups, friends and family), and Organizational, Community, and Public Policy levels/physical environment (environmental factors that affect food access and availability). The socio-ecological model provides a useful framework for achieving a better understanding of the multiple factors and barriers that impact dietary behaviors, and therefore can provide guidance for developing culturally appropriate and sensitive intervention strategies for African Americans. It is an integrative framework that shows great promise in moving the field closer to attaining the goal of improving dietary behaviors and nutritional status among African Americans