Purpose: The EML4-ALK fusion gene has been detected in ∼7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLC and in NSCLC cell lines. We also ...determined whether TAE684, a specific ALK kinase inhibitor, would inhibit
the growth of EML4-ALK -containing cell lines in vitro and in vivo .
Experimental Design: We screened 305 primary NSCLC both U.S. ( n = 138) and Korean ( n = 167) patients and 83 NSCLC cell lines using reverse transcription-PCR and by exon array analyses. We evaluated the efficacy
of TAE684 against NSCLC cell lines in vitro and in vivo .
Results: We detected four different variants, including two novel variants, of EML4-ALK using reverse transcription-PCR in 8 of 305 tumors (3%) and 3 of 83 (3.6%) NSCLC cell lines. All EML4-ALK -containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (<10 pack-years) cigarette smokers compared with current/former
smokers (6% versus 1%; P = 0.049). TAE684 inhibited the growth of one of three (H3122) EML4-ALK -containing cell lines in vitro and in vivo , inhibited Akt phosphorylation, and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to coactivation of epidermal growth factor receptor and ERBB2. The combination
of TAE684 and CL-387,785 (epidermal growth factor receptor/ERBB2 kinase inhibitor) inhibited growth and Akt phosphorylation
and led to apoptosis in the DFCI032 cell line.
Conclusions: EML4-ALK is found in the minority of NSCLC. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective
treatments for NSCLC patients whose tumors contain EML4-ALK .
The understanding of cancer family caregivers' needs and consequences has grown in recent years as more research has been directed toward this population. The physical and psychological impact of ...cancer family caregiving is significant with many associated negative outcomes including depression.
Purpose: Somatic mutations in the epidermal growth factor receptor (EGFR) have been detected in patients with non–small cell lung
cancer (NSCLC) and are associated with sensitivity to treatment with ...gefitinib or erlotinib. Our study explored the relationship
between the two most common types of somatic EGFR mutations, exon 19 deletions and the L858R point mutation, and outcomes
of patients following treatment with gefitinib or erlotinib.
Experimental Design: Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations. Patients with exon
19 deletion or L858R mutations were identified. The response rate, time to progression, and overall survival were determined
for the two groups.
Results: We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an
exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months;
P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus
10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate
analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted 18 of
23 (78%) versus 3 of 9 (33%); P = 0.04. No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated
patients.
Conclusions: Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared
with those with the L858R mutation. Pooling of greater numbers of patients and completion of prospective trials are needed
to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib,
erlotinib, and other EGFR inhibitors.
ABSTRACT
The naked mole‐rat (Heterocephalus glaber) has fascinated zoologists for at least half a century. It has also generated considerable biomedical interest not only because of its extraordinary ...longevity, but also because of unusual protective features (e.g. its tolerance of variable oxygen availability), which may be pertinent to several human disease states, including ischemia/reperfusion injury and neurodegeneration. A recent article entitled ‘Surprisingly long survival of premature conclusions about naked mole‐rat biology’ described 28 ‘myths’ which, those authors claimed, are a ‘perpetuation of beautiful, but falsified, hypotheses’ and impede our understanding of this enigmatic mammal. Here, we re‐examine each of these ‘myths’ based on evidence published in the scientific literature. Following Braude et al., we argue that these ‘myths’ fall into four main categories: (i) ‘myths’ that would be better described as oversimplifications, some of which persist solely in the popular press; (ii) ‘myths’ that are based on incomplete understanding, where more evidence is clearly needed; (iii) ‘myths’ where the accumulation of evidence over the years has led to a revision in interpretation, but where there is no significant disagreement among scientists currently working in the field; (iv) ‘myths’ where there is a genuine difference in opinion among active researchers, based on alternative interpretations of the available evidence. The term ‘myth’ is particularly inappropriate when applied to competing, evidence‐based hypotheses, which form part of the normal evolution of scientific knowledge. Here, we provide a comprehensive critical review of naked mole‐rat biology and attempt to clarify some of these misconceptions.
The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop ...drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.
This is a phase II, multicenter, open-label study of chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) and age > or = 70 years who were treated with erlotinib and evaluated to ...determine the median, 1-year, and 2-year survival. The secondary end points include radiographic response rate, time to progression (TTP), toxicity, and symptom improvement.
Eligible patients with NSCLC were treated with erlotinib 150 mg/d until disease progression or significant toxicity. Tumor response was assessed every 8 weeks by computed tomography scan using Response Evaluation Criteria in Solid Tumors. Tumor samples were analyzed for the presence of somatic mutations in EGFR and KRAS.
Eighty eligible patients initiated erlotinib therapy between March 2003 and May 2005. There were eight partial responses (10%), and an additional 33 patients (41%) had stable disease for 2 months or longer. The median TTP was 3.5 months (95% CI, 2.0 to 5.5 months). The median survival time was 10.9 months (95% CI, 7.8 to 14.6 months). The 1- and 2- year survival rates were 46% and 19%, respectively. The most common toxicities were acneiform rash (79%) and diarrhea (69%). Four patients developed interstitial lung disease of grade 3 or higher, with one treatment-related death. EGFR mutations were detected in nine of 43 patients studied. The presence of an EGFR mutation was strongly correlated with disease control, prolonged TTP, and survival.
Erlotinib monotherapy is active and relatively well tolerated in chemotherapy-naïve elderly patients with advanced NSCLC. Erlotinib merits consideration for further investigation as a first-line therapeutic option in elderly patients.
In non-small-cell lung cancer (NSCLC), clinical and biologic predictors for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor sensitivity have been identified in retrospective ...studies, and there is urgent need to validate these results in prospective trials. The ONCOBELL trial is a prospective phase II study evaluating gefitinib sensitivity in NSCLC patients who never smoked or have increased EGFR gene copy number or activation of the antiapoptotic protein Akt.
EGFR gene copy number was evaluated using fluorescence in situ hybridization (FISH), and presence of phospho-Akt was evaluated using immunohistochemistry. Additional tests included immunohistochemistry analysis of EGFR, FISH analysis of HER2, and mutation analysis of EGFR, HER2, and K-ras.
From November 2004 to February 2006, 183 patients were screened, and 42 patients were enrolled onto the trial. We observed one complete and 19 partial responses, for an overall response rate (RR) of 47.6% (95% CI, 32.5% to 62.7%). Median duration of response was 6.1 months, median time to progression (TTP) was 6.4 months, 1-year survival rate was 64.3%, and median survival time was not reached. EGFR FISH-positive patients, compared with negative patients, had higher RR (68.0% v 9.1%, respectively; P < .001), longer TTP (7.6 v 2.7 months, respectively; P = .02), and a trend for longer survival (median survival not reached v 7.4 months, respectively; P = .3). Therapy was well tolerated, and there were no drug-related deaths. Median follow-up time was too short for significance tests of differences in survival outcomes.
Gefitinib is active and well tolerated in patients with trial characteristics, and EGFR FISH analysis is an accurate predictor for such therapy.
Despite the reported benefits of multimodal surgical prehabilitation, it has not been widely implemented in many hospitals. We would like to share our experiences and challenges in successfully ...piloting a patient-centred prehabilitation programme at our hospital.
For the identification of the patients who most likely benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), molecular assays are ...considered to be of paramount importance. Given the heterogeneity of NSCLC at the molecular level, this study was conducted to determine the discrepancy in EGFR mutations between primary tumors and the corresponding lymph node metastasis.
Surgically resected 101 paired primary NSCLC and metastatic lymph nodes were evaluated for the EGFR mutations by direct DNA sequencing and heteroduplex analysis.
EGFR mutation was detected in 29.7% (30 of 101) of the primary tumors and in 27.7% of lymph node metastases (28 of 101) by either direct sequencing or heteroduplex analysis, respectively. By direct sequencing, 12 cases (11.9%) showed discordance in EGFR mutations between primary tumors and metastasis. In 11 cases, EGFR mutations were detected only in the primary tumor, whereas 1 case only in lymph node metastases. By heteroduplex analysis, 17 cases (16.8%) were discordant. Ten cases were primary tumor positive and lymph node negative, whereas seven cases were lymph node positive and primary tumor negative.
A considerable proportion of NSCLC showed discrepancy in EGFR mutations between primary tumors and metastatic lymph nodes, suggesting tumor heterogeneity at the molecular level during the process of metastasis.
PDF
