Bronchioloalveolar Pathologic Subtype and Smoking History Predict Sensitivity to Gefitinib in Advanced Non–Small-Cell Lung Cancer

Miller, Vincent A.; Kris, Mark G.; Shah, Neelain; Patel, Jyoti D.; Azzoli, Christopher G.; Gomez, Jorge; Krug, Lee M.; Pao, William; Rizvi, Naiyer A.; Pizzo, Barbara; Tyson, Leslie B.; Venkatraman, Ennapadam; Ben-Porat, Leah; Memoli, Natalie; Zakowski, M. F.; Rusch, Valerie W.; Heelan, Robert T.

doi:10.1200/jco.2004.08.158

Cited by 677 publications

(224 citation statements)

References 22 publications

Supporting

Mentioning

204

Contrasting

Unclassified

Order By: Relevance

“…Of these prognostic factors, only PS and lactic dehydrogenase played a significant prognostic role for OS in our study. Smoking history has been a well-known prognostic marker for survival in many clinical trials [9,10,14,15]. However, in our study, smoking history was not significantly associated with both PFS and OS.…”

Section: Discussioncontrasting

confidence: 55%

Prognostic Model to Predict Outcomes in Non-Small Cell Lung Cancer Patients with Erlotinib as Salvage Treatment

Kim

Lee²,

Sun³

et al. 2010

Oncology

View full text Add to dashboard Cite

Purpose: To devise a prognostic model based on clinical parameters for non-small cell lung cancer (NSCLC) patients treated with erlotinib as a salvage therapy. Patients and Methods: Between July 2006 and September 2008, two hundred fifty-seven metastatic/relapsed NSCLC patients who had been treated with erlotinib as a salvage therapy were analyzed retrospectively. Results: For the 257 patients, the median overall survival (OS) and progression-free survival (PFS) with erlotinib treatment were 12.4 and 2.8 months. Multivariate analysis showed that an ECOG performance status of 2 or more, an elevated serum LDH level, and the absence of skin rash were independent adverse prognostic factors for OS and that the presence of intra-abdominal metastasis, 2 or more prior chemotherapy regimens, and the absence of skin rash were prognostic factors for PFS. Patients were categorized into the following 4 prognosis groups on the basis of each adverse prognostic factor: good, intermediate, poor, and very poor prognosis. The median OS times for the good, intermediate, poor, and very poor prognosis groups were 22.0, 9.3, 5.4, and 2.7 months (p < 0.001) and the median PFS times were 6.5, 3.0, 1.2, and 0.9 months (p < 0.001). Conclusion: This prognostic model based on clinical parameters would be useful to identify patients who might be most likely to benefit from erlotinib therapy in clinical practice.

show abstract

Section: Discussioncontrasting

confidence: 55%

Prognostic Model to Predict Outcomes in Non-Small Cell Lung Cancer Patients with Erlotinib as Salvage Treatment

Kim

Lee²,

Sun³

et al. 2010

Oncology

View full text Add to dashboard Cite

show abstract

“…Analyses of both preclinical xenograft models (14) and specimens from gefitinib-sensitive and -refractory tumors (15) did not reveal any obvious relationship between EGFR expression levels and tumor sensitivity. Retrospective epidemiologic analyses suggested that gefitinib is more likely to be effective in Japanese patients (11), individuals with adenocarcinomas of the bronchioloalveolar carcinoma (BAC) subtype, and ''never smokers'' (16).…”

mentioning

confidence: 99%

EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib

Pao

Miller

Zakowski

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

4,011

106

2,899

View full text Add to dashboard Cite

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P ‫؍‬ 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinibrefractory tumors (P ‫؍‬ 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime (''never smokers''), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P ‫؍‬ 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.

show abstract

“…Gefitinib was associated with an objective tumor response rate of 10%-19% in a subset of patients, thus starting the era of personalized medicine in NSCLC. The initial clinical trial with gefitinib and other agents of its class noted that its highest efficacy was in certain subsets of mainly Asian, female, and never-smokers with adenocarcinoma histology (5,6). Understanding the biology behind these differential responses led to the discovery of the two sensitizing EGFR mutations (exon Molecular targeted therapy heralded a new era for the treatment of patients with oncogene-driven advanced-stage non-small-cell lung cancer (NSCLC).…”

Section: Era Of Targeted Therapy For Nsclcmentioning

confidence: 99%

Personalized therapy for lung cancer: Striking a moving target

Pakkala¹,

Ramalingam²

2018

JCI Insight

119

View full text Add to dashboard Cite

Bronchioloalveolar Pathologic Subtype and Smoking History Predict Sensitivity to Gefitinib in Advanced Non–Small-Cell Lung Cancer

Cited by 677 publications

References 22 publications

Prognostic Model to Predict Outcomes in Non-Small Cell Lung Cancer Patients with Erlotinib as Salvage Treatment

Prognostic Model to Predict Outcomes in Non-Small Cell Lung Cancer Patients with Erlotinib as Salvage Treatment

EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib

Personalized therapy for lung cancer: Striking a moving target

Contact Info

Product

Resources

About