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Molecular Characteristics of Bronchioloalveolar Carcinoma and Adenocarcinoma, Bronchioloalveolar Carcinoma Subtype, Predict Response to Erlotinib

Vincent A. Miller, Gregory J. Riely, Maureen F. Zakowski, Allan R. Li, Jyoti D. Patel, Robert T. Heelan, Mark G. Kris, Alan B. Sandler, David P. Carbone, Anne Tsao, Roy S. Herbst, Glenn Heller, Marc Ladanyi, William Pao, David H. Johnson

From the Thoracic Oncology Service, Division of Solid Tumor Oncology, Departments of Medicine, Pathology, Radiology, Human Oncology and Pathogenesis Program, Epidemiology and Biostatistics, and the Joan and Sanford Weill Medical College of Cornell University, Memorial Sloan-Kettering Cancer Center, New York, NY; Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL; Vanderbilt-Ingram Cancer Center, Nashville, TN; and the M.D. Anderson Cancer Center, Houston, TX.

Corresponding author: Vincent A. Miller, MD, Memorial Sloan-Kettering Cancer Center, Howard Building, Room 1012, 1275 York Ave, New York, NY 10021; e-mail: millerv{at}mskcc.org

	ABSTRACT

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Purpose We conducted this phase II trial to determine the efficacy of erlotinib in patients with bronchioloalveolar carcinoma (BAC) and adenocarcinoma, BAC subtype, and to determine molecular characteristics associated with response.

Patients and Methods Patients (n = 101) with BAC (n = 12) or adenocarcinoma, BAC subtype (n = 89), were enrolled. All patients received erlotinib 150 mg daily. Epidermal growth factor receptor (EGFR) mutation, EGFR copy number, EGFR immunohistochemistry (IHC), and KRAS mutation status were analyzed in available tumors. The primary end point was response rate (RR).

Results Overall RR was 22% (95% CI, 14% to 31%). In patients with pure BAC, the RR and median survival were 20% and 4 months, as compared with 23% and 19 months in those with adenocarcinoma, BAC subtype. No patient (zero of 18; 95% CI, 0% to 19%) whose tumor harbored a KRAS mutation responded to erlotinib. Patients with EGFR mutations had an 83% RR (15 of 18; 95% CI, 65% to 94%) and 23-month median OS. On univariate analysis, EGFR mutation and copy number were associated with RR and PFS. EGFR IHC was not associated with RR or progression-free survival (PFS). After multivariate analysis, only EGFR mutation was associated with RR and PFS. No molecular factors were associated with overall survival.

Conclusion Erlotinib is active in BAC and adenocarcinoma, mixed subtype, BAC. Testing for EGFR and KRAS mutations can predict RR and PFS after treatment with erlotinib in this histologically enriched subset of patients with non–small-cell lung cancer (NSCLC). These data suggest that histologic subtype and molecular characteristics should be reported in clinical trials in NSCLC using EGFR-directed therapy.

	INTRODUCTION

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Adenocarcinoma has become the most common type of non–small-cell lung cancer (NSCLC) diagnosed in the United States.¹ Bronchioloalveolar carcinoma (BAC), a subtype of adenocarcinoma, manifests as lepidic growth of tumor cells along the alveoli without stromal, vascular, lymphatic, or pleural invasion.² Defined in that rigorous fashion, BAC is uncommon, comprising approximately 1% to 4% of NSCLC.³ However, most tumors in which BAC is predominant have some areas where invasion is also present. Using WHO criteria, these invasive tumors are classified as adenocarcinoma mixed subtype and represent 50% of adenocarcinomas.² No reproducible clinical significance has been ascribed to any specific subtype of adenocarcinoma, and the component subtypes (papillary, acinar, solid, or BAC) are included only sporadically in pathology reports. Although pure BAC was heretofore largely a clinical curiosity, adenocarcinoma, mixed subtype with a BAC component (also referred to as adenocarcinoma with BAC features) is a common tumor.⁴

In early studies of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), erlotinib and gefitinib, clinicians noted that a disproportionate number of responses occurred in tumors classified as BAC or in patients with adenocarcinomas but with clinical features associated with BAC, including absent or more modest cigarette smoking histories.^5-8 These characteristics were hypothesized by us and others to be clinical markers for a molecular fingerprint of sensitivity to the EGFR-TKIs.

Within NSCLC, histology has not generally been useful in predicting response to cytotoxic therapy.⁹ However, moving beyond histologic description may provide better predictive and prognostic markers. Mutations in KRAS and EGFR are critical to the pathogenesis of a large number of lung adenocarcinomas, are mutually exclusive, and occur in approximately 40% of tumors from the United States and 70% of tumors from East Asian countries.^10,11 Mutations in KRAS are found in approximately 30% of human lung adenocarcinomas and, in mouse model systems, have been shown to cause lung adenocarcinomas.¹² More recently, mutations in EGFR have been identified in lung adenocarcinoma and have been associated with response to EGFR-TKI.^7,13,14 Mutations in EGFR occur in 13% of unselected US populations, 33% of unselected East Asian populations, and overall in 30% of adenocarcinomas.¹⁵ Expression of the two most common EGFR mutations, exon 19 deletions and exon 21 L858R substitutions, leads to lung adenocarcinomas in mouse model systems.^16,17

We sought to determine the activity of erlotinib in patients with pure BAC, adenocarcinomas that contained a proportion of BAC, or those tumors that had cytologic features of BAC when no histologic specimen was available.^2,18-20 After initiation of this trial, a number of factors were identified in a retrospective fashion as predictive of response or resistance to treatment with erlotinib. To assess the predictive values of these molecular factors, EGFR mutation, KRAS mutation, EGFR expression, and EGFR copy number were assessed in all available specimens.

	PATIENTS AND METHODS

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Eligibility Criteria
Eligible patients had histologic or cytologic evidence of BAC diagnosed by a pathologist at the participating centers. Patients were enrolled between July 2002 and May 2005. Patients must have had clinical stage IIIB, stage IV, or recurrent disease, and a measurable indicator lesion by Response Evaluation Criteria in Solid Tumor²¹ classification that had not been irradiated. Patients could have received no more than one prior chemotherapy regimen for advanced NSCLC and 3 weeks must have elapsed since prior chemotherapy or radiation therapy. Eligible patients had Karnofsky performance status (PS) 60% or Eastern Cooperative Oncology Group PS 2, WBC 3,000/µL, hemoglobin 9.0 g/dL, platelet count 100,000/µL, and adequate liver and kidney function. Patients were excluded if they had received prior erlotinib, gefitinib, cetuximab, or trastuzumab, or had concurrent active cancer. Patients with brain metastases that were radiographically stable and asymptomatic were eligible. All patients signed informed consent. The protocol was approved by the institutional review boards of the collaborating institutions.

Patient Evaluation and Treatment
Within 2 weeks of study entry, patients underwent history, physical examination, CBC, and serum chemistry panel. Computed tomography scanning of all relevant disease sites was performed within 4 weeks of study entry. Patients had a repeat computed tomography scan after 4 and 8 weeks of therapy, and every 8 weeks thereafter. Physical examination, CBC, and chemistry panel were performed before each 4-week cycle of erlotinib. Patients continued taking erlotinib unless they developed progressive disease or unacceptable toxicity. During the first 8 weeks of treatment, patients were seen on a weekly basis. During the third month, patients were evaluated every 2 weeks. Thereafter, evaluations were monthly. All patients were treated with erlotinib 150 mg daily, supplied by OSI Pharmaceuticals (Melville, NY).

Biostatistics
This multicenter, single-arm, two-stage, phase II trial sought to determine whether erlotinib treatment resulted in a clinically meaningful proportion of radiographic regressions. A Response Evaluation Criteria in Solid Tumor classification response rate (RR) of 15% or greater would be of interest in this patient population.²¹ If one response was noted in the first 21 patients, an additional 29 patients were to be accrued. If 12 patients in the first 50 patients demonstrated an objective response, the sample size was to be increased to 100 patients to provide additional pathologic material for correlative studies. Survival was defined as time from first treatment to time of death. Progression-free survival (PFS) was defined as the time from first treatment to documentation of progression or death. Time to event distributions were estimated using the Kaplan-Meier method.

Molecular Analyses
EGFR sequencing was performed using direct sequencing of exons 18 to 24 and polymerase chain reaction–based assays to detect exon 19 and 21 mutations. Microdissection was not performed. Direct sequencing can detect mutations present in 12% or more of the tumor sample, whereas polymerase chain reaction–based sequencing can detect mutations when as few as 6% of assayed cells represent tumor.^22,23 EGFR chromogenic in situ hybridization (CISH) was performed using a Zymed probe (Invitrogen, Carlsbad, CA). Signals were counted from 30 nuclei and the mean value was calculated.²⁴ EGFR immunohistochemistry (IHC) was performed using a DAKO (Carpinteria, CA) test and scored and interpreted according to standard human epidermal growth factor receptor 2 scoring guidelines. KRAS exon 2 mutations were identified by direct sequencing, which provides an estimated sensitivity of 75%.²³ When tissue resources were limited, studies were prioritized as EGFR mutation analysis, EGFR CISH, KRAS sequencing followed by EGFR IHC. Each of these variables was explored for relationship to response, PFS, and overall survival (OS) using Fisher's exact tests and log-rank tests, respectively. The likelihood ratio test from a log-linear model was used to determine the set of molecular variables that jointly predicted response. For PFS, the score statistic from the Cox proportional hazards model was used to determine these factors.

	RESULTS

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Baseline characteristics of the 101 patients treated are listed in Table 1. Patients were enrolled at three sites (81 at Memorial Sloan-Kettering Cancer Center [New York, NY], 14 at Vanderbilt-Ingram Cancer Center [Nashville, TN], and six at M.D. Anderson Cancer Center [Houston, TX]). Adenocarcinoma, mixed subtype, with BAC, was more common than BAC, which was identified in 12 patients (Table 1). Approximately two thirds of patients were women; 25% (25 of 101) had never smoked and an additional 20% had smoked for 15 pack-years or less, a cut value previously shown to discriminate patients more or less likely to have tumors harboring EGFR mutations.²⁵

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Progression-free survival and (B) overall survival.

To further refine our predictive abilities, we explored the association of combinations of markers and outcomes. Patients with EGFR mutation and EGFR CISH 4 had a 90% RR, 15-month median PFS, and 35-month median OS (Table 4). Conversely, patients without EGFR mutation and low EGFR copy number rarely responded to erlotinib treatment (two of 44 patients) and had much shorter median PFS and median OS. Among the 16 patients with partial response and for whom EGFR mutation status and EGFR CISH were known, 12 had EGFR mutations and, of these, seven had increased copy number; one patient had high copy number but no detectable EGFR mutation. In a plot of best response of indicator lesions and these molecular predictors, the eight greatest reductions were seen in individuals with EGFR mutations (Fig 2).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Maximal reduction for indicator lesions (Response Evaluation Criteria in Solid Tumor classification). KRAS mutations, EGFR mutations, and EGFR copy number are indicated. CISH, chromogenic in situ hybridization.

Nine patients died within 30 days of receiving erlotinib. In one patient, a contribution of erlotinib was likely. This patient died as a result of respiratory failure 3 weeks after beginning erlotinib despite antibiotics, high-dose corticosteroids and mechanical ventilation. Autopsy revealed findings consistent with interstitial lung disease. Five patients died as a result of progressive disease within 30 days of completing therapy. One patient each died as a result of thromboembolic disease, pneumothorax, and pneumonia during treatment.

	DISCUSSION

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Large trials in advanced NSCLC have suggested little difference in response to cytotoxic chemotherapy or survival based on tumor histology. As such, details about histologic subtypes of NSCLC, especially adenocarcinoma subtypes (papillary, acinar, bronchioloalveolar, solid, or mixed), have not been reported in clinical trials. When early trials of the EGFR-TKIs suggested preferential activity in patients with adenocarcinoma, particularly in tumors containing some BAC, investigators began to readdress the importance of pathologic subtype. We undertook this study to define the activity of erlotinib in patients with BAC and adenocarcinoma with BAC, and to characterize the molecular profile of sensitive and resistant patients. Some patients included herein were previously reported by us and formed the basis of our observation that activating mutations in EGFR were present in many patients with responses to erlotinib therapy.¹⁴

Our data show erlotinib to be an active agent in patients with BAC and adenocarcinoma with BAC. The RR of 22% and median survival of 17 months compare favorably with those reported by other groups for BAC-specific studies. Southwest Oncology Group studied a 96-hour infusion of paclitaxel in advanced BAC.²⁶ In that trial of 58 patients, partial responses were seen in 14% (eight of 58 patients) and stable disease was seen in an additional 40% (23 of 58 patients). The median survival was 12 months. Similarly, European Organisation for Research and Treatment of Cancer trial 08956 evaluated a 3-hour infusion of paclitaxel in patients with BAC who had received no prior chemotherapy.²⁷ Two partial responses among 18 patients were noted, and median survival was 9 months. West et al²⁸ reported a trial of gefitinib in BAC. An RR of 15% and median survival of 13 months were observed. These studies suggest that gefitinib and erlotinib provide comparable or perhaps superior efficacy to single-agent paclitaxel in BAC.

These studies provide indirect evidence that the survival of BAC is superior to that of other NSCLC histologies. Given that the histologic subtype of NSCLC may be an important prognostic factor in the context of currently available targeted therapies, histologic subtype should be determined rigorously and reported explicitly in clinical trials in NSCLC.

Molecular discriminators may be better than histology at predicting outcome for some patients. In this group of patients with BAC, or adenocarcinoma mixed subtype with BAC, and with tissue available for analysis, the use of KRAS and EGFR mutational analysis allows patients to be placed into one of three categories with dramatically different RRs (Table 4). Patients with a mutation in KRAS had an RR of 0%. Individuals without mutations in KRAS or EGFR had an RR of 9%. Patients with mutations in EGFR had an RR of 83%. However, EGFR mutation was not significantly associated with OS.

Although EGFR and KRAS mutation status was not a requisite for entry, we obtained results for one or more correlative study in 80% of patients. This high proportion of patients with tumor available is superior to previously published studies and makes the data reported here potentially more representative of this population.^10,29,30 This series confirms that mutations in exon 19 or 21 of EGFR are associated with a high RR to erlotinib, a long PFS, and a trend toward improved OS. Prospective studies have demonstrated RRs of 65% to 90% in clinical trials of gefitinib or erlotinib that mandated an EGFR mutation for treatment eligibility.^31-37 Whether the long survival we observed is due to a favorable prognosis of NSCLC harboring EGFR mutations, treatment with erlotinib, or both, is an area of active research.

EGFR copy number has also been associated with response to treatment with erlotinib and gefitinib.³⁸ In this study, we used CISH to assess gene copy number. CISH offers potential advantages over fluorescent in situ hybridization, including the ability to distinguish between areas of tumor and normal tissue in specimens that often have areas of tumor and normal tissue in close approximation. In this trial, we confirmed the association of increased EGFR copy number with both RR and PFS. Copy number was not associated with OS. In a multivariate analysis, EGFR copy number was not an independent predictor of radiographic response. The dependence of EGFR copy number on EGFR mutation status has been noted previously.³⁹ Presence of four copies of EGFR was identified in one third of patients and was associated with an RR of 43%. However, in patients who had increased EGFR copy number without EGFR mutation, the RR was 8%, similar to the RR for all patients without EGFR mutation (9%).

Nonetheless, not all patients with activating EGFR mutations are sensitive to erlotinib, and 20% to 30% of patients with objective regressions did not have EGFR mutations detected by our assays. Although the assay we used is relatively sensitive for detection of the more common EGFR exon 19 deletions and exon 21 point mutations, more sensitive assays may detect clinically relevant EGFR mutations missed by direct sequencing.⁴⁰ Additional patients garner benefit from erlotinib with protracted stable disease and no detectable EGFR mutation. Several lines of research (reviewed by Bunn et al³⁸) suggest that these individuals commonly have other evidence of dependence on EGFR pathway signaling. Our results support this contention. Individuals with or without EGFR mutations and four EGFR copies tended to have higher RRs than those with less than four copies (Appendix Table A1, online only). Thus, EGFR CISH and EGFR mutation may point to an even greater dependence on signaling and a truly enriched subgroup. Individuals with no molecular predictors of EGFR dependence (wild-type EGFR and EGFR copy number < 4) had a low RR and short PFS with erlotinib. EGFR protein expression by IHC did not predict RR, PFS, or OS after erlotinib treatment.

The poor RR and OS in patients with KRAS mutations are consistent with those of other studies.^10,23,41 The poor outcome of lung adenocarcinoma with KRAS mutations has also been noted in patients given adjuvant chemotherapy for early-stage NSCLC.⁴² Thus, the presence of a KRAS mutation may be both an adverse prognostic factor and a predictor of failure to benefit from erlotinib therapy in advanced disease.

The observation that erlotinib or gefitinib are preferentially active in adenocarcinomas, particularly in those tumors with some BAC component, and the subsequent discovery of activating mutations in EGFR as one of the molecular bases for this, have revolutionized the treatment of NSCLC. In individuals with tumors dependent on EGFR signaling, erlotinib is an option as initial therapy and may be associated with unparalleled survival in some cases. New variables including the subtypes of NSCLC, presence or absence of EGFR and KRAS mutation, and smoking history, in addition to more widely recognized predictors of survival such as PS and weight loss, need to be reported routinely in NSCLC trials. Future research should attempt to identify the molecular hallmarks of rapidly progressive BAC, elucidate the basis of erlotinib sensitivity in patients without demonstrable EGFR mutations, and investigate whether other subtypes of adenocarcinoma have characteristic molecular aberrations for which targeted therapy may exist.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Vincent A. Miller, Genentech (C), OSI Pharmaceuticals (C); Gregory J. Riely, Genentech (C); Mark G. Kris, Genentech (C); Alan B. Sandler, Genentech (C), OSI Pharmaceuticals (C); David P. Carbone, Genentech (C); Roy S. Herbst, Genentech (C) Stock Ownership: None Honoraria: Alan B. Sandler, Genentech; David P. Carbone, Genentech; Roy S. Herbst, Genentech Research Funding: Vincent A. Miller, Genentech, OSI Pharmaceuticals; Gregory J. Riely, Genentech; Maureen F. Zakowski, Genentech; Allan R. Li, Genentech; Robert T. Heelan, Genentech; Alan B. Sandler, Genentech; David P. Carbone, Genentech; Anne Tsao, Genentech; Roy S. Herbst, Genentech; Marc Ladanyi, Genentech; William Pao, Genentech; David H. Johnson, Genentech Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Vincent A. Miller, Jyoti D. Patel, Mark G. Kris, William Pao, David H. Johnson

Financial support: Vincent A. Miller

Administrative support: Vincent A. Miller

Provision of study materials or patients: Vincent A. Miller, Jyoti D. Patel, Mark G. Kris, Alan B. Sandler, David P. Carbone, Anne Tsao, Roy S. Herbst, William Pao, David H. Johnson

Collection and assembly of data: Vincent A. Miller, Gregory J. Riely, Maureen F. Zakowski, Jyoti D. Patel, Robert T. Heelan, Roy S. Herbst, Marc Ladanyi, William Pao, David H. Johnson

Data analysis and interpretation: Vincent A. Miller, Gregory J. Riely, Maureen F. Zakowski, Allan R. Li, David P. Carbone, Glenn Heller, Marc Ladanyi, William Pao, David H. Johnson

Manuscript writing: Vincent A. Miller

Final approval of manuscript: Vincent A. Miller, Gregory J. Riely, Maureen F. Zakowski, Allan R. Li, Jyoti D. Patel, Robert T. Heelan, Mark G. Kris, Alan B. Sandler, David P. Carbone, Anne Tsao, Roy S. Herbst, Glenn Heller, Marc Ladanyi, William Pao, David H. Johnson

	Appendix

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	ACKNOWLEDGMENTS

 
We thank the members of the Memorial Sloan-Kettering Lung Cancer Oncogenome Group for thoughtful discussion and review of the manuscript.

	NOTES

 
Supported by Genentech Inc, South San Francisco, CA, and grants from the National Institutes of Health (Grants No. CA68485, CA90949, and CA08748).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Travis WD, Travis LB, Devesa SS: Lung cancer. Cancer 75:191-202, 1995[CrossRef][Medline]

2. Travis WD, Brambilla E, Muller KM, et al: Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France, IARC Press, 2004

3. Read WL, Page NC, Tierney RM, et al: The epidemiology of bronchioloalveolar carcinoma over the past two decades: Analysis of the SEER database. Lung Cancer 45:137-142, 2004[CrossRef][Medline]

4. Ebright MI, Zakowski MF, Martin J, et al: Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma. Ann Thorac Surg 74:1640-1646, 2002[Abstract/Free Full Text]

5. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003[Abstract/Free Full Text]

6. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non–small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 21:2237-2246, 2003[Abstract/Free Full Text]

7. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004[Abstract/Free Full Text]

8. Miller VA, Kris MG, Shah N, et al: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non–small-cell lung cancer. J Clin Oncol 22:1103-1109, 2004[Abstract/Free Full Text]

9. O'Connell JP, Kris MG, Gralla RJ, et al: Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non–small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 4:1604-1614, 1986[Abstract/Free Full Text]

10. Eberhard DA, Johnson BE, Amler LC, et al: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non–small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23:5900-5909, 2005[Abstract/Free Full Text]

11. Tam IY, Chung LP, Suen WS, et al: Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res 12:1647-1653, 2006[Abstract/Free Full Text]

12. Fisher GH, Wellen SL, Klimstra D, et al: Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 15:3249-3262, 2001[Abstract/Free Full Text]

13. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004[Abstract/Free Full Text]

14. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004[Abstract/Free Full Text]

15. Shigematsu H, Gazdar AF: Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 118:257-262, 2006[CrossRef][Medline]

16. Politi K, Zakowski MF, Fan PD, et al: Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev 20:1496-1510, 2006[Abstract/Free Full Text]

17. Ji H, Li D, Chen L, et al: The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 9:485-495, 2006[CrossRef][Medline]

18. Zaman SS, van Hoeven KH, Slott S, et al: Distinction between bronchioloalveolar carcinoma and hyperplastic pulmonary proliferations: A cytologic and morphometric analysis. Diagn Cytopathol 16:396-401, 1997[CrossRef][Medline]

19. Ohori NP, Santa Maria EL: Cytopathologic diagnosis of bronchioloalveolar carcinoma: Does it correlate with the 1999 World Health Organization definition? Am J Clin Pathol 122:44-50, 2004[CrossRef][Medline]

20. Auger M, Katz RL, Johnston DA: Differentiating cytological features of bronchioloalveolar carcinoma from adenocarcinoma of the lung in fine-needle aspirations: A statistical analysis of 27 cases. Diagn Cytopathol 16:253-257, 1997[CrossRef][Medline]

21. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

22. Pan Q, Pao W, Ladanyi M: Rapid polymerase chain reaction-based detection of epidermal growth factor receptor gene mutations in lung adenocarcinomas. J Mol Diagn 7:396-403, 2005[Abstract/Free Full Text]

23. Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17, 2005[CrossRef][Medline]

24. Bhargava R, Gerald WL, Li AR, et al: EGFR gene amplification in breast cancer: Correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod Pathol 18:1027-1033, 2005[CrossRef][Medline]

25. Pham D, Kris MG, Riely GJ, et al: Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol 24:1700-1704, 2006[Abstract/Free Full Text]

26. West HL, Crowley JJ, Vance RB, et al: Advanced bronchioloalveolar carcinoma: A phase II trial of paclitaxel by 96-hour infusion (SWOG 9714)—A Southwest Oncology Group study. Ann Oncol 16:1076-1080, 2005[Abstract/Free Full Text]

27. Scagliotti GV, Smit E, Bosquee L, et al: A phase II study of paclitaxel in advanced bronchioloalveolar carcinoma (EORTC trial 08956). Lung Cancer 50:91-96, 2005[CrossRef][Medline]

28. West HL, Franklin WA, McCoy J, et al: Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126. J Clin Oncol 24:1807-1813, 2006[Abstract/Free Full Text]

29. Bell DW, Lynch TJ, Haserlat SM, et al: Epidermal growth factor receptor mutations and gene amplification in non–small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 23:8081-8092, 2005[Abstract/Free Full Text]

30. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005[Abstract/Free Full Text]

31. Morikawa A, Inoue A, Suzuki T, et al: Prospective analysis of the epidermal growth factor receptor gene mutations in non-small cell lung cancer in Japan. J Clin Oncol 24:383s, 2006 (suppl; abstr 7077)

32. Paz-Ares L, Sanchez JM, Garcia-Velasco A, et al: A prospective phase II trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). J Clin Oncol 24:369s, 2006 (suppl; abstr 7020)

33. Sunaga N, Yanagitani N, Kaira K, et al: Phase II study of the efficacy of gefitinib in patients with non-small cell lung cancer with the EGFR mutations. J Clin Oncol 24:409s, 2006 (suppl; abstr 7183)

34. Sutani A, Nagai Y, Udagawa K, et al: Phase II study of gefitinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) gene mutations detected by PNA-LNA PCR clamp. J Clin Oncol 24:383s, 2006 (suppl; abstr 7076)

35. Inoue A, Suzuki T, Fukuhara T, et al: Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non–small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 24:3340-3346, 2006[Abstract/Free Full Text]

36. Cappuzzo F, Toschi L, Trisolini R, et al: Clinical and biological effects of gefitinib in EGFR FISH positive/phospho-akt positive or never smoker non-small cell lung cancer (NSCLC): Preliminary results of the ONCOBELL trial. J Clin Oncol 24:369s, 2006 (suppl; abstr 7023)

37. Kris MG, Pao W, Zakowski MF, et al: Prospective trial with preoperative gefitinib to correlate lung cancer response with EGFR exon 19 and 21 mutations and to select patients for adjuvant therapy. J Clin Oncol 24: 369s, 2006 (suppl; abstr 7021)

38. Bunn PA Jr, Dziadziuszko R, Varella-Garcia M, et al: Biological markers for non-small cell lung cancer patient selection for epidermal growth factor receptor tyrosine kinase inhibitor therapy. Clin Cancer Res 12:3652-3656, 2006[Free Full Text]

39. Takano T, Ohe Y, Sakamoto H, et al: Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non–small-cell lung cancer. J Clin Oncol 23:6829-6837, 2005[Abstract/Free Full Text]

40. Engelman JA, Mukohara T, Zejnullahu K, et al: Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR -amplified lung cancer. J Clin Invest 116:2695-2706, 2006[CrossRef][Medline]

41. Tsao M, Zhu C, Sakurada A, et al: An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non-small cell lung cancer. J Clin Oncol 24:365s, 2006 (suppl; abstr 7005)

42. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-2597, 2005[Abstract/Free Full Text]

Submitted June 11, 2007; accepted October 26, 2007.

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