Bronchioloalveolar carcinoma (BAC) is a subset of pulmonary adenocarcinoma characterized by distinct and unique pathological, molecular, radiographic, and clinical features. While the incidence of pure BAC is rare, comprising only 1% to 4% of non–small-cell lung cancer (NSCLC), mixed subtypes (including BAC with focal invasion and adenocarcinoma with BAC features) represent as much as 20% of adenocarcinomas—and that figure may be increasing. Despite the longstanding recognition of this entity, there is no established treatment paradigm for patients with multifocal BAC, resulting in competing approaches and treatment controversies. Current options for multifocal BAC include both surgery and systemic therapies. Unfortunately, prospective data on systemic approaches are limited by study design and small patient numbers; there are only seven phase II studies involving four therapies. This article evaluates key characteristics of BAC, including the current understanding of histopathology and tumor biology. In addition, it comprehensively reviews the systemic phase II studies in an attempt to clarify the therapeutic challenges in this disease. It also includes the first proposed treatment paradigm that integrates both EGFR mutational status and the sub-histologies, mucinous and nonmucinous BAC.
Bronchioloalveolar carcinoma (BAC) is a subset of pulmonary adenocarcinoma characterized by distinct and unique pathological, molecular, radiographic, and clinical features. BAC was initially described by Malassez in 1876. The term “bronchioloalveolar carcinoma” was coined by Liebow in 1960 and identifies a well-differentiated tumor (adenocarcinoma) with neoplastic cells that spreads along alveoli without stromal reaction or invasion, and with preservation of alveolar architecture. Although the pathological assessment of this tumor is still evolving, the current (1999) definition of BAC by the World Health Organization (WHO) is restricted to lesions with a pure bronchioloalveolar growth pattern in which there is no evidence of invasion of stroma, pleura, or lymphatic spaces. The clinical applicability of this definition remains in question, considering that BAC most often presents as admixed adenocarcinoma, with the clinical course of these tumors often differing from that of both pure BAC and adenocarcinoma. The incidence of pure BAC is rare, comprising only 1% to 4% of non–small-cell lung cancer (NSCLC); however, these mixed subtypes, including BAC with focal invasion and adenocarcinoma with BAC features, represent as much as 20% of adenocarcinomas—and their frequency may be increasing.
As BAC becomes a more recognized entity within the pathological continuum of adenocarcinoma, several controversies have emerged regarding the appropriate management of these tumors, especially those that represent multifocal or unresectable disease. First, while BAC features may be prognostic of improved survival, it remains unclear whether the percentage of BAC admixed within a tumor is prognostic of outcome or predictive of therapy efficacy. For example, should those adenocarcinomas with greater BAC features be more conservatively managed than those with less BAC? Second, there is an increasing awareness that two subtypes of BAC lesions exist: mucinous and nonmucinous. Whether this pathological distinction is clinically relevant and whether it should guide management decisions remain unclear; these questions will be addressed in the discussion section of this review. Finally, it has been demonstrated consistently that patients with advanced-stage BAC have a disproportionately high response to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Recent phase III data in patients with advanced NSCLC have demonstrated the EGFR mutation to be a reliable predictor of response to TKIs in the front-line setting. However, whether response to TKIs in BAC is exclusively mediated by the EGFR mutation that is more frequently found in this subtype of tumor has yet to be prospectively evaluated. In this review, we attempt to evaluate these controversies as we discuss the key characteristics and current management of multifocal/unresectable BAC.
Histopathology of BAC
The definition of BAC has evolved significantly over the years. In 1960, when Averill Liebow gave the tumor its current name, BAC was defined as a subtype of adenocarcinoma with four features: well-differentiated cytology, an origin distal to recognizable bronchi, a proclivity for lymphatic and aerogenous spread, and a tendency to grow across intact alveolar septa. Liebow asserted, however, that this last feature was probably “imaginary,” implying that despite seemingly preserved architecture, invasion was a likely feature. In 1999, a major shift occurred in the WHO classification: BAC was redefined as a neoplasm that demonstrated pure lepidic growth with a lack of invasion of stroma, blood vessels, or pleura. The modification essentially restricted BAC to carcinoma in situ and was maintained in the 2004 revision of the criteria. Currently, tumors that are predominantly BAC and that have areas of invasion are classified as “mixed subtype adenocarcinomas.”
The WHO decision to reclassify BAC as a distinct pathological entity was largely based on seminal work by Noguchi and colleagues, who examined 236 cases of small (less than 2 cm), surgically resected peripheral adenocarcinomas with mediastinal and pulmonary hilar lymph node dissection. Samples were separated into groups by histology, and patients were monitored longitudinally for survival. In patients with Noguchi type A histology (localized bronchioloalveolar carcinoma [LBAC]) and type B histology (LBAC with foci of alveolar collapse), 0% showed lymph node metastasis, and survival was 100% at 5 years. However, among patients with Noguchi type C histology (LBAC with active fibroblastic proliferation), 28% had lymph node metastasis, and 5-year survival was 75%. Furthermore, patients with poorly differentiated adenocarcinoma (Noguchi type D histology) had a 52% 5-year survival rate. These results demonstrated that BAC had a distinct clinical course differing from that of adenocarcinoma and suggesting that this type of tumor warranted its own classification.
Two major subtypes of BAC are recognized by the WHO—mucinous BAC and nonmucinous BAC—along with a third category that represents a combination of the two (Figure 1). Increasing evidence suggests that the major subtypes represent biologically distinct entities and underscores the necessity of distinguishing between the two in pathology specimens.
The nonmucinous variant is the clinically predominant subtype, occurring in 40% to 60% of cases. Nonmucinous BAC tumors tend to present grossly as solitary peripheral nodules and are histologically composed of cuboidal or columnar cells with eosinophilic or clear cytoplasm, with or without vacuolization.[12,13] Nonmucinous BAC is recognized as comprising two cell types: Clara cells, with apical snouts and PAS+ granules; and type 2 pneumocytes, often with eosinophilic nuclear inclusions. No clinical or prognostic difference has been ascribed to a predominance of either cell type. Immunohistochemically, the nonmucinous variant of BAC exhibits a pattern similar to that of conventional adenocarcinoma, with cytokeratin 7 (CK7) and thyroid transcription factor 1 (TTF1) positivity and cytokeratin 20 (CK20) negativity. BAC with nonmucinous histology is more often dependent on EGFR pathway mutations and is consequently more sensitive to EGFR-targeted therapy.
Mucinous BAC occurs in anywhere from 25% to 50% of patients.[11,13] In contrast to nonmucinous tumors, mucinous BAC more commonly presents with extensive disease, manifested as multiple nodules or diffuse consolidation (pneumonic pattern). Because of the more advanced stage at diagnosis, overall prognosis is poorer. Histologically, cells are tall and columnar with basal nuclei and abundant mucin.[12,13] The tumor is thought to arise from metaplastic goblet cells. In mucinous BAC, immunohistochemistry (IHC) results tend to be more variable: CK7 is usually positive, as in nonmucinous BAC; however, CK20 is positive, and TTF1 is usually negative—or weak and patchy if positive. K-ras mutations are more commonly detected in mucinous BAC, likely accounting for the relative insensitivity of this subclass to EGFR-based treatments.
In patients with mixed subtype adenocarcinoma, the exact contribution of a bronchioloalveolar component to prognosis has been the subject of debate. In the only Western study to address this question, Ebright and colleagues reported no significant difference in survival between groups with pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features. The study did include patients with pure BAC who had multifocal disease and pneumonic-type presentations; these patients had poorer expected outcomes. In contrast to the Ebright data, multiple previous Japanese studies have provided evidence—in addition to that of Noguchi’s work—to support a favorable prognosis for specimens with large proportions of BAC and minimal invasion.[16-19] Terasaki and colleagues grouped specimens according to increasing proportions of BAC and reported that groups with either pure BAC or BAC with minimal areas of invasion were less likely to have pleural invasion or metastatic spread to lymph nodes or vasculature. These studies suggest that tumors with higher proportions of BAC may be prognostically more favorable.
In light of the possible differences in clinical behavior between BAC with minimal invasion and tumors with larger invasive components, some authors have proposed that a category called “minimally invasive adenocarcinoma” be established in future classifications. Sakurai and colleagues demonstrated that the prognosis of BAC with stromal invasion limited to the area of tumor growth or the periphery of the tumor scar was equal to that seen in pure BAC. Similarly, Yim and colleagues reported that the prognosis of patients with BAC and invasion of less than 5 mm was equivalent to that of patients with BAC and no evidence of invasion. In 2004, however, a consensus definition of “minimally invasive” BAC was not recommended by the WHO panel on the basis of lack of sufficient evidence. As further data become available, it is possible that this category may be formally separated, considering its increased incidence and clinical relevance.
1. Barkley JE, Green MR. Bronchioloalveolar carcinoma. J Clin Oncol. 1996;14:2377-86.
2. Liebow A. Bronchiolo-alveolar carcinoma. Adv Intern Med. 1960;10:329-58.
3. Travis WD, Colby TV, Corrin B, et al., editors. Histological typing of lung and pleural tumors. 3rd ed. Berlin: Springer-Verlag; 1999.
4. Raz DJ, He B, Rosell R, Jablons DM. Bronchioloalveolar carcinoma: a review. Clin Lung Cancer. 2006;7:313-22.
5. Travis WD, editor. World Health Organization, International Agency for Research on Cancer, international Association for the Study of Lung Cancer, International Academy of Pathology. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon Oxford: IARC Press, Oxford University Press; 2004.
6. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-57.
7. Inoue A, Kobayashi K, Usui K, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol. 2009;27:1394-400.
8. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-8.
9. Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer. 1995;75:2844-52.
10. Garfield DH, Cadranel J. The importance of distinguishing mucinous and nonmucinous bronchioloalveolar carcinomas. Lung. 2009;187:207-8.
11.West H. Emerging approaches to advanced bronchioloalveolar carcinoma. Curr Treat Options Oncol. 2006;7:69-76.
12. Moran CA. Pulmonary adenocarcinoma: the expanding spectrum of histologic variants. Arch Pathol Lab Med. 2006;130:958-62.
13. Yousem SA, Beasley MB. Bronchioloalveolar carcinoma: a review of current concepts and evolving issues. Arch Pathol Lab Med. 2007;131:1027-32.
14. Finberg KE, Sequist LV, Joshi VA, et al. Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. J Mol Diagn. 2007;9:320-6.
15. 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. 2002;74:1640-6; discussion 6-7.
16. Yokose T, Suzuki K, Nagai K, et al. Favorable and unfavorable morphological prognostic factors in peripheral adenocarcinoma of the lung 3 cm or less in diameter. Lung Cancer. 2000;29:179-88.
17. Suzuki K, Yokose T, Yoshida J, et al. Prognostic significance of the size of central fibrosis in peripheral adenocarcinoma of the lung. Ann Thorac Surg. 2000;69:893-7.
18. Sakurai H, Maeshima A, Watanabe S, et al. Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis. Am J Surg Pathol. 2004;28:198-206.
19. Yim J, Zhu LC, Chiriboga L, et al. Histologic features are important prognostic indicators in early stages lung adenocarcinomas. Mod Pathol. 2007;20:233-41.
20. Terasaki H, Niki T, Matsuno Y, et al. Lung adenocarcinoma with mixed bronchioloalveolar and invasive components: clinicopathological features, subclassification by extent of invasive foci, and immunohistochemical characterization. Am J Surg Pathol. 2003;27:937-51.
21. Dacic S. Minimally invasive adenocarcinomas of the lung. Adv Anat Pathol. 2009;16:166-71.
22. Travis WD GK, Franklin W. Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinical importance and research relevance of the 2004 World Health Organization pathologic criteria. Journ Thorac Oncol. 2006;1:S13-S9.
23. Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell. 2005;121:823-35.
24. Besson A, Hwang HC, Cicero S, et al. Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev. 2007;21:1731-46.
25. Yanagi S, Kishimoto H, Kawahara K, et al. PTEN controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice. J Clin Invest. 2007; 117:2929-40.
26. Dacic S, Finkelstein SD, Yousem SA. Clonal selection of adenocarcinoma of the lung as determined by loss of heterozygosity. Exp Mol Pathol. 2005;78:135-9.
27. Sasatomi E, Johnson LR, Aldeeb DN, et al. Genetic profile of cumulative mutational damage associated with early pulmonary adenocarcinoma: bronchioloalveolar carcinoma vs stage I invasive adenocarcinoma. Am J Surg Pathol. 2004;28:1280-8.
28. Yamasaki M, Takeshima Y, Fujii S, et al. Correlation between morphological heterogeneity and genetic alteration within one tumor in adenocarcinomas of the lung. Pathol Int. 2000;50:891-6.
29. Wislez M, Beer DG, Wistuba I, et al. Molecular biology, genomics, and proteomics in bronchioloalveolar carcinoma. J Thorac Oncol. 2006;1(9 Suppl):S8-12.
30. Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc. 2009;6:201-5.
31. Bianchi F, Nicassio F, Di Fiore PP. Unbiased vs biased approaches to the identification of cancer signatures: the case of lung cancer. Cell Cycle. 2008;7:729-34.
32. Garfield DH, Cadranel J, West HL. Bronchioloalveolar carcinoma: the case for two diseases. Clin Lung Cancer. 2008;9:24-9.
33. Marchetti A, Martella C, Felicioni L, et al. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol. 2005;23:857-65.
34. Sakuma Y, Matsukuma S, Yoshihara M, et al. Distinctive evaluation of nonmucinous and mucinous subtypes of bronchioloalveolar carcinomas in EGFR and K-ras gene-mutation analyses for Japanese lung adenocarcinomas: confirmation of the correlations with histologic subtypes and gene mutations. Am J Clin Pathol. 2007;128:100-8.
35. Hirsch FR, Herbst RS, Olsen C, et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol. 2008;26:3351-7.
36. Erman M, Grunenwald D, Penault-Llorca F, et al. Epidermal growth factor receptor, HER-2/neu and related pathways in lung adenocarcinomas with bronchioloalveolar features. Lung Cancer. 2005;47:315-23.
37. Wang C, Yang R, Yue D, Zhang Z. Expression of FAK and PTEN in bronchioloalveolar carcinoma and lung adenocarcinoma. Lung. 2009;187:104-9.
38. Trigaux JP, Gevenois PA, Goncette L, et al. Bronchioloalveolar carcinoma: computed tomography findings. Eur Respir J. 1996;9:11-6.
39. Bonomo L, Storto ML, Ciccotosto C, et al. Bronchioloalveolar carcinoma of the lung. Eur Radiol. 1998;8:996-1001.
40. Sabloff BS, Truong MT, Wistuba II, Erasmus JJ. Bronchioalveolar cell carcinoma: radiologic appearance and dilemmas in the assessment of response. Clin Lung Cancer. 2004;6:108-12.
41. Gandara DR, Aberle D, Lau D, et al. Radiographic imaging of bronchioloalveolar carcinoma: screening, patterns of presentation and response assessment. J Thorac Oncol. 2006;1(9 Suppl):S20-6.
42. Raz DJ, Kim JY, Jablons DM. Diagnosis and treatment of bronchioloalveolar carcinoma. Curr Opin Pulm Med. 2007;13:290-6.
43. Kuriyama K, Seto M, Kasugai T, et al. Ground-glass opacity on thin-section CT: value in differentiating subtypes of adenocarcinoma of the lung. AJR Am J Roentgenol. 1999;173:465-9.
44. Matsugama H. Proportion of ground-glass opacity on high-resolution compted tomography in clinical T1 N0 M0 adenocarcinoma of the lung a predictor of lymph node metastasis. J Thoracic Cardiovasc Surg. 2002;124:221-2.
45. Nakata M, Sawada S, Saeki H, et al. Prospective study of thoracoscopic limited resection for ground-glass opacity selected by computed tomography. Ann Thorac Surg. 2003;75:1601-5; discussion 5-6.
46. Nakamura H, Saji H, Ogata A, et al. Lung cancer patients showing pure ground-glass opacity on computed tomography are good candidates for wedge resection. Lung Cancer. 2004;44:61-8.
47. Travis WD, Garg K, Franklin WA, et al. Evolving concepts in the pathology and computed tomography imaging of lung adenocarcinoma and bronchioloalveolar carcinoma. J Clin Oncol. 2005;23:3279-87.
48. Patsios D, Roberts HC, Paul NS, et al. Pictorial review of the many faces of bronchioloalveolar cell carcinoma. Br J Radiol. 2007;80:1015-23.
49. Shah RM, Balsara G, Webster M, Friedman AC. Bronchioloalveolar cell carcinoma: impact of histology on dominant CT pattern. J Thorac Imaging. 2000;15:180-6.
50. Jung JI, Kim H, Park SH, et al. CT differentiation of pneumonic-type bronchioloalveolar cell carcinoma and infectious pneumonia. Br J Radiol. 2001;74:490-4.
51. Im JG, Han MC, Yu EJ, et al. Lobar bronchioloalveolar carcinoma: “angiogram sign” on CT scans. Radiology. 1990;176:749-53.
52. Akira M, Atagi S, Kawahara M, et al. High-resolution CT findings of diffuse bronchioloalveolar carcinoma in 38 patients. AJR Am J Roentgenol. 1999;173:1623-9.
53. Aquino SL, Halpern EF, Kuester LB, Fischman AJ. FDG-PET and CT features of non-small cell lung cancer based on tumor type. Int J Mol Med. 2007;19:495-9.
54. Sun JS, Park KJ, Sheen SS, et al. Clinical usefulness of the fluorodeoxyglucose (FDG)-PET maximal standardized uptake value (SUV) in combination with CT features for the differentiation of adenocarcinoma with a bronchioloalveolar carcinoma from other subtypes of non-small cell lung cancers. Lung Cancer. 2009;66:205-10.
55. Heyneman LE, Patz EF. PET imaging in patients with bronchioloalveolar cell carcinoma. Lung Cancer. 2002;38:261-6.
56. Yap CS, Schiepers C, Fishbein MC, et al. FDG-PET imaging in lung cancer: how sensitive is it for bronchioloalveolar carcinoma? Eur J Nucl Med Mol Imaging. 2002;29:1166-73.
57. Wang Y. FDG-PET in bronchial alveolar carcinoma. Chinese-German J Clin Oncol. 2006;5:P54-P7.
58. Tanaka R, Horikoshi H, Nakazato Y, et al. Magnetic resonance imaging in peripheral lung adenocarcinoma: correlation with histopathologic features. J Thorac Imaging. 2009;24:4-9.
59. Ohno Y, Hatabu H, Takenaka D, et al. Dynamic MR imaging: value of differentiating subtypes of peripheral small adenocarcinoma of the lung. Eur J Radiol. 2004;52:144-50.
60. Fujimoto K. Usefulness of contrast-enhanced magnetic resonance imaging for evaluating solitary pulmonary nodules. Cancer Imaging. 2008;8:36-44.
61. Dumont P, Gasser B, Rouge C, et al. Bronchoalveolar carcinoma: histopathologic study of evolution in a series of 105 surgically treated patients. Chest. 1998;113:391-5.
62. Carretta A, Canneto B, Calori G, et al. Evaluation of radiological and pathological prognostic factors in surgically-treated patients with bronchoalveolar carcinoma. Eur J Cardiothorac Surg. 2001;20:367-71.
63. Liu YY, Chen YM, Huang MH, Perng RP. Prognosis and recurrent patterns in bronchioloalveolar carcinoma. Chest. 2000;118:940-7.
64. Furak J, Trojan I, Szoke T, et al. Bronchioloalveolar lung cancer: occurrence, surgical treatment and survival. Eur J Cardiothorac Surg. 2003;23:818-23.
65. Laskin J SA, Johnson D. Redefining Bronchioloalveolar Carcinoma. Seminars in Oncology. 2005;32:329-35.
66. Barlesi F, Doddoli C, Thomas P, et al. Bilateral bronchioloalveolar lung carcinoma: is there a place for palliative pneumonectomy? Eur J Cardiothorac Surg. 2001;20:1113-6.
67. Christiani DC, Pao W, DeMartini JC, et al. BAC consensus conference, November 4-6, 2004: epidemiology, pathogenesis, and preclinical models. J Thorac Oncol. 2006;1(9 Suppl):S2-7.
68. Regnard JF, Santelmo N, Romdhani N, et al. Bronchioloalveolar lung carcinoma: results of surgical treatment and prognostic factors. Chest. 1998;114:45-50.
69. Rena O, Papalia E, Ruffini E, et al. Stage I pure bronchioloalveolar carcinoma: recurrences, survival and comparison with adenocarcinoma of the lung. Eur J Cardiothorac Surg. 2003;23:409-14.
70. Roberts PF, Straznicka M, Lara PN, et al. Resection of multifocal non-small cell lung cancer when the bronchioloalveolar subtype is involved. J Thorac Cardiovasc Surg. 2003;126:1597-602.
71. Atkins KA. The diagnosis of bronchioloalveolar carcinoma by cytologic means. Am J Clin Pathol. 2004;122:14-6.
72. Marchevsky AM, Changsri C, Gupta I, et al. Frozen section diagnoses of small pulmonary nodules: accuracy and clinical implications. Ann Thorac Surg. 2004;78:1755-9.
73. Miller DL, Rowland CM, Deschamps C, et al. Surgical treatment of non-small cell lung cancer 1 cm or less in diameter. Ann Thorac Surg. 2002;73:1545-50; discussion 50-1.
74. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-8.
75. Duruisseaux M, Cadranel J, Biron E, et al. Major and prolonged response to pemetrexed in two cases of lung adenocarcinoma with bronchioloalveolar carcinoma features. Lung Cancer. 2009;65:385-7.
76. 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. 2005;16:1076-80.
77. Scagliotti GV, Smit E, Bosquee L, et al. A phase II study of paclitaxel in advanced bronchioloalveolar carcinoma (EORTC trial 08956). Lung Cancer. 2005;50:91-6.
78. 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. 2003;21:2237-46.
79. 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. 2004;350:2129-39.
80. 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. 2004;22:1103-9.
81. Kris MG, Sandler A, Miller M, et al. Cigarette smoking history predicts sensitivity to erlotinib: results of a phase II trial in patients with bronchioloalveolar carcinoma (BAC) [abstract]. J Clin Oncol. 2004;145(July 15 Suppl):7062.
82. West HL, Franklin WA, McCoy J, et al. Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126. J Clin Oncol. 2006;24:1807-13.
83. Hirsch FR GD, McCoy J. Increased EGFR gene copy number detected by FISH is associated with increased sensitivity to gefitinib in patients in patients with bronchioloaveolar carcinoma (BAC)(S0126). J Clin Oncol. 2005;24(628s).
84. Franklin WA CK, Gumerlock PH. Association between activation of ErbB pathway genes and survival following gefitinib treatment in advanced BAC (SWOG 0126). Proc Amer Soc Cli Oncol. 2004;23(620s).
85. Miller VA, Riely GJ, Zakowski MF, et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol. 2008;26:1472-8.
86. Cadranel J, Quoix E, Baudrin L, et al. IFCT-0401 Trial: a phase II study of gefitinib administered as first-line treatment in advanced adenocarcinoma with bronchioloalveolar carcinoma subtype. J Thorac Oncol. 2009;4:1126-35.
87. Ramalingam S, Lee J, Belani CP, et al. Cetuximab for the treatment of advanced bronchioloalveolar carcinoma (BAC): an Eastern Cooperative Oncology Group phase II study (ECOG 1504). J Clin Oncol. 2010;28(15s).
88. 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. 2006;12:3652-6.
89. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-32.
90. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521-9.
91. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004;305:1163-7.
92. Higashiyama M, Kodama K, Yokouchi H, et al. Prognostic value of bronchiolo-alveolar carcinoma component of small lung adenocarcinoma. Ann Thorac Surg. 1999;68:2069-73.
93. Koga T, Hashimoto S, Sugio K, et al. Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia. Am J Clin Pathol. 2002;117:464-70.
94. Okubo K, Mark EJ, Flieder D, et al. Bronchoalveolar carcinoma: clinical, radiologic, and pathologic factors and survival. J Thorac Cardiovasc Surg. 1999;118:702-9.