Bronchioloalveolar Carcinoma Features Research Articles

Paired Phase II Studies of Erlotinib/Bevacizumab for Advanced Bronchioloalveolar Carcinoma or Never Smokers With Advanced Non–Small-cell Lung Cancer: SWOG S0635 and S0636 Trials

BackgroundBefore mutation testing of the epidermal growth factor receptor (EGFR) gene was recognized as highly associated with the activity of EGFR tyrosine kinase inhibitors (TKIs), clinically defined patient populations with bronchioloalveolar carcinoma (BAC) and never smokers were identified as likely to benefit from EGFR TKIs. From preclinical and clinical data suggesting potentially improved efficacy with a combination of an EGFR TKI and the antiangiogenic agent bevacizumab, the Southwestern Oncology Group (SWOG) initiated paired phase II trials to evaluate the combination of erlotinib/bevacizumab in patients with advanced BAC (SWOG S0635) or never smokers with advanced lung adenocarcinoma (SWOG S0636). Materials and MethodsEligible patients with BAC or adenocarcinoma with BAC features (SWOG S0635) or never smokers with advanced lung adenocarcinoma (SWOG S0636) received erlotinib 150 mg/day with bevacizumab 15 mg/kg until progression or prohibitive toxicity. Never smokers with BAC were preferentially enrolled to SWOG S0636. The primary endpoint for both trials was overall survival. ResultsA total of 84 patients were enrolled in the SWOG S0635 trial and 85 in the SWOG S0636 trial. The objective response rate was 22% (3% complete response) in the SWOG S0635 trial and 50% (38% confirmed; 3% complete response) in the SWOG S0636 trial. The median progression-free survival was 5 and 7.4 months in the S0635 and S0636 trials, respectively. The median overall survival was 21 and 29.8 months, respectively. Toxicity consisted mainly of rash and diarrhea in both trials. ConclusionAlthough the field has moved toward molecular, rather than clinical, selection of patients as optimal candidates for EGFR TKI therapy, these results support the hypothesis that a subset of patients in whom erlotinib is particularly active could receive an incremental benefit from the addition of bevacizumab.

Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor.

HER2, a well established oncogenic member of EGFR family, is among the most intensely investigated kinase drug targets. In contrast to hotspot mutations of EGFR, few mutations of HER2 locate in activation loop within kinase domain. We previously reported the molecular mechanism underlying hyper kinase activity of HER2H878Y, a mutation located in activation loop. However, its tumorigenicity in vivo and relevant therapeutics remain to be determined. Here, we report for the first time that HER2H878Y was tumorigenic in vivo in lung adenocarcinoma transgenic mouse model. Induced expression of HER2H878Y in lung epithelial compartments resulted in formation of poorly differentiated lung adenocarcinoma with bronchioloalveolar carcinoma (BAC) features. Strikingly, we found that these tumors depended on continuous expression of HER2H878Y for maintenance. Typical HER2 downstream signaling mediators, including PLCγ1, STAT5 and AKT, were hyperactivated in HER2H878Y driven lung tumors. More importantly, administration of HKI-272, a tyrosine kinase inhibitor (TKI), efficiently shrank HER2H878Y driven tumors in transgenic mouse model. Moreover, we found that combinational treatment with HKI272 and mTOR inhibitor, Rapamycin, showed a superior cytotoxicity to H878Y mutant transformed cells and enhanced activity to elicit apoptosis and inhibit growth in situ in tumorous area. Our work therefore showed that HER2H878Y mutant was a reasonable drug target. Hence, our work supported the assessment of HKI-272/rapamycin treatment in clinical trials.

Expression of CLDN1 and CLDN10 in lung adenocarcinoma in situ and invasive lepidic predominant adenocarcinoma

BackgroundNon-mucinous bronchioloalveolar carcinoma (BAC) is considered the early stage of lung adenocarcinoma and is classified as the lung adenocarcioma in situ (AIS) by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. This study was designed to investigate the gene expression differences between AIS (formerly non–mucinous BAC) and invasive lepidic predominant adenocarcinoma (LPA, formerly non-mucinous BAC pattern with >5 mm invasion, mixed type adenocarcinoma with BAC features) and to investigate the mechanism of the progression of lung adenocarcinoma in situ to invasive adenocarcinoma.MethodsGene expression analysis was performed by using Agilent 4 × 44 K Whole Human Genome Oligo Microarray on 10 fresh frozen tissue samples of AIS and LPA, respectively. Real time RT-PCR was used to validate the differential expression of 13 genes selected by cDNA microarray on fresh frozen tissue samples from 41 patients with lung adenocarcinoma and 4 genes were confirmed. These 4 genes were then validated by western blotting. Immunohistochemical staining for these validated genes was performed on formalin-fixed, paraffin-embedded tissue samples from 81 cases of lung adenocarcinomna.ResultsWe identified a 13 gene expression signature by comparative analysis of gene expression. Expression of these genes strongly differed between AIS and LPA. Four genes (MMP-2, c-fos, claudin 1 (CLDN1) and claudin 10(CLDN10)) were correlated with the results of microarray and real time RT-PCR analyses for the gene-expression data in samples from 41 patients with lung adenocarcinoma. As confirmed by western blotting, the expression levels of MMP-2 and c-fos were higher in LPA than those in AIS; the expression levels of CLDN1 and CLDN10 in LPA were lower than those in AIS. Immunohistochemical staining for these genes in samples from 81 cases of lung adenocarcinoma demonstrated the expressions of CLDN1 and CLDN10 were correlated with overall survival of patients with lung adenocarcinoma.ConclusionsCLDN1 and CLDN10 may play important roles in the development of AIS to LPA. Overexpression of CLDN1 and CLDN10 indicates a favorable prognosis for overall survival in some patients with lung adenocarcinoma. Expression of CLDN10 may be regulated by the c-fos pathway.

Southwestern Oncology Group Phase II Trial (S0526) of Pemetrexed in Bronchioloalveolar Carcinoma Subtypes of Advanced Adenocarcinoma

BackgroundPemetrexed, a multitargeted antifolate drug, is an active agent in non–small-cell lung cancer (NSCLC), especially adenocarcinomas. Based on preclinical data supporting the relevance of alpha-folate receptors in adenocarcinoma of the bronchioloalveolar carcinoma (BAC) subtype, this trial was designed to assess pemetrexed in patients with this pathologic subtype of lung adenocarcinoma. Patients and MethodsPatients with histologically confirmed stage IIIB (with malignant pleural effusion) or stage IV adenocarcinoma with BAC features or pure BAC were eligible. Treatment consisted of pemetrexed, 500 mg/m2, administered intravenously every 21 days. ResultsOf 27 patients enrolled, 24 were eligible and assessable for adverse events: Toxicity was primarily hematologic, consisting of leukopenia/neutropenia, thrombocytopenia, and anemia. The median follow-up among patients still alive (n = 8) was 35 months (range, 26-47 months). Among 17 patients with measurable disease, the response rate was 23% (all partial responses; 95% confidence interval [CI], 10%-56%). The median progression-free survival (PFS) and overall survival (OS) were 6 and 25 months, respectively. ConclusionPemetrexed is active and well tolerated and, in patients with adenocarcinoma BAC subtypes, likely related to its underlying mechanism of action as a multitargeted antifolate drug.

Positron emission tomography in bronchioloalveolar carcinoma of the lung

ObjectivesThis study assessed the maximum standard uptake value of positron emission tomography–computed tomography in patients of pulmonary adenocarcinoma with bronchioloalveolar carcinoma features and whether SUVmax correlates with pathological status, lymph node metastasis, and prognosis. MethodsWe retrospectively reviewed 674 patients diagnosed with non-small-cell lung cancer between January 2002 and June 2009. Patients with clinical stage I–II disease underwent a preoperative PET–CT scan followed by anatomic resection. We reviewed the clinical features of 209 patients with an average follow-up of 87 months. ResultsWe analyzed clinical variables for 40 patients with BAC features and 169 patients without BAC features. Age, sex, location, and number of dissected lymph nodes, carcinoembryonic antigen level, and lymphovascular invasion had no difference between the two groups. Compared with non-BAC patients, patients with BAC features had a lower SUVmax (2.51 ± 2.02 vs 4.98 ± 4.03, p < 0.001), lower ratio of SUVmax (1.10 ± 0.34 vs 1.22 ± 0.27, p = 0.014), better tumor differentiation (p < 0.001), and smaller tumor size (2.30 ± 1.41 vs 2.97 ± 1.71, p < 0.03). The negative prediction rate was 87.08% for N2 and 80.80% for N1 disease. All patients in the BAC group were alive after the operation. The five-year survival rate of patients without BAC features was 71.2%. ConclusionsPreoperative SUVmax of PET–CT was more accurate at predicting negative N2 than N1 disease. BAC is associated with markedly better prognosis compared with invasive adenocarcinoma and may be cured with surgical resection Aggressive surgical resection is recommended even for patients with false-negative N2 disease.

A somatic TSHR mutation in a patient with lung adenocarcinoma with bronchioloalveolar carcinoma, coronary artery disease and severe chronic obstructive pulmonary disease

In a screen for thoracic malignancy-associated markers, thyroid stimulating hormone receptor (TSHR) was identified as a candidate as it binds to the previously-characterized lung cancer marker NKX2-1. We screened for mutations in all coding regions of the TSHR gene in 96 lung adenocarcinoma samples and their matched adjacent normal lung samples. We found one patient with a somatic mutation at codon 458 (exon 10), which is located at the transmembrane domain where most TSHR mutations have been found in thyroid-related diseases. This patient had lung adenocarcinoma with BAC (bronchioloalveolar carcinoma) features in the setting of a prior medical history significant for carotid stenosis and severe chronic obstructive pulmonary disease (COPD). In order to characterize the genetic features of TSHR in lung cancer, we checked for TSHR expression and copy number in the 96 lung cancer tissues. TSHR protein expression was generally overexpressed in multiple thoracic malignancies (adenocarcinoma, squamous cell carcinoma and malignant pleural mesothelioma) by immunohistochemistry. Our data suggest that aberrant TSHR function may contribute to lung cancer development or a subgroup of lung cancer with specific clinical phenotypes.

SWOG S0635 and S0636: Phase II trials in advanced-stage NSCLC of erlotinib (OSI-774) and bevacizumab in bronchioloalveolar carcinoma (BAC) and adenocarcinoma with BAC features (adenoBAC), and in never-smokers with primary NSCLC adenocarcinoma (adenoCa).

7517 Background: Despite recent changes to lung adenoCa pathologic classification, adv stage BAC remains a definable and clinically applicable entity. Patients (pts) with BAC, as well as never-smoking (NS) pts with adv lung adenoCa, have emerged as relevant clinical subpopulations with a high probability of clinical benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), likely related to the high proportion of activating mutations in the EGFR gene in such pts. Based on these results and the potential for increased clinical activity conferred by addition of B to E, SWOG initiated a pair of phase II trials of this combination in pts with adv BAC (S0635) or NS pts with adv lung adenoCa (S0636). Methods: NS pts with BAC or adenoBAC were preferentially enrolled on S0636. A total of 78 and 85 eligible pts were enrolled and treated on the S0635 and S0636 trials, respectively. Patients received E 150 mg PO daily and B 15 mg/kg IV q21 days until progression or prohibitive toxicity. Tumor tissue submission for pathologic review and assessment of molecular markers was mandated. Results: Pt demographics of the two trials are as shown in the table below. RECIST response rate among 61 BAC pts on S0635 with measurable disease was 18%, and among 53 NS pts on S0636, it was 47%. Median progression-free survival is 5 and 8 months (mo) on S0635 and S0636, respectively; median overall survival (OS) is 17 and 26 mo on S0635 and S0636, respectively. Toxicity consisted primarily of rash, diarrhea, and hypertension; no treatment-related deaths were reported. Molecular marker studies will be presented separately. Conclusions: In populations selected by clinical parameters, E withB is associated with modest toxicity and encouraging clinical efficacy that exceeded the prespecified OS threshold of 16 mo in studies of both adv BAC and NS pts, exceeding two years in NS pts. [Table: see text]

Differentially expressed genes between pure bronchioloalveolar carcinoma and pure bronchioloalveolar carcinoma features by genechip

Objective To investigate the genetic differences between pure bronchioloalveolar carcinoma (BAC) and invasive mixed type adenocarcinoma with BAC features (AWBF) and to explore the molecular mechanism of pure BAC progression.Methods Total RNA was extract froml6 lung tissue specimens,includig 8 cases of BAC and 8 cases of AWBF.The BAC and AWBF were analyzed for gene expression profiles using the Agiilent 4 * 44K arrays.Differentially expressed candidate genes were validated using quantitative real-time polymerase chain reaction (PCR).The SPSS software was used for the analysis.Two-sided values of P were given,and statistical signifcance was set at P ＜ 0.01.Results We selected 43 genes correlated with tumor progression and metastasis.A total of 23 genes were significantly higher in the AWBF and 20 genes were lower.Of the 43 validated genes,CLDN18 and ATF-2 were found to have ＞ 10 fold higher expression in AWBF (P ＜0.01 ) than in BAC.Conclusion CLDN18 and ATF-2 may be related with the progression of BAC to AWBF.Furthermore,targeting these genes may be a promising way for AWBF treatment. Key words: Bronchioloalveolar carcinoma; Differentially expresse ; Genes expression

Abstract IA4: Defining the mechanisms of tumorigenesis by mutant EGFR using mouse models

Abstract Mutations in exons encoding the epidermal growth factor receptor (EGFR) are found in 10–15% of lung adenocarcinomas. The two most common mutations: a point mutation in exon 21 that leads to substitution of an arginine for a leucine at position 858 and small in-frame deletions in exon 19 are associated with sensitivity to the specific tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Approximately 70% of tumors harboring EGFR mutations respond to treatment with these drugs, however 30% of these tumors exhibit primary resistance to treatment with these agents. Moreover, responses are transient and, on average, within a year of initiating treatment patients who initially respond eventually develop TKI-inhibitor-resistant disease. Drug resistance, in most cases, is due to a secondary mutation in EGFR (EGFR T790M). Other less frequent mechanisms of resistance include MET amplification, PIK3CA mutations and transformation to small cell lung cancer. However, the mechanism of resistance is still unknown in approximately 30% of cases. More effective treatment of patients with EGFR mutant lung cancer requires a better understanding of the mechanisms of primary and acquired resistance to EGFR TKIs and the development of strategies to overcome this resistance. To study these problems in vivo, we developed tetracycline-inducible transgenic mouse models of EGFR mutant lung cancer. Expression of lung cancer associated EGFR mutants gives rise to lung adenocarcinomas with bronchioloalveolar carcinoma features that are dependent upon the continuous activity of mutant EGFR for survival. Thus, treatment of the mice with erlotinib leads to tumor regression and long-term treatment with the drug gives rise to drug-resistant tumors that harbor some of the alterations observed in human TKI-resistant tumors such as the T790M mutation. Current efforts to use these mouse models to: 1) study mechanisms of primary and acquired resistance to EGFR TKIs and 2) evaluate new therapies to overcome resistance to first generation TKIs will be discussed.

Bortezomib for Patients with Advanced-Stage Bronchioloalveolar Carcinoma: A California Cancer Consortium Phase II Study (NCI 7003)

Bronchioloalveolar carcinoma (BAC), a subtype of non-small cell lung cancer, is a difficult disease to treat with low response rates with cytotoxic chemotherapy. Bortezomib, a proteasome inhibitor, has demonstrated objective responses in patients with BAC in early-phase clinical trials. We conducted a phase II study of bortezomib in patients with advanced-stage BAC. Patients with advanced BAC, adenocarcinoma with BAC features or BAC with adenocarcinoma features, and less than two prior regimens were eligible. Prior epidermal growth factor receptor (EGFR) inhibitor therapy was allowed. Bortezomib was administered intravenously at 1.6 mg/m on days 1 and 8 of every 21-day cycle until disease progression or unacceptable toxicity. The primary end point was response rate. The Simon two-stage design was used. Forty-two patients were enrolled, and the study was halted early for slow accrual. Patient characteristics were female 55%, median age 68 years, and Eastern Cooperative Oncology Group performance status of 0 and 1 in 31 and 11 patients, respectively. Twenty-six (62%) patients had received prior therapy with an EGFR inhibitor. A median of four cycles of therapy were administered. Objective responses were noted in 5%, whereas 57% had disease stabilization. The median progression-free survival and overall survival were 5.5 and 13.6 months, respectively. Grade 3 diarrhea and fatigue were noted in three and five patients, respectively. Bortezomib is tolerated well and is associated with modest anticancer activity in patients with advanced BAC, including patients who progressed on EGFR inhibitor therapy.

Abstract 1417: Molecular abnormalities associated to the progression of lung adenocarcinomas with BAC features from non-invasive to invasive patterns

Abstract Background: Most invasive lung adenocarcinomas (LAC) consist of mixed histological growth patterns including a non-invasive component referred as bronchioloalveolar carcinoma (BAC). Invasive LACs with BAC features are suspected to evolve from pure non-invasive (BAC) tumors. However, in this tumor type there is limited information about the molecular abnormalities associated to the progression from non-invasive to the invasive components. Materials and methods: To perform a detailed mapping analysis of molecular abnormalities comparing non-invasive and invasive sites in lung AC with BAC features we selected archival tumor tissue specimens from 77 LACs with more than 10% of non-invasive component out of 553 available tumors. Using whole histologic sections, we analyzed on each component (non-invasive and invasive) the immunohistochemical (IHC) expression of five markers known to be deregulated in lung AC, including EGFR, Her2-Neu, TTF-1, BRG1 and p53. We also compared in both tumor components the status of EGFR gene copy number gain (CNG) by fluorescent in situ hybridization and mutation of EGFR (exon 18-21) and KRAS (codons 12 and 13) by PCR-based sequencing using DNA extracted from microdissected tissue. For EGFR, we defined 2 types of CNGs: low (trysomy and low-polysomy), and high (high-polysomy and amplification). Results: Most cases had similar levels of expression in the non-invasive and invasive components of LAC for all IHC markers: EGFR, 54/70, 77%; Her2-Neu, 56/71, 79%; p53, 58/72, 80%; TTF-1, 57/71, 80%; and BRG1, 70/73, 96%. In a subset of cases, we found that the invasive component of LAC showed higher frequency of overexpression than non-invasive sites of EGFR (invasive 14/70, 20% vs. non-invasive 2/70, 3%) and Her2Neu (13/71, 18% vs. 2/71, 3%). EGFR mutations of exons 18-21 were found in 11/44 (20%) LAC, and in 7 (64%) mutant tumors the mutations were detected only in the invasive component. KRAS mutations were found in 14/56 (25%) tumors, and in all mutant tumors the mutations were found in both the non-invasive and corresponding invasive components. Any EGFR CNG was found in the invasive component of 20/56 (36%) tumors, including 9 cases with high CNG (4 high-polysomy and 5 gene amplification). In most (16/20, 80%) tumors the invasive component demonstrated higher CNG levels than the corresponding non-invasive sites. Interestingly, all 5 invasive tumors with EGFR amplification did not show such of abnormality in the corresponding non-invasive site. Conclusions: Our findings suggest that in LAC with BAC features the overexpression of EGFR and Her2Neu, and EGFR gene abnormalities (CNGs and mutations) are associated with the progression of non-invasive to invasive components of the tumors. In contrast, in LAC with KRAS mutation this abnormality commences at the non-invasive stage of tumor development. Supported by grant from Uniting Against Lung Cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1417. doi:10.1158/1538-7445.AM2011-1417

Cetuximab for the Treatment of Advanced Bronchioloalveolar Carcinoma (BAC): An Eastern Cooperative Oncology Group Phase II Study (ECOG 1504)

Inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase have demonstrated modest anticancer activity in advanced bronchioloalveolar carcinoma (BAC). We conducted a phase II study to evaluate cetuximab for the treatment of advanced BAC. Patients with advanced-stage pure BAC or adenocarcinoma with BAC features, fewer than two prior chemotherapy regimens, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 were eligible. Those with prior EGFR inhibitor therapy were excluded. Cetuximab was given as a weekly intravenous infusion at 250 mg/m(2) after an initial loading dose of 400 mg/m(2) in week 1. The primary end point was determination of response rate. EGFR and KRAS mutations were evaluated by pyrosequencing. Seventy-two patients were enrolled and 68 met eligibility requirements. Characteristics of patients included median age, 71 years; sex, 57% females; PS 0 or 1, 88% of patients; and smoking status, 19% never-smokers. Central pathology review confirmed the diagnosis in 45 of 49 available specimens. Approximately 50% of patients received more than two cycles of therapy (> 8 weeks). Skin rash was the most common toxicity (grade 3, 15%). The confirmed response rate was 7%, and stable disease was observed in 35%. The median survival and progression-free survival were 13 and 3.3 months, respectively. Only one of the six patients with an EGFR mutation and one of the seven patients with a KRAS mutation had a partial response. Cetuximab was associated with modest efficacy in patients with advanced BAC, despite a low response rate. EGFR and KRAS mutations were not predictive of response to cetuximab.

Frequency of EGFR and KRAS Mutations in Japanese Patients with Lung Adenocarcinoma with Features of the Mucinous Subtype of Bronchioloalveolar Carcinoma

Adenocarcinoma of the lung, especially bronchioloalveolar carcinoma (BAC) and adenocarcinoma with BAC features (AWBF), is potentially sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs); however, the efficacy seems to differ between the histologic subtypes. Mucinous BAC and AWBF (MBAC/AWBF) are not particularly responsive to EGFR-TKIs compared with nonmucinous BAC/AWBF (N-MBAC/AWBF). This may be due to the rarity of EGFR mutations and high frequency of KRAS mutations in MBAC/AWBF in contrast to N-MBAC/AWBF. One hundred ninety-one patients with adenocarcinoma of the lung underwent surgery at our institution. There were 59 patients (30%) diagnosed with BAC/AWBF; 20 had MBAC/AWBF (10%) and 39 had N-MBAC/AWBF (20%). We isolated 44 tissue specimens from these patients (20 consecutive cases of MBAC/AWBFs and 24 randomly chosen cases of N-MBAC/AWBFs as the control group), and we analyzed them for EGFR and KRAS mutations. We used the peptide nucleic acid-locked nucleic acid polymerase chain reaction clump method to detect EGFR mutations and conventional DNA sequencing to identify KRAS mutations. EGFR mutations were found in three of the 20 MBAC/AWBFs (15%) and in 14 of the 24 N-MBAC/AWBFs (58%) (p = 0.005). In addition, there were 14 KRAS mutations identified in the 20 MBAC/AWBFs (70%) and seven in the 24 N-MBAC/AWBFs (29%) (p = 0.0144). The incidence of EGFR mutation is low and that of KRAS mutation is frequent in MBAC/AWBFs. Conversely, the incidence of EGFR mutation is high and KRAS mutation is low in N-MBAC/AWBFs. Based on these findings, EGFR-TKIs may not be effective in patients with MBAC/AWBF.

The clinical application value of PET/CT in adenocarcinoma with bronchioloalveolar carcinoma features

The goal of our study was to demonstrate the clinical usefulness of positron emission tomography/computed tomography (PET/CT) for adenocarcinoma with bronchioloalveolar carcinoma (BAC) features, through evaluating the relationship between the intrathoracic lymph node metastases and maximum standardized uptake value (SUVmax), tumor size of the primary tumor and the ratio of BAC component and analysing the correlation of SUVmax, tumor size and the ratio of BAC component. This was a retrospective study. Forty-five patients with focal peripheral lung adenocarcinoma with BAC features were included in this study and underwent the PET/CT scan. Twenty-one patients were women and 24 were men. None of the patients had insulin-dependent diabetes and the serum glucose levels in all patients just before (18)F-FDG was injected were less than 120 mg/dl. The diagnosis of the lesion was made by surgical histopathology. All patients underwent successful surgery, and pathologic examination confirmed that 34 of 118 excised nodal groups in 18 patients were proved to be positive for malignancy. Univariate analysis revealed 3 potential factors related to intrathoracic lymph node metastases: SUVmax (P = 0.002); the ratio of BAC component (P = 0.002); maximum dimension of a tumor on mediastinal window setting images (mDmax, P = 0.025). The maximum dimension of a tumor on pulmonary window setting images (pDmax, P = 0.373) had no significance. A receiver operating characteristic (ROC) curve based on SUVmax, mDmax and the ratio of BAC component was constructed, the area under curve (AUC) was 85.2, 70.3 and 81.5% separately. There was no statistical significance between AUC of SUVmax and AUC of the ratio of BAC component (Z = 0.901, P = 0.368). The AUC of SUVmax and AUC of the ratio of BAC component were significantly higher than AUC of mDmax (Z = 2.112, P = 0.035; Z = 2.016, P = 0.042).The SUVmax and the ratio of BAC component had significant inverse correlation (r = -0.85, P < 0.01). The mDmax and the ratio of BAC component had significant inverse correlation (r = -0.69, P < 0.01). The SUVmax and mDmax had significant correlation (r = 0.60, P < 0.01). PET/CT would be clinically useful for adenocarcinoma with BAC features, because SUVmax obtained by PET/CT can predict the incidence of intrathoracic lymph node metastases at preoperative stages and even for inoperable patients.

Cetuximab for the treatment of advanced bronchioloalveolar carcinoma (BAC): An Eastern Cooperative Oncology Group phase II study (ECOG 1504).

7522 Background: Inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase have demonstrated modest anticancer activity in pts with advanced BAC, a disease that is refractory to standard chemotherapy regimens. We conducted a phase II study to evaluate cetuximab, an antibody against EGFR, for the treatment of advanced BAC. Methods: Pts with advanced stage pure BAC or adenocarcinoma with BAC features, presence of measurable disease, 0 or 1 prior chemotherapy regimen, and ECOG performance status (PS) of 0-2 were eligible. Prior EGFR inhibitor therapy was not permitted. Cetuximab was given as a weekly i.v. infusion at 250 mg/m2 from week 2 onwards after an initial loading dose of 400 mg/m2 in week 1 until disease progression. The primary endpoint was determination of response rate. EGFR and KRAS mutations were evaluated by pyrosequencing. Results: 72 pts were enrolled and 68 met all eligibility criteria. Pt characteristics were: median age- 71 yrs, female– 57%; ECOG PS 0 or 1– 88%; no prior chemotherapy- 68%; and never smokers- 18%. Central pathology review confirmed the diagnosis in 45 out of 47 available specimens (mucinous- 35%; non-mucinous- 20%; Adeno with BAC features- 16%, pure BAC -29%). Approximately 50% of pts received more than 2 cycles of therapy (> 8 weeks). Skin rash was the most common toxicity (any grade 71%; grade 3- 15%) and hypomagnesemia was noted in 26%. The confirmed response rate was 6% and SD was observed in 37% of pts. The median survival was 13 m and the 1- and 2-year survival rates were 52% and 37% respectively. The median PFS was 3.2 m with a 6- months PFS rate of 22%. Tumor tissues were available from 55 pts for evaluation of EGFR and KRAS mutation status. Analysis of EGFR exon 20 polymorphisms demonstrate an allele frequency of Q787Q G = 0.55, A = 0.45; T790M, C = 1.0. Complete EGFR and KRAS mutation analysis will be presented at the meeting. Conclusions: The efficacy of cetuximab is comparable with that of EGFR TK inhibitors in the treatment of advanced BAC despite low response rates by RECIST. Supported in part by PHS Grants CA23318, CA66636, CA21115, CA21076 and from the NCI, NIH and the Department of Health and Human Services. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, ImClone Systems, Lilly ImClone Systems

The Role of Pemetrexed in Lung Adenocarcinoma, Mixed Subtype with Bronchioloalveolar Carcinoma Features

Bronchioloalveolar carcinoma (BAC) and adenocarcinoma with bronchioloalveolar features (ADC-WBF) belong to the same anatomo-clinical entity and show very similar epidemiologic, clinical and biological characteristics. However there is a lack of consensus for the treatment of unresectable forms. Although epidermal growth factor receptor tyrosine kinase inhibitors and paclitaxel do have some efficacy, the aim of this review is to assess the role that pemetrexed, a new generation antifolate, could play in this context. Pemetrexed has proved to be particularly effective in advanced lung adenocarcinomas and unresectable mesotheliomas, and cases of major and sustained responses of ADC-WBF to pemetrexed have been reported. The preclinical rationale explaining this efficacy is that it inhibits the growth of BAC cell lines in vitro. BAC tumors overexpress FR-alpha, a protein involved in pemetrexed intracellular transport, at rates higher than those observed in lung adenocarcinomas and mesotheliomas and it would seem that pemetrexed efficacy is correlated to FR-alpha expression. The role played by thymidylate synthase expression level in sensitivity to pemetrexed also needs to be specifically explored in ADC-WBF. The results of two phase II trials, SWOG 0526 and IFCT 05-04, will hopefully provide decisive information on the relevance of pemetrexed in ADC-WBF management and the molecular predictors of response.

Non-mucinous and mucinous subtypes of adenocarcinoma with bronchioloalveolar carcinoma features differ by biomarker expression and in the response to gefitinib

There is no optimal established therapy for treating advanced or recurrent adenocarcinoma with bronchioloalveolar carcinoma features (ADC-BAC), and it remains unclear whether chemotherapy achieves therapeutic results comparable to those seen in the more common non-small lung carcinoma subtypes. In order to improve the decisions made during the treatment of advanced ADC-BAC, we attempted to better characterize the mucinous and non-mucinous ADC-BAC subtypes. Fifty pathological samples were obtained from 62 patients included in a multicenter prospective phase II trial (IFCT0401) conducted to evaluate gefitinib as a first-line therapy for non-resectable ADC-BAC. These samples were centrally reviewed and re-classified as non-mucinous ( n = 25) or mucinous ( n = 25) subtypes. We demonstrated that demographic data, clinical characteristics and stage at presentation (extrathoracic versus lung metastasis, as well as TNM staging) did not distinguish between the two subtypes. In contrast, three biological markers (PAS staining, TTF-1 expression and EGFR genomic gain combined with mutation analysis) enabled us to independently segregate all but 2 of the 50 patients into the mucinous and non-mucinous ADC-BAC subtypes. Finally, only mucinous tumors appeared to be resistant to epidermal growth factor receptor -tyrosine kinase inhibitors (EGFR-TKIs). Additional prospective studies are required to better approach therapeutic strategy in mucinous tumors, which are a distinct entity from non-mucinous tumors.

Genetic evolution of EGFR and the clonal origin of adenocarcinomas exhibiting various degrees of bronchioloalveolar carcinoma

e22050 Background: EGFR mutations may accumulate during multistage progression of bronchioloalveolar carcinoma (BAC), leading to heterogeneity within the tumor. Moreover, intrapulmonary emersions are the predominant sites of BAC progression in the absence of other distant metastases. In cases of emerging bilateral lung lesions during the follow-up to complete resection, the issue of how to differentiate between lesions originating from multifocal BACs or distant metastases/local recurrence is an important and unresolved issue. This study was performed to determine whether sequential adenocarcinoma with BAC features emerges in the lung field arises from a single clone or multiple clones in the same individual. Methods: Samples of adenocarcinomas exhibiting various degrees of BAC were obtained by thoracotomy. Sequential specimens were obtained on detection of novel lesions in the lung field. Genomic DNA was extracted from the specimens, and the presence of activating mutations in EGFR was analyzed by direct sequencing. Our pathological findings, sequential imaging, and EGFR sequence data were compared to monitor evidence of cancer evolution. Results: Based on an analysis of EGFR in tumor specimens from 428 lung cancer patients, fifteen cases of sequential BAC-related adenocarcinoma obtained by thoracotomy were identified. Together with alterations in BAC/adenocarcinoma components, the EGFR-TKI untreated series with at least one episode of EGFR-activating mutations represented three typical models: no significant EGFR evolution for a single clone, genetic alterations from mutant to wild-type EGFR for multifocal lesions, and a switch from wild-type to mutant EGFR, which might exhibit uncertain circumstances of cancer progression. Conclusions: Genetic analysis in conjunction with pathological and radiological diagnoses can be used to explore the origin of multifocal BAC. The single clone model indicates subsequent disease progression, whereas genetic alterations from mutations to wild-type EGFR are suggestive of secondary primary carcinoma. When additional lesions emerge after radical resection of BAC-related lung cancer, sequential tumor samples should be obtained for further evaluation. No significant financial relationships to disclose.

Major and prolonged response to pemetrexed in two cases of lung adenocarcinoma with bronchioloalveolar carcinoma features

Bronchioloalveolar carcinoma (BAC) and adenocarcinoma mixed subtype with bronchioloalveolar features (ADC-WBF) represent a unique anatomo-clinical entity accounting for some 20% of non-small cell lung cancers (NSCLC). These tumors seem less sensitive to chemotherapy than other NSCLC. We report two cases of advanced ADC-WBF treated with second-line and fourth-line pemetrexed. Major and durable radiological response associated with clinical and functional improvement was achieved in both patients, without important drug toxicity. After treatment arrest, the two patients experienced progressive disease but responded to retreatment with pemetrexed. Recent data suggest that paclitaxel-based chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors could be an acceptable therapeutic strategy in unresectable CBA and ADC-WBF. The cases reported here and preclinical findings suggest a therapeutic efficacy of pemetrexed in these tumors. Prospective studies are required to evaluate this hypothesis.

Genomic markers for malignant progression in pulmonary adenocarcinoma with bronchioloalveolar features

Bronchioloalveolar carcinoma (BAC), a subtype of lung adenocarcinoma (ADC) without stromal, vascular, or pleural invasion, is considered an in situ tumor with a 100% survival rate. However, the histological criteria for invasion remain controversial. BAC-like areas may accompany otherwise invasive adenocarcinoma, referred to as mixed type adenocarcinoma with BAC features (AWBF). AWBF are considered to evolve from BAC, representing a paradigm for malignant progression in ADC. However, the supporting molecular evidence remains forthcoming. Here, we have studied the genomic changes of BAC and AWBF by array comparative genomic hybridization (CGH). We used submegabase-resolution tiling set array CGH to compare the genomic profiles of 14 BAC or BAC with focal area suspicious for invasion with those of 15 AWBF. Threshold-filtering and frequency-scoring analysis found that genomic profiles of noninvasive and focally invasive BAC are indistinguishable and show fewer aberrations than tumor cells in BAC-like areas of AWBF. These aberrations occurred mainly at the subtelomeric chromosomal regions. Increased genomic alterations were noted between BAC-like and invasive areas of AWBF. We identified 113 genes that best differentiated BAC from AWBF and were considered candidate marker genes for tumor invasion and progression. Correlative gene expression analyses demonstrated a high percentage of them to be poor prognosis markers in early stage ADC. Quantitative PCR also validated the amplification and overexpression of PDCD6 and TERT on chromosome 5p and the prognostic significance of PDCD6 in early stage ADC patients. We identified candidate genes that may be responsible for and are potential markers for malignant progression in AWBF.