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Background: Myeloid cell leukemia-1 (Mcl-1) is a member of the B-cell lymphoma 2 family known to play a significant role in the regulation of apoptosis. Mcl-1 expression has been studied in nonsmall cell lung cancer (NSCLC) cell lines but has not been previously evaluated as a prognostic factor in clinical samples., Materials and Methods: Formalin-fixed, paraffin-embedded sections from 119 NSCLC, including 33 squamous cell carcinomas (SCC), 55 adenocarcinomas (AC), and 31 either pure adenocarcinoma in situ (AIS) or AC with lepidic features were immunostained by an automated method with rabbit polyclonal Mcl-1. Cytoplasmic Mcl-1 (cMcl-1) immunoreactivity was scored based on intensity and percentage of positive tumor cells in both tumor and adjacent benign epithelium in each case. MCL1 amplification was determined by hybrid capture-based comprehensive genomic profiling (CGP) on a separate cohort of 9393 NSCLC samples., Results: Intense diffuse cMcl-1 overexpression was noted in 35/119 (29%) tumors overall and correlated with tumor type (52% AIS vs. 31% AC vs. 6% SCC, P < 0.0001), tumor grade (48% grade 1 vs. 14% grade 2 vs. 31% grade 3, P = 0.007), small tumor size (36% ≤3.0 cm vs. 16% >3.0 cm, P = 0.016), and lengthened survival within the AIS subgroup (100% alive vs. 42% expired, P = 0.018) while showing a trend toward correlation with nonrecurrent disease overall (32% nonrecurrent vs. 11% recurrent, P = 0.072) and within the AC subgroup (33% nonrecurrent vs. 0% recurrent, P = 0.092). MCL1 amplification was identified in 569 (6%) of 9393 NSCLC by CGP., Conclusions: cMcl-1 overexpression appears to occur independently from MCL1 gene amplification in NSCLC and correlates with AIS histologic type, lower tumor grade, smaller tumor size, nonrecurrent disease, and increased survival., Competing Interests: There are no conflicts of interest

Aims: Small cell lung cancer (SCLC) carries a poor prognosis, and the systemic therapies currently used as treatments are only modestly effective, as demonstrated by a low 5-year survival at only ∼5%. In this retrospective collected from March 2013 to study, we performed comprehensive genomic profiling of 98 small cell undifferentiated lung cancer (SCLC) samples to identify potential targets of therapy not currently searched for in routine clinical practice., Methods: DNA from 98 SCLC was sequenced to high, uniform coverage (Illumina HiSeq 2500) and analysed for all classes of genomic alterations., Results: A total of 386 alterations were identified for an average of 3.9 alterations per tumour (range 1–10). Fifty-two (53%) of cases harboured at least 1 actionable alteration with the potential to personalise therapy including base substitutions, amplifications or homozygous deletions in RICTOR (10%), KIT (7%), PIK3CA (6%), EGFR (5%), PTEN (5%), KRAS (5%), MCL1 (4%), FGFR1 (4%), BRCA2, (4%), TSC1 (3%), NF1 (3%), EPHA3 (3%) and CCND1. The most common non-actionable genomic alterations were alterations in TP53 (86% of SCLC cases), RB1 (54%) and MLL2 (17%)., Conclusions: Greater than 50% of the SCLC cases harboured at least one actionable alteration. Given the limited treatment options and poor prognosis of patients with SCLC, comprehensive genomic profiling has the potential to identify new treatment paradigms and meet an unmet clinical need for this disease.

Matrix metalloproteinases (MMP's) 3, 10 and 11 (also known as stromelysins 1, 2 and 3, respectively), and matrix metalloproteinase 7 (also known as matrilysin), produced by stromal fibroblast-like cells in the vicinity of various malignancies, are suspected to have an ability to degrade components of extracellular matrix, thus promoting spread of the tumor. MMP's also have been found in epithelial tumor cells in various cancers. Tissue sections from 95 cases of non-small cell lung cancer (NSCLC) were immunostained with antibodies against MMP 3, MMP 10 and MMP 11 and sections from 99 cases of NSCLC were immunostained with an antibody against MMP 7. Cytoplasmic immunoreactivity in the tumor cells was semiquantitatively scored for intensity and distribution and correlated with tumor type, tumor grade, stage, tumor size, lymph node positivity, metastasis and survival. Overexpression of MMP 10 and MMP 11 correlated with higher grade for NSCLC (p = 0.029 and p = 0.016, respectively), and also in a subset of adenocarcinomas (AC) (p = 0.015 and p = 0.009, respectively). Also, MMP 10 and MMP 11 correlated with lymph node involvement in NSCLC (p = 0.025 and p = 0.027 respectively). No correlation was found for MMP 3. Overexpression of MMP-7 correlated with tumor stage (p = 0.0001) and was associated with adverse clinical outcome (p = 0.0001) in NSCLC and also in separate squamous cell carcinoma (SCC) (p = 0.003) and AC (p = 0.004) tumor groups.

Background: Trastuzumab is a monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER-2). Nonsmall cell lung carcinoma (NSCLC) overexpresses HER-2 protein in approximately 20% of cases. In the current study, the authors combined trastuzumab with weekly taxanes in an attempt to improve outcomes over standard chemotherapy in patients with advanced NSCLC., Methods: The primary objective was to determine whether docetaxel plus trastuzumab or paclitaxel plus trastuzumab was the superior regimen based on response and toxicity, and to determine whether either regimen was appropriate for further testing in a randomized Phase III trial. After stratification based on the results of HER-2 immunohistochemistry, chemotherapy-naive patients were randomized to receive trastuzumab plus docetaxel or trastuzumab plus paclitaxel. The study was designed so patients with or without HER-2 overexpression would be distributed equally between the study arms., Results: Immunohistochemistry for HER-2 protein expression was attempted for 182 pathologic samples from 169 patients. Twenty-eight of the 179 evaluable samples (16%) revealed 2+ or 3+ staining. The objective response rate was 23% (7 of 30 patients) in the patients treated with docetaxel plus trastuzumab and 32% (11 of 34 patients) in the patients treated with paclitaxel plus trastuzumab (P=0.76, Wilcoxon test). No difference was noted in the median survival (16 mos vs. 14 mos) or 1-year survival (57% vs. 55%) (P=0.998). Toxicities were mild in both treatment arms. No difference with regard to response rates or survival was noted between HER-2-positive (2+ or 3+) and HER-2-negative (0-1+) patients., Conclusions: The expression of HER-2 protein in patients with advanced NSCLC in this study was found to be similar to that reported in previous series. The response rates and toxicities for patients treated with docetaxel and trasuzumab or paclitaxel and trasuzumab were not significantly different, though survival in both arms was better than expected. HER-2 expression status did not appear to affect outcomes for this uniform group of patients who were treated in a comparable fashion. Because of the infrequency of HER-2 overexpression, and the absence of improved outcomes in patients with NSCLC who were treated with trastuzumab plus chemotherapy in other studies, neither regimen tested will be advanced to a Phase III trial., (Copyright 2005 American Cancer Society)

CD44, a cell adhesion molecule, has been implicated in tumor invasion and metastasis in certain malignancies. We studied the expression of CD44 standard (CD44s) and variant isoforms (CD44v) in 98 non-small cell lung carcinomas (NSCLCs) by immunohistochemistry and correlated the observations with clinical outcome. Formalin-fixed, paraffin-embedded archival tissues from 49 squamous cell carcinomas (SCCs) and 49 adenocarcinomas (ACs) were immunostained after microwave irradiation with monoclonal antibodies against CD44s and CD44v3, v4/5, v6, v7/8, and v10, and the results were correlated with histological tumor type, tumor stage, recurrence, and survival rates. SCCs of the lung showed strong membranous expression of each of the CD44s, v3, v4/5, v6, and v10 proteins in comparison with ACs (P < .0001). Staining for CD44 v4/5 was overwhelmingly positive in SCCs (72%) as compared with ACs (2.2%). Intense immunoreactivity for CD44v6 was present in 19 of 20 (95%) metastatic lung carcinomas. The bronchiolar basal cells and alveolar pneumocytes were positive for CD44s, v3, and v6. CD44s and variant isoform expression did not correlate with tumor stage, recurrence, and survival rates. In conclusion, there is significant immunopositivity of CD44s and variant isoforms in SCCs over ACs of the lung. Expression of CD44v6 may suggest an increased risk for local lymph node metastasis in NSCLCs. CD44v4/5 reactivity may be useful to discriminate squamoid differentiation in poorly differentiated NSCLCs.