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Full-text article is free to read on the publisher website. INTRODUCTION In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated with pemetrexed, low thymidylate synthase (TS) expression is associated with better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level. METHODS Treatment-naive patients with nonsquamous non-small-cell lung cancer (stage IIIB/IV) had four cycles of first-line chemotherapy with pemetrexed/cisplatin. Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability. TS expression (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), and quantitative reverse-transcriptase polymerase chain reaction. Cox regression was used to assess the association between H-scores and progression-free/overall survival (PFS/OS) distribution estimated by the Kaplan-Meier method. Maximal χ analysis identified optimal cutpoints between low TS- and high TS-expression groups, yielding maximal associations with PFS/OS. RESULTS The study enrolled 70 patients; of these 43 (61.4%) started maintenance treatment. In 60 patients with valid H-scores, median (m) PFS was 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS was 9.6 (95% CI, 7.3-15.7) months. Higher nuclear TS expression was significantly associated with shorter PFS and OS (primary analysis IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At the optimal cutpoint of nuclear H-score (70), mPFS in the low TS- versus high TS-expression groups was 7.1 (5.7-8.3) versus 2.6 (1.3-4.1) months (p = 0.0015; hazard ratio = 0.28; 95%CI, 0.16-0.52; n = 40/20). Trends were similar for cytoplasm H-scores, quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints (OS, response, and disease control). CONCLUSIONS The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts. © 2013 by the International Association for the Study of Lung Cancer.

Background Diagnostic bronchial biopsy samples from lung cancer patients may be used for molecular biologic analyses to help select therapy and provide prognostic information. Some have suggested that direct molecular analysis of bronchial biopsy fragments may be feasible, bypassing histologic examination. We analyzed a series of 100 bronchial biopsy specimens in lung cancer patients to assess the frequency and quantity of tumor present in biopsy samples. Methods The proportion of tumor in bronchial biopsy specimens was assessed by measuring the tumor area in histologic sections using computer-aided morphometry. Results In only 48% of cases did all the biopsy fragments contain some tumor. The median number of fragments obtained at bronchoscopy was 4; median number actually containing tumor was 3. The mean total surface area of tumor (as a percentage of the total sample area) in biopsy fragments was, for all cases, 33.4%; median area 28%. Biopsies with small cell carcinoma had more tumor (mean area 46.5%, median 49%; p = 0.0006) than all other non-small cell carcinoma cases. Conclusion Malignant bronchial biopsy samples frequently contain limited amounts of primary carcinoma. Often, one or more of the biopsy fragments will not contain tumor. This has important implications for the storage and use of bronchial biopsy samples for genetic analysis.

Introduction The emergence of treatments for non-small cell lung carcinoma (NSCLC) with differential efficacy and toxicity between subtypes has highlighted the importance of specific pathologic NSCLC subtyping. Most NSCLCs are inoperable, and pathologic diagnosis is made only on small tissue samples that are prone to diagnostic inaccuracy. In a substantial proportion of cases, standard morphology cannot specifically subtype the tumor, necessitating a diagnosis of NSCLC-not otherwise specified (NOS). Histochemical staining for mucin and immunohistochemical (IHC) identification of NSCLC subtype-associated markers could help predict the final subtype of resected NSCLCs diagnosed as NSCLC-NOS on preoperative bronchial biopsy samples. Methods Paraffin sections of 44 bronchial biopsy samples diagnosed as NSCLC-NOS were stained for mucin (Alcian blue/periodic acid Schiff) and thyroid transcription factor 1 by IHC–(markers of adenocarcinoma), and for S100A7, cytokeratin 5/6, high molecular weight cytokeratins, and p63 proteins–markers of squamous cell carcinoma. A predictive staining panel was derived from statistical analysis after comparing staining profiles with the final postsurgical NSCLC subtype. This panel was prospectively applied to 82 small biopsy samples containing NSCLC. Results True NSCLC subtype of undifferentiated NSCLC samples was best predicted using Alcian blue/periodic acid Schiff plus p63 and thyroid transcription factor 1 IHC, allowing specific subtyping in 73% of NSCLC-NOS cases with 86% accuracy. When applied prospectively, this staining panel showed 100% concordance with specific NSCLC morphologic subtyping in small biopsies. Conclusion This approach can facilitate treatment selection by accurately predicting the subtype in undifferentiated NSCLC biopsies, reducing to 7% the proportion of cases without a definite or probable histologic subtype.

Introduction: In a previous biomarker discovery project using gene-expression profiling we identified Serpin B3 (SB3) as a predictor of resistance to platinum doublet chemotherapy (PtC) in non–small-cell lung cancer (NSCLC). This independent prospective study was designed to confirm the predictive utility of SB3. Methods: SB3 immunohistochemistry was scored by previously validated criteria (score 0=negative, score 1=1%–10% tumor cells positive, score 2=11%–50% tumor cells positive, and score 3=>50% tumor cell positive) in 197 patients with stage IV NSCLC treated with PtC. This provided 80% power to detect a median survival increase from 150 days in patients with an SB3 immunohistochemistry score of 2 or more to 300 days in those with an SB3 score of 0 or 1. Results: Thirty-six percent of NSCLCs stained positive for SB3. Median survival for SB3 negative/score 0 was 332 days, SB3 positive/score 1 was 268 days, and SB3 positive/score 2 or 3 was 120 days ( p = 0.004). Cox proportional hazards analysis demonstrated that SB3 positivity is an independent predictor of survival (hazard ratio=1.87; 95% confidence interval, 1.29–2.71; p = 0.001).The disease control rate in SB3 score 0, 1=65%, and score of 2 or more=20 % ( p = 0.002), with median survival 306 days (score 0, 1) versus 120 days (score ≥2, hazard ratio=1.71; 95% confidence interval. 1.14–3.10; p = 0.002). Conclusions: SB3-positive immunohistochemistry score of 2 or more (>10% tumor cells positive) identifies a subgroup of patients with stage IV NSCLC who have a poor survival (median 120 days) when treated with PtC, similar to that estimated for untreated or chemo-refractory stage IV NSCLC. Further prospective qualification using biospecimens from randomized studies is needed, but SB3 seems to be a useful biomarker that identifies a highly resistant subgroup in whom PtC should be avoided.

Background: Treatment and survival rates within Scotland for patients with lung cancer seem lower than in many other European countries. No study of lung cancer has attempted to specifically investigate the association between variation in investigation, comorbidity, and treatment and outcome between different centers. Methods: Patient demographics, World Health Organization/Eastern Cooperative Oncology Group performance status, and primary treatment modality were recorded. In addition to recording the comorbidities present in each patient, the severity of each comorbidity was graded on a 4-point scale (0–3) using validated severity scales. Data were collected as the patient was investigated and entered in an anonymized format into a database designed for the study. Results: Prospectively collected data from 882 patients diagnosed with lung cancer in four Scottish centers. A number of statistically significant differences were identified between centers. These included investigation, treatment between centers (i.e., surgical rates), age, tumor histology, smoking history, socioeconomic profile, ventilatory function, and performance status. Predictors of declining performance status included increasing severity of a number of comorbidities, age, lower socioeconomic status, and specific centers. Conclusions: This study has identified many significant intercenter differences within Scotland. We believe this to be the first study to identify nontumor factors independent of performance status that together limit the ability to deliver radical, possibly curative, therapy to our lung cancer population. It is only by identifying such factors that we can hope to improve on the relatively poor outlook for the majority of Scottish patients with lung cancer.