Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Although it is clear that tobacco smoking is a major cause of lung cancer, about half of all women with lung cancer worldwide are never-smokers. Despite a declining smoking population, the incidence of non-small cell lung cancer (NSCLC), the predominant form of lung cancer, has reached epidemic proportions particularly in women. Emerging data suggest that factors other than tobacco, namely endogenous and exogenous female sex hormones, have a role in stimulating NSCLC progression. Aromatase, a key enzyme for estrogen biosynthesis, is expressed in NSCLC. Clinical data show that women with high levels of tumor aromatase (and high intratumoral estrogen) have worse survival than those with low aromatase. The present and previous studies also reveal significant expression and activity of estrogen receptors (ERα, ERβ) in both extranuclear and nuclear sites in most NSCLC. We now report further on the expression of progesterone receptor (PR) transcripts and protein in NSCLC. PR transcripts were significantly lower in cancerous as compared to non-malignant tissue. Using immunohistochemistry, expression of PR was observed in the nucleus and/or extranuclear compartments in the majority of human tumor specimens examined. Combinations of estrogen and progestins administered in vitro cooperate in promoting tumor secretion of vascular endothelial growth factor and, consequently, support tumor-associated angiogenesis. Further, dual treatment with estradiol and progestin increased the numbers of putative tumor stem/progenitor cells. Thus, ER- and/or PR-targeted therapies may offer new approaches to manage NSCLC.

Purpose

PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies.

Experimental Design

PF299804 was administered once daily continuously (schedule A), and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken pre-dose and after 14 days of treatment, to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non-small cell lung cancer (NSCLC) patients.

Results

121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/day. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non-small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804.

Conclusions

The MTD of PF299804 is 45 mg/day. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients.

Selumetinib (AZD6244; ARRY-142886) is a tight-binding, uncompetitive inhibitor of MEK1/2 currently in clinical development. We evaluated the effects of selumetinib in 31 human breast cancer cell lines and 43 human non-small cell lung cancer (NSCLC) cell lines to identify characteristics correlating with in vitro sensitivity to MEK inhibition. IC50 less than 1µM (considered sensitive) was seen in 5 of 31 breast cancer cell lines and 15 of 43 NSCLC cell lines, with a correlation between sensitivity and raf mutations in breast cancer cell lines (p= 0.022) and ras mutations in NSCLC cell lines (p= 0.045). Evaluation of 27 of the NSCLC cell lines with Western blots demonstrated no clear association between MEK and PI3K pathway activation and sensitivity to MEK inhibition. Baseline gene expression profiles were generated for each cell line using Agilent gene expression arrays to identify additional predictive markers. Genes associated with differential sensitivity to selumetinib were seen in both histologies, including a small number of genes in which differential expression was common to both histologies. In total, these results suggest that clinical trials of selumetinib in breast cancer and NSCLC might select patients whose tumors harbor raf and ras mutations respectively.

Background

This study was designed to assess the prevalence of smoking at time of lung cancer diagnosis in a surgical patient cohort referred for cardiothoracic surgery.

Methods

Retrospective study of lung cancer patients (n = 626) referred to three cardiothoracic surgeons at a tertiary care medical center in Southern California from January 2006 to December 2008. Relationships among years of smoking cessation, smoking status, and tumor histology were analyzed with Chi-square tests.

Results

Seventy-seven percent (482) had a smoking history while 11.3% (71) were current smokers. The length of smoking cessation to cancer diagnosis was <1 year for 56 (13.6%), 1-10 years for 110 (26.8%), 11-20 years for 87 (21.2%), 21-30 years for 66 (16.1%), 31-40 years for 44 (10.7%), 41-50 years for 40 (9.7%) and 51-60 years for 8 (1.9%). The mean cessation was 18.1 ± 15.7 years (n = 411 former smokers). Fifty-nine percent had stage 1 disease and 68.0% had adenocarcinoma. Squamous cell carcinoma was more prevalent in smokers (15.6% vs. 8.3%, p = 0.028); adenocarcinoma was more prevalent in never-smokers (79.9% versus 64.3%, p = 0.0004). The prevalence of adenocarcinoma varied inversely with pack year (p < 0.0001) and directly with years of smoking cessation (p = 0.0005).

Conclusions

In a surgical lung cancer cohort, the majority of patients were smoking abstinent greater than one decade before the diagnosis of lung cancer.