Person:

Chirieac, Lucian

BACKGROUND There are no reliable markers able to identify patients with non-small cell lung cancer (NSCLC) likely to metastasize to the brain. We investigated associations between immunohistochemical markers and development of brain metastases in patients with NSCLC.

METHODS We performed a hospital-based, case-control study of patients with newly diagnosed NSCLC between 1989 and 2003 that developed brain metastases who had available pathology material from both primary NSCLC and brain metastases. The control patients had NSCLC and no evidence of brain metastases. We examined NSCLC for expression of Ki-67, caspase-3, VEGF-A, VEGF-C, E-cadherin and EGFR in 54 surgical pathology specimens using immunohistochemistry and evaluated associations with development of brain metastases.

RESULTS Brain metastases developed after a median time of 12.5 months (range 1.7-89.4 months) from the diagnosis of NSCLC. A significantly increased risk of developing brain metastases was associated with patients who had high Ki-67 (adjusted odds ratio 12.2, 95% CI, 2.4 to 70.4, P<0.001), low caspase-3 (adjusted odds ratio 43.0, 95% CI, 5.3 to >100, P<0.001), high VEGF-C (adjusted odds ratio 14.6, 95% CI, 2.0 to >100, P<0.001), and low E-cadherin (adjusted odds ratio 3.6, 95% CI, 0.9 to 16.4, P=0.05), in the primary NSCLC. No significant risk was observed with VEGF-A and EGFR. A high Ki-67 was also associated with a shorter overall survival (P=0.04).

CONCLUSIONS Patients with NSCLC and high Ki-67, low caspase-3, high VEGF-C, and low E-cadherin in their tumors may benefit from close surveillance since they may have an increased risk of developing brain metastases.

Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to first-generation EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.

Purpose Lung cancer, of which 85% is non–small-cell (NSCLC), is the leading cause of cancer-related death in the United States. We used genome-wide analysis of tumor tissue to investigate whether single nucleotide polymorphisms (SNPs) in tumors are prognostic factors in early-stage NSCLC.

Patients and Methods One hundred early-stage NSCLC patients from Massachusetts General Hospital (MGH) were used as a discovery set and 89 NSCLC patients collected by the National Institute of Occupational Health, Norway, were used as a validation set. DNA was extracted from flash-frozen lung tissue with at least 70% tumor cellularity. Genome-wide genotyping was done using the high-density SNP chip. Copy numbers were inferred using median smoothing after intensity normalization. Cox models were used to screen and validate significant SNPs associated with the overall survival.

Results Copy number gains in chromosomes 3q, 5p, and 8q were observed in both MGH and Norwegian cohorts. The top 50 SNPs associated with overall survival in the MGH cohort (P ≤ 2.5 × 10−4) were selected and examined using the Norwegian cohort. Five of the top 50 SNPs were validated in the Norwegian cohort with false discovery rate lower than 0.05 (P < .016) and all five were located in known genes: STK39, PCDH7, A2BP1, and EYA2. The numbers of risk alleles of the five SNPs showed a cumulative effect on overall survival (Ptrend = 3.80 × 10−12 and 2.48 × 10−7 for MGH and Norwegian cohorts, respectively).

Conclusion Five SNPs were identified that may be prognostic of overall survival in early-stage NSCLC.