The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets.
In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated.
Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds.
New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration.
The risk of fatal adverse events (FAEs) due to bevacizumab-based chemotherapy has not been well described; we carried out an updated meta-analysis regarding this issue.
METHODS: An electronic search of Medline, Embase and The Cochrane Central Register of Controlled Trials was conducted to investigate the effects of randomized controlled trials on bevacizumab treatment on cancer patients. Random or fixed-effect meta-analytical models were used to evaluate the risk ratio (RR) of FAEs due to the use of bevacizumab.
RESULTS: Thirty-four trials were included. Allocation to bevacizumab therapy significantly increased the risk of FAEs; the RR was 1.29 (95% CI:1.05-1.57). This association varied significantly with tumor types (P = 0.002) and chemotherapeutic agents (P = 0.005) but not with bevacizumab dose (P = 0.90). Increased risk was seen in patients with non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer. However, FAEs were lower in breast cancer patients treated with bevacizumab. In addition, bevacizumab was associated with an increased risk of FAEs in patients who received concomitant agents of taxanes and/or platinum.
CONCLUSION: Compared with chemotherapy alone, the addition of bevacizumab was associated with an increased risk of FAEs among patients with special tumor types, particularly when combined with chemotherapeutic agents such as platinum.
The histologic pattern of pulmonary adenocarcinoma is highly heterogeneous and considered to be an important prognostic factor. The predominant histologic pattern is emphasized in the 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society classification, but few studies present a detailed investigation of the histologic changes and prognosis pulmonary adenocarcinoma using resected specimens.
Methods. We examined 125 cases of surgically resected pulmonary adenocarcinoma and carefully observed histologic patterns. Invasive adenocarcinoma was divided into 3 groups according to a modified histologic classification system: group 1 had a lepidic or papillary predominant pattern with ≤10% solid or micropapillary pattern; group 2 had an acinar predominant pattern with ≤10% of the solid or micropapillary pattern; and group 3 had a solid or micropapillary predominant pattern, or any predominant pattern with >10% solid or micropapillary pattern.
Results. Proportions of predominant lepidic, papillary, acinar, solid, and micropapillary patterns were 11 (9.3%), 8 (6.8%), 54 (45.8%), 38 (32.2%), and 7 (5.9%), respectively. Vague areas between 2 different patterns were frequently observed, which were considered as transitional areas for one pattern to the other pattern (gradual dedifferentiation). Modified histologic classification was significantly associated with disease-free and overall survival rate (P = .026 and .010, respectively) using the Kaplan-Meier survival test, and an independent prognostic factor (P = .016) in overall survival using the Cox regression test.
Conclusion. Pulmonary adenocarcinoma demonstrates heterogeneous histologic patterns with gradual dedifferentiation, and this modified histologic classification is an important prognostic factor for patients with pulmonary adenocarcinoma.
Increased understanding of inter-tumoral heterogeneity at the genomic level has led to significant advancements in the treatment of solid tumors. Functional genomic alterations conferring sensitivity to targeted therapies can take many forms, and appropriate methods and tools are needed to detect these alterations.
This review provides an update on genetic variability among solid tumors of similar histologic classification, using non-small cell lung cancer (NSCLC) and melanoma as examples. We also discuss relevant technological platforms for discovery and diagnosis of clinically actionable variants and highlight the implications of specific genomic alterations for response to targeted therapy.