I have no basic science research experience, but when the opportunity to join a laboratory project was offered to me as a clinical fellow, I joined simply because I was interested in the experience and what I could potentially learn from it. Currently, I am involved in a research project assessing whether or not microRNAs (miRNAs) can predict brain metastases in patients with triple-negative and HER2-positive breast cancer. The question originated from observations in the clinic that brain metastases are more common in patients with this subtype of breast cancer.
The concept of miRNA is relatively new. MiRNAs are short, non-encoding ribonucleic acids (RNAs) that regulate the transcription of messenger RNA. As I began working in the lab, I quickly gained insight into the other side of medicine: the laboratory! There, I extracted total RNA with pipettes for accurate measurement of different reagents and used a stopwatch to determine the multiple incubation periods in varying temperatures. As with any scientific endeavor, challenges have arisen. Difficulties obtaining older tissue samples is one. Obtaining suboptimal final products on polymerase chain reaction after several hours of working is another. However, approaching these challenges with perseverance and resourcefulness has made this project move forward, albeit slowly.
I do not have results to share yet, but later goals include identifying the individual targets and mechanisms of miRNAs that give rise to brain metastases. Future implications include identifying higher-risk patients by using miRNA as a biomarker in serum or tissue, and perhaps using these as targets for treatment. It’s bedside to bench and back again! Reverse translational medicine is not novel. Perhaps the best examples in oncology are those involving the epidermal growth factor receptor (EGFR).
The EGFR Story in Lung Cancer
In May of 2003, the FDA approved gefitinib, an orally administered EGFR tyrosine kinase inhibitor, as therapy for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who were refractory to established cancer treatments (both a platinum drug and docetaxel). Tumor response rate was used as a surrogate marker. The overall response rate to gefitinib was around 10%.1
In other words, most patients treated with gefitinib did not respond. However, in about 10% of patients, a dramatic and rapid response was observed. Subsequently, a phase 3 trial was designed to determine the survival advantage of gefitinib in the NSCLC population as a whole. The ISEL (Iressa Survival Evaluation in Lung Cancer) trial enrolled 1692 patients with previously treated, locally advanced, or metastatic NSCLC, and randomized the patients to gefitinib or placebo.
The results were disappointing. Gefitinib provided no significant survival advantage over placebo (5.6 months vs 5.1 months), although further analysis did reveal improved median survival in 2 subgroups in favor of the gefitinib arm: 1) never-smokers (8.9 months vs 6.1 months; P = .012), and 2) Asian patients (9.5 months vs 5.5 months; P = .01).2
Following a second clinical trial that failed to demonstrate a survival benefit, the FDA revised the labeling for gefitinib in 2005. This limited the use of the drug to patients currently receiving and benefitting from, or who previously received and benefitted from, gefitinib.1
Researchers were curious why gefitinib produced a survival advantage in particular subgroups (never-smokers and patients of Asian origin).2
For this reason, Lynch and colleagues examined the molecular mechanisms behind these results and noted somatic mutations in the tyrosine kinase domain of the EGFR gene in 8 of 9 patients with gefitinib-responsive lung cancer; such mutations were found in 0 of the 7 non-responders. The results of their work suggest that screening for such mutations in patients with lung cancer may help identify those who will respond to gefitinib.3
Other groups of investigators have published similar results independently.4