Abstract and Introduction
The identification of molecular subtypes of non-small-cell lung cancer has transformed the clinical management of this disease. This is best exemplified by the clinical success of targeting the EGFR or ALK with tyrosine kinase inhibitors in the front-line setting. Our ability to further improve patient outcomes with biomarker-based targeted therapies will depend on a more comprehensive genetic platform that can rationally interrogate the cancer genome of an individual patient. Novel technologies, including multiplex genotyping and next-generation sequencing are rapidly evolving and will soon challenge the oncologist with a wealth of genetic information for each patient. Although there are many barriers to overcome, the integration of these genetic platforms into clinical care has the potential to transform the management of lung cancer through improved molecular categorization, patient stratification, and drug development, thereby, improving clinical outcomes through personalized lung cancer medicine.
The discovery of genetic alterations that drive tumor progression in subsets of non-small-cell lung cancer (NSCLC) has transformed the clinical management of this disease. In particular, recent therapeutic advances in NSCLC have been established by focusing on unique somatic genetic variations between patients that predict response to targeted therapies. This biomarker-driven paradigm in NSCLC has not only revealed significant interpatient tumor heterogeneity, but also extensive intratumor heterogeneity. While this biological variability poses significant challenges to identify clinically relevant driver genes, our ability to molecularly dissect individual tumor types and classify them based on their genetic profile provides tremendous opportunity to rationally design and therapeutically target these genetic events to improve patient care.
The prototypical example of how genotype-directed, biomarker-driven lung cancer care can dramatically change an entire treatment paradigm is exemplified through the discovery of EGFR mutations in NSCLC that predict tumor responsiveness and improve progression-free survival (PFS) during therapy with EGFR tyrosine kinase inhibitors (TKIs) compared with standard chemotherapy. More recently, the identification of the EML4-ALK gene rearrangement is yet another example of a therapeutic biomarker that has demonstrated tremendous clinical success as a predictive marker of effective ALK inhibitor (crizotinib) treatment. These two clinically validated oncogenic drivers exemplify the unique benefits of genotype-directed targeted therapy and demonstrate the importance of patient stratification to enrich and enhance treatment responses in drug development and clinical trials.
As the list of potential oncogenic drivers in lung cancer continues to grow, our ability to match an individual patient's tumor profile to a specific targeted therapy hinges upon a comprehensive molecular diagnostic platform that can not only rapidly screen for known targetable genes, but also identify novel actionable drug targets that can be therapeutically exploited to improve clinical outcomes. In this review, we will outline the current genomic landscape of targetable oncogenic driver mutations in lung adenocarcinoma and explore the current and future molecular diagnostics tools to detect and therapeutically guide the treatment of patients with NSCLC.
Personalized Medicine. 2014;11(3):309-321. © 2014 Future Medicine Ltd.