I recently attended the 14th World Conference on Lung Cancer (WCLC), a biennial multidisciplinary meeting for medical oncologists, surgeons, pulmonologists, radiation oncologists, and pathologists. The medical oncology portion of this conference was abuzz with excitement about the prospects of molecularly targeted therapies.Five years ago, few would have predicted that lung cancer would be the disease leading the way into the personalized medicine era in oncology. The recent discovery of a small number of critical genes that act as driving mutations for non-small cell lung cancer (NSCLC) has set the stage for the development of targeted agents against these mutations.
Gene mutations and molecular targeting
The Lung Cancer Mutation Consortium, comprised of 14 US-based cancer centers and sponsored by the National Cancer Institute, reported at the conference that mutations could be identified in 54% of adenocarcinomas, including genes such as KRAS, EGFR, BRAF, HER2, PI3KCA, ALK,MET, and others. Each of these genes has drugs either in clinical development or already marketed for other diseases with the same genetic alterations.Of note is that 97% of these mutations were mutually exclusive, suggesting that only one drug will be necessary to treat each of the subgroups. Proof of this concept is the development of crizotinib, a small molecule that inhibits the EML4-ALK fusion gene/protein with remarkable activity—over 80% of patients respond to this drug. Its approval is eagerly awaited.
Another exciting report presented at the WCLC investigated genetic abnormalities in the second most common subtype of NSCLC—squamous cell. Investigators used a combination of methods to identify genetic mutations, amplifications, or deletions in almost two-thirds of patients with this disease, setting the stage for molecularly targeted treatment in this group as well.
We already have adopted pathway inhibition as a standard in lung cancer patients who harbor an epidermal growth factor receptor (EGFR) mutation, with increasing evidence suggesting that tyrosine kinase inhibitors such as erlotinib (Tarceva) are superior for first-line treatment of EGFR-mutated adenocarcinoma. Molecular diagnostics to guide treatment in the community setting is now firmly established in the most common diseases we see—breast, colon, and lung cancers.
And yet amid all of this excitement regarding novel pathways,validated targets, next-generation massively parallel sequencing, and so on, we must not forget that the majority of cancers are treated in both the adjuvant and metastatic setting with tried-and-true chemotherapeutic or endocrine agents. I even make a point of telling the fellows training with me that I am fairly confident that they will be giving chemotherapy throughout their careers, although it will certainly not dominate as it does today.
Revisiting mechanisms of action
All oncologists need to refamiliarize themselves with the mechanisms of action for the drugs that we use daily. In truth, each of the traditional chemotherapy agents are in fact targeting a cellular molecular pathway. It’s just that we previously lacked the technology and knowledge to identify the specific target. For that reason, I am excited about two comprehensive reviews in this issue of Community Oncology.
The first is a discussion of the estrogen receptor signaling pathway by Adam Brufsky (page 343).Much exciting knowledge has been gained over the past decade in understanding mechanisms of resistance to this oldest of validated targets. Now, trying to block alternative pathways of estrogen receptor activation in conjunction with aromatase inhibitors or other endocrine agents is the focus of much active research.
Also in this issue is a comprehensive review by Michael Trigg and Anne Flanagan-Minick of the mechanisms of action of commonly used anticancer agents (page 357). This is essential reading, as it discusses both classic cytotoxic agents and newer signal transduction modifiers. But perhaps most importantly, this review emphasizes the current thinking that most advanced epithelial tumors will not be brought under control with a single therapeutic agent, a lesson we learned in the era of cytoxic drugs only. In fact, it is likely that the landscape will be dramatically more complex as agents from different classes are necessarily combined to achieve maximum effect.
More and more it appears that integrating personalized medicine into a system of practice-based guidelines will be a formidable challenge. Still, there is a great opportunity for community oncologists to prove value to their third-party payers and directly to patients for the high-level decision making required to provide optimal care. Such decision making must be part of the value equation as reimbursement moves away from margins on drug acquisition and to oncologists providing the best care based on their knowledge and informatics resources.