Targeted therapy may be the wave of the future, and the “one treatment fits all” mentality may soon be a thing of the past. In order to have access to these targeted therapies, however, it is necessary for tumors to be tested for any mutations that would indicate the type of therapy most appropriate in a particular case. Depending on which particular mutation the tumor may harbor, the patient’s treatment can be matched with what will potentially offer the best response rates in that specific case. Unfortunately, not all doctors and oncologists are aware that tumor testing exists, or that targeted therapies are available. If your doctor is not familiar with these options, it is highly advisable to seek a second opinion from a lung cancer specialist well versed on the subject.
To have a tumor tested, there needs to be enough available tissue. This tissue may be obtained through surgery, VATS (video-assisted thoracoscopic surgery), CT-guided core needle biopsy, etc. Tumor samples obtained in these ways should provide enough material for analysis. Tissue obtained through fine needle aspiration may not prove adequate. Simply put, the larger the sample, the more likelihood of confirming the presence of a mutation. Many academic centers, as well as certified laboratories, offer tumor testing services. Additionally, fourteen medical facilities in the U.S. are participating in a federally funded study called the Lung Cancer Consortium Protocol, offering advanced lung cancer patients a free screening of their tumors for genetic mutations, some of which may be targets for treatment with existing or experimental therapies. Tumors will be tested at no cost to the participant, and if applicable, medical professionals will notify them of clinical trials that specifically target the mutation found in their tumors. A database will also be compiled so that as new therapies are developed, patients can be contacted and linked to new trials.
While a number of different mutations have been identified in lung cancer to date, effective targeted therapies have not yet been developed for all of them. At the present time, the three mutations most commonly tested for are the EGFR, ALK, and KRAS genes. Since a positive result for one of these mutations generally means that the tumor will test negative for the others, treatment can be focused on where the best results may be obtained. Following is a chart showing the breakdown of currently identified non-small cell lung cancer mutations.
EGFR Gene Mutations
Non-small cell lung cancer is the most common form of lung cancer with adenocarcinomas being the most common sub-type. 20% to 30% of tumors of adenocarcinoma histology have the EGFR mutation. These mutations predominate in female never-smokers. Currently, the two drugs of choice for targeted therapy of this mutation have been Tarceva (erlotinib) with a response rate of 82%, and Iressa (gefitinib), with a response rate of 72%. Both of these drugs are classified as tyrosine kinase inhibitors and work by slowing or blocking the activity of a specific protein called Epidermal Growth Factor Receptor 1 (HER1/EGFR) which allows cancer cells to multiply. They are not chemotherapy drugs and are taken in pill form as prescribed by the doctor. While studies have shown these drugs to be successful in helping patients with the EGFR mutation to live longer, they appear to be somewhat limited by the ultimate development of resistance; approximately 50% eventually show the emergence of a second mutation. Second-generation EGFR inhibitors are in development, but efficacy has been limited due to toxicity.
ALK Gene Mutations
Approximately 2% to 7% of non-small cell lung cancers are ALK (anaplastic lymphoma kinase) mutations. Patients with ALK rearrangements are generally younger than most non-small cell lung cancer patients and are often never to light smokers. Recently, researchers have determined that a new drug, crizotinib, shows efficacy in patients with this mutation. Crizotinib targets the “driver kinase”, blocking its activity and preventing the tumor from growing. Data obtained from clinical trials have shown that in patients who had received prior treatments that either failed or worked only for a brief period of time, crizotinib offered a 72% chance the tumor would shrink or remain stable for at least six months. As with the EGFR inhibitors, however, tumors tend to adapt to target therapies, and eventually render them ineffective. The Food and Drug Administration approved crizotinib - which will be sold under the name Xalkori - for advanced-stage non-small cell lung cancer which has been determined to be ALK (anaplastic lymphoma kinase) positive.