Frequency of oncogenic drivers detected. Data from Kris et al. 
The work-up of patients is dependent on when the diagnosis of lung cancer is made. If a patient is found to have a nodule or mass in the lung by chest radiograph or CT scan, then this can be worked up appropriately in a multidisciplinary format with input from a dedicated thoracic surgeon. This scenario and the accompanying complete work-up are beyond the scope of this chapter and are readily found in both thoracic surgery and pulmonary medicine textbooks. It should be noted that a standard part of the work-up is a positron emission tomography (PET) scan . This test has excellent sensitivity and specificity in determining if a patient is stage 4 . If a patient is found with stage 4 disease, then a non-bone site that can be biopsied in the least invasive fashion in the most reliable way of obtaining adequate tissue is determined. This point, not performing a biopsy of a bone lesion, is critical as the processing of bone biopsies by pathology renders the tissue inadequate for mutational analysis. Other than bone, all other sites of disease show equal efficacy for determination of the presence of oncogenic drivers . Once tissue is obtained, it should be processed in the standard fashion along with immunohistochemistry to confirm that the tumor is of lung origin and that it is an adenocarcinoma . Once this is done, testing for oncogenic divers should be mandatory. Currently, only adenocarcinomas undergo testing for oncogenic drivers , but early data demonstrates that a small percentage of squamous cell lung cancers do contain targetable oncogenic drivers .
There is variety in individual institutional practices on when testing for oncogenic drivers should be performed. Some institutions do not currently recommend testing for every lung cancer specimen. Other institutions routinely test all lung cancer cases regardless of stage. Others perform this testing only at the request of a treating physician. Despite these institutional practices most oncologists uniformly recommend it for all advanced-stage lung cancer patients and then will not proceed with chemotherapy until the results of these tests are available .
The other scenario that occurs commonly is when the diagnosis of lung cancer is returned on a bone biopsy that is obtained during open treatment of a fracture. In these scenarios the patient should be immediately referred to a medical oncologist for further evaluation and work-up. The reason for this referral is as stated above regarding the processing by pathology of the specimen obtained during the fracture surgery makes it unusable for mutation analysis testing. As part of this referral, an oncologist will obtain a PET scan and MRI of the brain to complete staging and determine the extent of disease. They will then coordinate a biopsy to obtain enough tissue for mutational analysis. Normally, an endobronchial ultrasound and biopsy of a mediastinal lymph node will be all that is required to obtain enough tissue for appropriate analysis. However, there are times when a biopsy of the primary tumor is required. This can be done under image guidance with a core needle biopsy; rarely is a thoracoscopic approach required to obtain tissue.
Endobronchial ultrasound is routinely done by both pulmonologists and thoracic surgeons and is an outpatient procedure. Other options to biopsy lymph nodes include mediastinoscopy, which is generally only performed by a thoracic surgeon . This procedure is performed as an outpatient and is considered safe . The advantage that it may have over endobronchial ultrasound is that more tissue is obtained for pathological testing. Discussion with pathology and the treating medical oncologist can be beneficial to determine how much tissue is required and what procedure can provide enough tissue in the safest manner for the patient.
Identifying mutations and drug development has redefined both how we describe the disease and treat the patient. There are currently 11 oncological drugs that are approved for other indications that target 7 of the oncological drivers found in lung cancer. Both the number of drugs and the targets are expected to increase in the coming years.
There are two interesting findings that are being seen with patients that have oncogenic drivers identified. One deals with the survival of these patients compared to those that do not have oncogenic drivers. The other deals with survival based upon appropriate targeted therapy in those with oncogenic drivers. In patients with an oncogenic driver not treated with a targeted therapy who are compared to those with no identifiable oncogenic driver, there is an increase of median overall survival of 6 months. In all patients with an identified oncogenic driver, those treated with an appropriate targeted therapy have a median survival 12 months longer than similar patients who did not receive an appropriate targeted therapy . Thus, patients undergoing appropriate targeted therapy for an oncogenic driver that is identified in their tumor have an increase in median overall survival over those that do not have an oncogenic driver of nearly 18 months.
One major issue that occurs with nearly all targeted therapies is that, over time, the tumor either secondarily mutates or develops an acquired resistance to the drug. This, in general, occurs within 2 years after starting the drug, regardless of the drug or the mutation . Once this occurs, the patients again begin to experience progression of their disease. Attempts to change to newer drugs, that also target the identifiable oncogenic driver, have been studied with some positive results . Others have tried combining cytotoxic drugs with targeted therapies after failure of first-line chemotherapy . These studies with wild-type tumors do not show a benefit to adding a targeted therapy when an oncogenic driver was not identified.
Still others have tried using cytotoxic chemotherapy once the tumor develops resistance and then retrying the original targeted chemotherapy that the patient was previously taking after completion of a number of cycles of cytotoxic chemotherapy . This management plan is known as a second-line therapy or regiment. Unfortunately, results using second-line therapies are diminished when compared to results of primary therapy.
A new frontier that is just starting to be investigated for advanced-stage lung cancer is the use of immunotherapies. Drugs such as ipilimumab and PD-1 ligand are being utilized and investigated in patients with non-small-cell lung cancer [15, 16]. While these drugs have shown promise in early studies in the non-small-cell lung cancer setting, further studies are warranted. An increasing number of trials nationally and internationally using combination of standard and targeted therapies with or without immunotherapies in appropriate patients are under way.