With lung cancer being the most deadly cancer in the United States and elsewhere in the world, the advent of molecular diagnostic tests has brought new hope to patients battling lung cancer. Now, a decade after the advent of biomarker testing for lung cancer, a standardized approach to testing for EGFR mutations and ALK gene rearrangements, as well as targeted therapies, offers lung cancer patients the opportunity to improve their survival time and quality of life. Recently, three leading academic institutions, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC) and the American Academy of Molecular Pathology (AMP), released an evidence-based guideline for molecular lung cancer testing, recommending that all lung adenocarcinoma patients undergo genetic testing for the selection of targeted therapies, such as epidermal growth factor receptor (EGFR) inhibitors (e.g. erlotinib and gefitinib ) and mesenchymal lymphoma kinase (ALK) tyrosine kinase inhibitors (e.g., crizotinib). The guideline was published April 3, 2013, in Arch Pathol Lab Med, JMol Diagn and J Thorac Oncol online. “The key recommendation of the guideline, and the part that makes the most sense for lung cancer patients, is the statement that all patients with advanced lung adenocarcinoma should be screened for EGFR and ALK gene abnormalities, and that the test results can determine whether the patient is a candidate for tyrosine hormone inhibitor therapy.” Dr. Marc Ladanyi, a pathologist and member of the IASLC, noted at the Molecular Diagnostic Services meeting at Memorial Sloan-Kettering Cancer Center in New York. Evidence-based medical evidence suggests that patients with lung cancer have a significantly improved prognosis if they undergo genetic testing and select appropriate targeted therapeutic agents. Therefore, the guidelines recommend that all patients with lung adenocarcinoma, regardless of gender, race, smoking or other clinical risk factors, should undergo genetic testing, with EGFR mutations and ALK fusions being the tests of choice. EGFR and ALK testing is not indicated for patients with non-adenocarcinoma lung cancer, including squamous cell carcinoma alone, small cell carcinoma alone, and large cell lung cancer without evidence of adenocarcinoma differentiation by immunohistochemistry. The timing of EGFR and ALK status testing is: at diagnosis in patients with advanced lung cancer suitable for treatment; and at recurrence or progression of disease in patients with previous lung cancer who were staged earlier but did not receive genetic testing. Additional guidelines include: – Testing is available for both primary and metastatic cancers. – Test results should be available within 10 days, and if the laboratory cannot meet this timeline, necessary changes will need to be made to ensure this standard.C This could be an internal improvement or the selection of another standard laboratory. (Consensus) – KRAS testing cannot be used alone as the sole criterion for determining whether a patient meets the indication for anti-EGFR therapy. – For patients with acquired resistance to EGFR inhibitors, a minimum of 5% of cells sampled may be tested for EGFR T790M secondary chromosomal mutations. – PCR is not recommended to replace fluorescence in situ hybridization (FISH) to determine if a patient is suitable for ALK inhibitor therapy. – EGFR and ALK testing is not recommended for lung cancers lacking adenocarcinoma features, such as “simple” squamous lung cancer, “simple” small cell lung cancer, or large cell lung cancer without immunohistochemical evidence of adenocarcinoma differentiation, in the case of samples from patients with total lung resection. Large cell lung cancer without immunohistochemical evidence of adenocarcinoma differentiation. The authors point out that the view of community-based primary care hospitals tends to be that genetic testing of lung cancer patients who smoke is a waste. In fact, this view is wrong; 5% to 10% of patients with smoking lung adenocarcinoma test positive for genes and therefore benefit from targeted therapy. James Jett of the National Jewish Health noted that the guidelines would improve the prognosis for a large number of lung cancer patients. Lung adenocarcinoma is the most common type of lung cancer, accounting for 60 to 70 percent of cases. Jett emphasized that the guidelines are well suited for stage IV lung cancer, which is a “treatable but incurable disease. Without treatment, the median survival for patients with advanced lung cancer is only 4 to 5 months, with standard chemotherapy extending survival to 9 months and EGFR inhibitors extending survival to 2 years. In addition, targeted therapies are usually oral drugs that are less toxic than chemotherapy drugs, so patients treated with these drugs have a better quality of life. He believes that routine genetic testing for lung cancer patients will be available in the near future. Regina Vidaver, executive director of the National Lung Cancer Partnership, also said that testing for genetic abnormalities is becoming part of the standard of care for lung cancer. Similar to the molecular testing being done in breast cancer, molecular mapping related to targeted therapies for cancer patients can help provide individualized treatment options for patients. This guideline explains a number of important questions, including: When to perform molecular testing? How should molecular testing be performed? Should other genes in lung cancer also be routinely tested? How should molecular testing for lung cancer be achieved? “In the United States, up to 20 percent of patients with lung adenocarcinoma, the most common type of lung cancer, will test positive for these two biomarkers,” said Philip T. Cagle, MD, PhD, director of the Pathology and Genomics Research Unit at Methodist Hospital in Texas, APLM editor, and CAP member. “This is critical for identifying the indication population, and the new targeted drugs will benefit more patients with indications with fewer side effects than conventional chemotherapy.” Lung cancer patient Richard Heimler, whose molecular diagnostic tests indicated he had five years to live, underwent lung and brain surgery to remove the tumor focus after his initial diagnosis in 2004. However, in 2008, multiple lesions appeared in his body and Richard Heimler enrolled in a clinical trial to determine if he was a candidate for targeted therapy. “As a result, I tested positive for the ALK gene abnormality and was started on a targeted drug tablet,” Richard Heimler says. “The amazing thing is that the treatment did not cause the debilitating side effects common with chemotherapy. This culmination of scientific progress gives me hope that I can spend more time sharing it with my family and watching my children grow up.” In the age of precision medicine, this guide provides pathologists, oncologists, and other cancer health professionals with the highest level of medical recommendations available today regarding molecular testing for lung cancer. “There is consensus among the three organizations on how relevant mutation testing should be implemented,” said Neal I. Lindeman, MD, PhD, director of molecular diagnostics at Brigham and Women’s Hospital and an AMP member. “Experts focused on molecular diagnostics and lung cancer research worked closely together to develop guidelines to minimize disagreements and provide more accurate recommendations for patient care.” The CAP Center for Pathology and Laboratory Quality, an authority on the development of evidence-based guidelines and consensus recommendations, led the guideline development effort. The expert panel that developed the recommendations consisted of world-renowned scholars in relevant fields. “Guidelines are an important step in ensuring that patients benefit from the latest molecular scientific advances in lung cancer,” said Dr. Ladanyi. “As new research leads to the development of further evidence-based recommendations, we hope to see other guidelines on lung cancer biomarkers emerge.” Following the publication of the guidelines, CAP, IASLC, and AMP have successively launched clinical tools and related materials for pathologists and clinicians to review these findings and recommendations. Yang Xiaobing, Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine