If you ever remind a cigarette smoker of its impending risks of lung cancer, often you are scoffed at with “there are so many non-smokers, who get lung cancer…I might as well smoke”. Well! they aren’t completely wrong. A non-smoker may also get lung cancer due to second hand smoke, pollution and carcinogens (eg. asbestos) at the work place. So, is the smoker really correct when he ridicules your advice? Not really. One, that people who smoke cigarettes are 15 to 30 times more likely to get lung cancer or die from lung cancer than people who do not smoke. Second, lung cancer of a smoker and that of a non-smoker are not exactly similar.
Let’s see how lung cancer originates and how they are treated. Cancer causing agent such as cigarette smoke enter the lungs and come in contact with the cells that form the inner lining of the lungs. Effectively, they make change(s) in the DNA of these cells called “mutations”. Some of these DNA changes or mutation(s), make a cell go berserk and make them divide uncontrollably leading to tumor formation. Some of the initial sign and symptoms of lung cancer are: cough that doesn’t go away, coughing blood, chest pain, loss of weight/ appetite, shortness of breath etc. When patient goes to a cancer doctor, s/he performs certain tests- 1. Sputum cytology: looking for cancer cells in sputum 2. Chest X-ray and CT scan: taking images to detect the tumor. 3. Biopsy and histopathological exam: to classify the cancer into subtypes. Earlier, all these examinations used to help the cancer doctor choose a chemotherapy treatment. From 2009 onwards, newer drugs called targeted therapies proved themselves to be better than chemotherapy in terms of increased overall survival and reduced side effects, in lung cancer patients. These were pills one could pop orally and one does not have to go to doctor’s clinic for chemotherapy administration. Various targeted therapies for lung cancer are currently approved by US FDA: Erlotinib (Tarceva), Afatinib (Gilotrif), Gefitinib (Iressa), Osimertinib (Tagrisso), Necitumumab (Portrazza), Crizotinib (Xalkori), Ceritinib (Zykadia), Alectinib (Alecensa), Brigatinib (Alunbrig), Dabrafenib (Tafinlar), Trametinib (Mekinist), Bevacizumab (Avastin), Ramucirumab (Cyramza). Newer and more effective targeted therapies are made every year. However, each targeted therapy acts against a specific mutation(s). For eg. Gefitinib (Iressa), acts against mutation(s) in a gene called EGFR and Crizotinib (Xalkori) acts against mutation(s) in ALK gene, hence a patient with ALK mutation cannot be treated by Gefitinib and vice versa. Thus currently a cancer doctor invariably gets lung tumor assessed in a genomics laboratory. Genomic lab analyses the tumor DNA and detects the precise gene mutation which is driving the cancer. Subsequent to the test, cancer doctor may prescribe a targeted therapy.
Interestingly smoker’s and non-smoker’s tumor DNA look very different.
Even for an untrained eye, it would be quite evident that mutation picture associated with a smoker and that with a non-smoker looks very different. That is the case indeed. Frequently, the mutations that drive these two separate type are tumor are different and hence their treatment also differs. Smokers are usually associated with a subtype of lung cancer called squamous cell carcinoma while non-smokers are typically associated with adenocarcinoma. Non-smokers (adenocarcinoma) are frequently detected with mutations in EGFR and ALK genes that can be treated by multiple targeted therapies. On the other hand lung cancer of smokers (squamous cell carcinoma) are frequently driven by gene mutations that aren’t EGFR or ALK, but by PIK3CA, FGFR1 etc and there are no FDA approved targeted therapies to treat mutations in these genes in lung cancer patients. Even if a smoker is detected with adenocarcinoma, frequently the driving mutation comes out to be in KRAS gene which again can’t be treated by any existing targeted therapy. In fact patients with KRAS mutations appear to have a shorter survival than patients with normal KRAS. Also, a tumor with KRAS mutation, usually does not have a simultaneous mutation in targetable EGFR, ALK, ROS1 and BRAF genes. Thus a smoker will more often than not have a tumor that can’t be treated by a targeted therapy, hence may end up getting treated by platinum based chemotherapy such as Cisplatin.
Thus, here we see that smoking not only increases the risk of getting lung cancer by 15 to 30 times, but it may frequently lead to a tumor that may can’t be yet treated by new generation of targeted therapies.
At Neuberg Center of Genomic Medicine, Ahmedabad, we perform state of the art test called OncoCEPT solid (CEPT: Comprehensive Evaluation for Personalized Treatment). This single test analyses all possible targetable mutation in any lung tumor and helps cancer doctor choose the best course of treatment. OncoCEPT solid is based on state of the art Next Generation Sequencing (NGS) platform.
Dr. Siddharth Srivastava
Chief Scientist (Molecular Oncology)
Neuberg Center of Genomic Medicine, Ahmedabad
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