Non-Small+Cell+Lung+Cancer


 * Adenocarcinoma of the Lung**

A 44-year-old African American male was admitted to the hospital for shortness of breath and coughing up blood. He has a family history going back several generations on his father’s side of non-small cell lung cancer (NSCLC). The patient has no history of smoking and has never lived with someone who has smoked. He is 6’0’’ in height and weighs 175 pounds. The patient works as a software developer in Palo Alto, where he lives an active lifestyle with his family of four. He eats a balanced diet and exercises 5 times a week. The past couple of months, the patient has been experiencing a persistent cough and some chest discomfort. He is also complaining of feeling fatigued. When examined, the patient is found to be wheezing upon inhalation and exhalation. After further tests, the patient has been diagnosed with anaplastic lymphoma kinase-positive (ALK+) adenocarcinoma lung cancer, a specific type of non-small cell lung cancer. Adenocarcinoma is the most common form of lung cancer for smokers andno nsmokers alike. Adenocarcinoma lung cancer is a less aggressive form of lung cancer, when diagnosed at advanced stage. The patient’s race is a risk factor for getting adenocarcinoma lung cancer makes him 20% more likely to develop lung cancer than Caucasian males. His age doesn’t play a large risk factor because only 1.6 percent of lung cancer patients are diagnosed under the age of 45 years -old. On top of his age, his history of non-smoking also makes him an unlikely candidate for developing this form of cancer. The primary risk factor is his family history of non-small cell lung cancer. He most likely inherited a mutated form of the anaplastic large cell kinase gene, which is aknown oncogene. This resulted in the fusion protein EMLA-ALK2that allowed excessive cell proliferation in glandular cells found in the peripheral lung tissue.

For the last couple of months, the patient has been complaining of fatigue.Tumor growth on the outside of the patient’s lungs caused a build up of pressure on his lungs. This pressure decreases the tidal volume of oxygen the patient can inhale causing him to feel short of breath and have chest discomfort. The decrease in tidal volume prevents maximum oxygen exchange and can be one cause of fatigue because the body isn’t getting the necessary amount of oxygen required for cellular processes.

Adenocarcinoma of the lung is a cancer of the mucus producing and secreting glandular cells in the lungs. These cells are responsible for producing mucin proteins, which are the molecular basis of mucus. Most lung cancer cells show an overproduction of secreted and transmembrane mucin proteins. This causes an increased volume of mucus inside the lung, which further decreases gas exchange in the lungs. The build up of mucus in the lungs covers the capillary beds within the alveoli preventing gas exch ange. Over-proliferation of mucus can also irritate and damage lung tissue. This is the cause of the patient’s persistent cough, wheezes and coughing up blood. Mucin proteins play an important role in the growth, survival, and the metastasis of adenocarcinoma of the lung. Tumors are covered in a protective sheath of mucus. Mucus aids in the transmittance and survival of growth signals within tumors, allowing them to proliferate continuously. Mucin also helps cancer cells evade immune detection. Lastly, mucin is absorbed by the patient’s lymphatic system, which provides a method for cancerous cells to metastasize to other parts of the body. Although mucus production in adenocarcinoma of the lung is a slow process and are typically well-differentiated. This means they are less aggressive than less well differentiated lung cancers and are slow to metastasize to other parts of the body making them easier to treat.

The patient underwent multiple diagnostic tests including, but not limited to: chest x-rays, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scans and needle biopsies; to determine how far his cancer had progressed. The American Joint Committee on Cancer provides a systematic method, the [|TNM staging system], to describe the growth and spread of NSCLC based on three qualities of the cancer. They are: Together these three qualities are used to determine the stage (0-IV) of the cancer. The patient is found to have an advanced form of adenocarcinoma of the lung, stage IV.
 * 1) T, indicating the size and location of the primary tumor.
 * 2) N, describing if the cancer has spread to the nearby lymph nodes.
 * 3) M, indicating if the tumor has metastasized to other organs, such as the brain, bones, liver and kidneys.

=**What it means to be ALK positive**= How did his cancer become stage IV? What determines the specific characteristics and attributes that allowed it to become so advanced? Much like humans, cancer cells’ DNA makes them unique. The series of mutations to a person’s genome defines how the cancer behaves. It was once thought that the pathway to cancer was reproducible, meaning each type of cancer was defined by a specific series of mutations in a person’s genome. Today, however, it is known that cancer is more dynamic, and it can evolve through multiple highly variable pathways. It is the specific pathway of mutations that occur, that gives each patients’ cancer its’ uniqueness. However, some mutations are commonly seen in specific types of cancer known as oncogenes. It is imperative to understand what these oncogenes are and what molecular impact they have on the cell in order to be able to target them to fight cancer. To better understand his cancer, the patient wanted to better understand what it meant to be anaplastic lymphoma kinase (ALK) positive.

In 2007, Hiroyuki Mano, MD, PhD and his colleagues discovered an oncogene caused by rearrangement in the anaplastic lymphoma kinase (ALK) coding genes in non-small cell lung cancer (NSCLC). More specifically, they found a specific translocation on chromosome 2p of the echinoderm microtubule-associated protein-like 4 (EML4) gene portion and the ALK gene portion. This translocation is found in 6.7% of all NSCLC patients and most commonly found in adenocarcinomas of the lung. Wild-type ALK genes encode for proteins in the receptor tyrosine kinase (RTK) family, which are cell surface receptors that regulate cell growth, development, and reparative processes. At a cellular level, ATK proteins share the regulation of important signaling pathways with RTK signaling proteins on the cell surface. An example of this is the RAS signaling pathway, which is involved in cell growth. ATK proteins are stimulated at the cell surface, which causes them todimerize and activate downstream signaling, which is important for several cellular processes such as cell growth and division (Figure 1).

The EML4-ALK oncogene is caused by the inversion of intron thirteen of EML4 and relocation of it upstream of the ALK exon twenty-one (Figure 2).This causes a fusion between the EML4 and ALK coding regions about 4 kilobases (kb) in length. Bothsections are now in the opposite orientation on chromosome 2p as the wild-type ALK and EML4. This new orientation causes a redistribution of the kinase region of ALK proteins from the cell membrane to the cytoplasm. This causes them to be independent of extracellular signaling for dimerization and activation. It is as if someone removed the speed limit and stop signs in the cell and now the cancerous cell does not have to obey any rules that were once regulated by signaling molecules. This fusion also causes ALK proteins to be fused to the N-terminus region of the EML4 proteins. The N-terminus has important dimerization potential that allows for ALK proteins to be constantly activating signaling pathways necessary for cell growth and proliferation.

There are three main pathways that the EML4-ALK fusion activates that are responsible for excessive proliferation, cell survival and phenotypic changes in adenocarcinomas of the lung.The first is the continual activation of the RAS signaling pathway that causes an accelerated entry into S phase of the cell cycle. Ras causes an increased expression of cyclin A and cyclin D, which causes increased transcription of genes needed for proliferation. The upregulation of cyclin D1 and cyclin A promotes uncontrollable cell-cycle progression because it downregulates the inhibitory molecule p21 and pushes the cell through the cell cycle (Figure 3**)**. The cancer cell can no longer pause the cell cycle in order to assess any cell damage or environmental stimuli but rather just continue proliferating at a high rate and accumulating more and more mutations.



The second and third pathways are both involved in adenocarcinoma of the lungs ability to avoid cell death, or apoptosis. These pathways are the activation of the janus kinase (JAK) and signal transducer and activator of transcription (STAT) and PI3K-Akt pathways in the cell. These pathways regulate downstream anti-apoptotic molecules. The STAT pathway, when overexpressed, increases the concentration of anti-apoptotic factors in the cytoplasm, so that the cell evades death. One anti-apoptotic factor that is upregulated is survivin. Survivin inhibits the transcription of proteases needed for apoptosis. On topof that, the activation of the PI3K pathway causes the inhibition and upregulation of several proteins that allow the cancer cell to evade cell death (Figure 4). One key effect this pathway has is the inhibition of BAD, which normally binds to the anti-apoptotic proteins Bcl-2 and Bcl-xL. Bcl-2 and Bcl-xL are responsible for inhibiting the release of signaling molecules from the mitochondria to activate the apoptotic cascade. Inhibiting BAD stops the cell from signaling for apoptosis to begin, thus allowing for the cell to escape apoptosis.



Cells with the EML4-ALK translocation are shown to have an oncogene addiction. Like drug-addicts need drugs to survive, they need the EML4-ALK fusion as an oncogenic driver to survive. This fusion allows them to proliferate continuously and accumulate mutations without being stopped by the body’s natural anti-tumor defense system, apoptosis. This addiction is the perfect marker to target for treatment. Crizotinib (Xalkori) is a small-molecule inhibitor that targets cells with the translocation. By binding to a specific region on the EML4 protein, it inhibits the phosphorylation of ALK proteins and stops the cancer cells from being able to proliferate and evade apoptosis. This is more effective than systemic treatment of adenocarcinoma of the lung with chemotherapy because Crizotinib only affects cells with the mutation. In healthy cells, EML4 does not play a vital role in phosphorylating proteins involved in signal cascades, which can cause cell death. The side effects of Crizotinib are much less than severe than chemotherapy because it does not kill of large amounts of healthy cells and it increases the median survival rate to 9.6 months.

=**Treatment**= Patients with stage IV adenocarcinoma of the lung have less than a ten percent chance of surviving five-years after being diagnosed. The patient's best optionsfor treatment are targeted therapy: like Crizotinib, chemotherapy, radiation or a combination of the three. The patient was found to have more than one tumor in both of his lungs, and in his lymph nodes and it has also metastasized to his brain. Any form of cancer is difficult to treat once it has spread throughout the body. Each case is unique and each treatment plan should be customized to the patient and to their cancer. In this case, the cancer has spread from the patient’s lungs and has metastasized to the brain. Approximately forty percent of all adenocarcinoma of the lungs develop brain metastases and only ten percent of these are found at the time of diagnosis. The median survival rate of brain metastases from non-small cell lung cancer is 7.8 months, so treatment has to start immediately after diagnosis. Through brain imaging and a PET scan, the doctors have been able to find out that the patient is lucky enough to only have one site of metastasis, a solitary brain tumor.

The patient has two options for treating his brain tumor: surgery or undergoing stereotactic radiosurgery. Both of these options will be followed up with radiation to the whole brain. Along with treating his metastases, he will also receive treatment for his primary cancer in his lungs. Surgery is often recommended if the brain tumor can be easily reached and if there are no other signs that it has spread elsewhere. Surgery is done through a hole in the skull called a [|craniotomy]and usually doesn’t damage “vital areas of the brain that control movement, sensation, and speech”. There is a potential for complications to occur during surgery such as bleeding or damaging surrounding tissues. The risks associated with resecting a brain tumor can be but limited to: general weakness, headaches, memory problems and in severe cases stroke, coma or death. There is also a recovery period depending on the location of the brain tumor. These potential risks of surgery have to be weighed against the possibility of successfully removing every cancerous cell from his brain, making him one step closer to defeating his cancer.

The patient also has the option of undergoing radiotherapy or radiosurgery (SR) treatment, if the tumor is not easily located within the brain. This is a form of radiation therapy that uses high-energy x-rays to fight cancer cells. SR delivers precise large amounts of radiation to the tumor in either one (radiosurgery) or several sessions (radiotherapy). One method of giving radiation is called the [|Gamma knife]. In this treatment, approximately 200 beams of low dose radiation are directed at different angles that converge together around the tumor. This method is usually only given over short amounts of time. Another method is to have one high radiation beam move around the head to reach different angles on the tumor, which is called the X-Knife. Each session lasts about 15 to 30 minutes and they are not painful.

The side effects associated with both types of radiation are: fatigue, skin irritation, hair loss and a small risk developing a secondary cancer from radiation. Side effects typically go away within two weeks after ending radiation therapy, but late side effects may take up to years to develop. Fatigue can be caused by multiple factors and is usually unclear. Some known causes are anemia, fluid imbalance in the blood, stress from the treatment, excess physical activity, etc. The patient should also expect skin problems ranging from mild redness to blistering at the site of radiation, much like those associated with sunburns. These typically resolve themselves once radiation has stopped. Hair loss or alopecia also at the site of radiation can occur due to excess damage to the hair follicle that causes the hair to fall out. Hair typically grows back after the treatment has stopped. Long-term risks are the potential of the patient acquiring a second cancer from radiation later on in life due to the excess damage to their DNA caused by radiation. Radiation causes cancer cells to die because it causes so much DNA damage that the cancer cells can no longer function. Doctors know the dosages of radiation that doesn’t permanently damage normal cells. At low dosages, normally healthy tissues are able to repair DNA damage caused by radiation, while cancer cells lack this ability. This causes the tumor to shrink and, in the best-case scenario, disappear completely. But, there is the potential the healthy tissues aren’t able to repair the damage and this leads to a secondary cancer. Doctors recommend that the patient receives counseling along with radiation therapy to help them learn how to manage and live with their side effects.

Both treatments will be followed up with whole brain radiation (WBR). The purpose of this is to kill off any cancerous cells that may have been left behind in surgery or survived radiotherapy treatment. Risk factors associated with WBR are headaches, hair loss, nausea, vomiting and fatigue. The cause of headaches is usually swelling of the brain tissue. Swelling can be prevented with medications prescribed by the patient’s doctor. A long-term risk of whole brain radiation is excessive brain tissue death, which can lead to poor mental function, and loss of memory. One studies showed that patients give WBR in conjunction with radiotherapy or surgery showed a 88.9% improvement on the [|Karnofsky performance status] (KPS) scale compared to the 43% improvement without WBR. It also showed that these patients also had an increase in their quality of life after receiving WBR treatment. KPS is a quantitative way to assess the quality of a patient’s well-being and their ability to perform daily activities. It can be used to adjust medicine dosages, to assess a patient’s recovery and ability to function and even to determine if a patient is qualified for a clinical trial.

This patient’s cancer metastasized by invading his lymphatic vessels around the primary cancer and using the lymphatic system as a pathway to the brain. The cancerous cells then, through extravasation, escape the lymphatic system into the brain and move to a perivascular position. The perivascular position is anywhere around blood vessels, where cancer cells can induce angiogenic growth. Angiogenic growth is when tumor cells form their own vessels to supply itself with nutrients and oxygen. Non-small cell lung cancer metastases are more likely to have angiogenic growth while other forms of metastatic tumors induce cooperative growth. This is when tumors grow around previous blood vessels and capillaries and hijack them to supply the tumor with the necessary nutrients and oxygen to grow. This angiogenic growth allowed the tumor to grow without impacting a large part of the brain making it easier to resect. The average weekly cost of having the tumor resected with WBR is about $524, while the weekly cost for radiosurgery with WBR is only $270. After carefully thinking about the side effects, and cost benefit analysis of both surgery and radiosurgery; the patient decided to have his tumor resected. He felt that because it was easily assessable and had less severe side effect that surgery would offer him a better quality of life.

In conjunction with the therapy for the brain tumor, the patient also receives treatment for his primary cancer in his lungs. The patient decided to have his adenocarcinoma of the lung biopsied to testfor an anaplastic lymphoma kinase (ALK ) biomarkers. The patient tested positive for an alteration in his ALK genes. These genes, when mutated, cause proliferative cell growth in cancerous tissues. Only five percent of patients with non-small-cell lung cancer have ALK rearrangements, meaning only 60,000 patients each year are diagnosed with this molecular subtype of NSCLC. Mutations in the ALK genes caused an EML4-ALK protein fusion through chromosomal translocation on chromosome two. EML4 is a family of echinoderm microtubule-associated protein, and when fused with ALK, it causes the cell to continuously proliferate. Doctors recommend that the best course of action for the patient is to take Xalkori Crizotinib, a targeted the rapy. This targeted therapy in stage IV non-small-cell lungs, especially adenocarcinomas, has shown to increase “progression-free survival [to] 7.7 months” with a “65% response rate” in patients who take it. Crizotinib contains 10 μM of the chemical inhibitor WHI-P154, which inhibits EML4-ALK tyrosine phosphorylation of EML4-ALK. This stops the tyrosine kinase activity of EML4-ALK fusion proteins and induces cell death in tumors.

On top of being the most successful treatment for stage IV adenocarcinoma of the lung, Crizotinib also allows the patient to maintain a relatively normal lifestyle. For the next few months of his life, he will have to take Crizotinib pills twice a day. This beats having to go to the hospital everyday to receive chemotherapy, allowing him at be at home with his kids and wife and continue working. This frees him from a life spent in a clinic receiving chemotherapy, which was once the only method of fighting NSCLC. The most common side effects of taking Crizotinib are vision problems, such as double or blurred vision and sensitivity to light, and gastrointestinal problems, such as nausea and diarrhea. More severe side effects are liver problems and abnormal heart rhythms. The side effects associated with chemotherapy are fatigue, loss of hair, severe nausea, and shortness of breath. Patients who took both chemotherapy and Crizotinib reported having a greater quality of life and experiencing a decrease in their symptoms of lung cancer. Doctors may not be able to cure the patient of his stage IV adenocarcinoma of the lung, but it is of the utmost importance that they do everything in their ability to increase the patient’s quality of life and amount of time they have left.

Crizotinib is not perfect though, like chemotherapy, NSCLC cells acquire resistance to the drug within about of year of the first treatment. Approximately one-third of the patients receiving this chemotherapy will become resistant to the treatment. This resistance can be caused by two mechanisms : a mutation in the ALK tyrosine kinase domain or the activation of an alternative pathway that bypasses ALK proteins (Figure 5). Overall, this is better than the 68% of patients who became chemoresistant through multiple pathways. Because there are less pathways involved in resistance for crizotinib, it makes researching new targeted treatments affecting the mutations involved in resistance a little bit easier .

The patient, after taking Crizotinib, has shown great response to the treatment. His tumor has been progression-free for 8 months, meaning that the patient’s cancer hasn’t gotten worse. His primary tumor has just about disappeared and no new metastases have been found. There may come a time when his cancer becomes resistant to treatment and begins to grow again. When that time comes, his team of doctors will collaborate and determine the best steps to take from there.

Although his doctors played a key role in his treatment, the patient’s knowledge of his cancer made all the difference. Once he found out that he was more susceptible to ALK mutations, he advocated for a diagnostic test. These diagnostic tests are not part of the standard of care for patients who present with adenocarcinoma of the lung and it made all the difference for this patient. Had the doctors not known he was EML4-ALK positive, he wouldn’t have been treated with Crizotinib, the standard of treatment for ALK positive patients and potentially wouldn’t be alive and well today. The key advice he gives to any cancer patient is to become an expert in your cancer and then advocate for what you feel is best, whether it’s a certain diagnostic tests, clinical trials, chemotherapies or a targeted therapies. As for him, it seems like things are starting to look up.

Aperçu :

When diagnosed with cancer the important thing to remember is to always be your own advocate. Always make decisions that you feel are best and push for the diagnostic tests and treatment you want.