The Chronicles of Ke Xu

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The Xu Family


Ke Xu is a first generation, Asian-American female. In 1992, while Ke's mother was in her third trimester, both Ke's parents and grandparents moved to America. The family moved to America from China so Ke could live the American dream and become a successful doctor. Although Ke does not know what type of doctor she wants to become, she knows she wants to dedicate her life to helping others as her family dedicated their lives to helping her. When Ke graduated high school she was accepted to Santa Clara University. Today, Ke is 22 years old and has entered her final quarter at Santa Clara University. Her favorite class this quarter is Cancer Biology.

Ke is studying lung cancer in her cancer biology course. This topic makes her uneasy because she, her grandparents, and her parents have been smoking since they were sixteen years of age. Her cancer biology course taught her that those who smoke are at a high risk for developing lung cancer. To protect herself and her family, she made an appointment with the family doctor to have everyone screened. Unfortunately, both Ke and her grandmother were diagnosed with adenocarcinoma of the lungs. Ke was stunned because she never displayed symptoms; she did not know people who have recently developed adenocarcinoma are typically asymptomatic[1] .


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Non-small Cell Cancerous Mass

Ke was diagnosed with lung cancer via a bronchoscopy. A bronschophy is a procedure in which a pathologist uses a scope to observe the inside of the lungs. This is to detect any irregular masses that could potentially be cancerous. Dr. Islas recommended this because it is one of the most effective screening processes. He then confirmed it was cancer by the use of a MRI scan. An MRI scan provides images of the chest cavity and reveals the size, position, and nature of the cancerous mass. Ke’s doctor chose this method over others (CT scan and needle biopsy) because it is non-invasive, unlike its counterparts. He chose a non-invase procedure because he wishes to treat Ke immediately - any additional surgery will delay her cancer treatment. In addition, the sensitivity of a MRI scan is between 85-95%, which makes it an extremely effective diagnostic tool. Once the doctor confirmed Ke had lung cancer he then had to determine which type of cancer Ke has (American Cancer Society).To confirm exactly what type of cancer Ke has, Dr. Islas examined additional blood tests for markers. Markers are elements in the blood that are associated with certain lung cancers. This is expensive but necessary to determine which course of treatment is best for the patient. To determine which course of treatment is best for the patient Dr. Islas must also know if her cancer has metastasized. To ensure that the cancer has not spread, Dr. Islas ordered a bone scan to determine if the cancer has spread to the bones.
Once Dr. Islas had the results of the bone scan and blood markers, he determined that Ke is in the first stage of non-metastatic adenocarcinoma of the lung. There are four stages for andenocarcinoma of the lungs: the first stage is confined to the lungs while the fourth stage has metastasized to surrounding tissues and organs; the second and third stages are in between the two ends. Since Ke has stage one adenocarcinoma, Dr. Islas determined that surgery is the most promising course of action to eradicate her cancer (American Cancer Society, 2). However, he wishes to discuss all the possibilities and success rates of the other types of treatment so Ke can make an informed decision. After all, she is the most important member of her cancer fighting team. First, Dr. Islas discussed the various surgeries Ke can receive.
Ke's doctor, Dr. Islas, is a very kind man - he remained with her to answer any and all of her questions. Ke's first question is a popular one, "Why me?" Dr. Islas informed Ke that she was predisposed to adenocarcinoma because of her gender and ethnicity. Her doctor informed her that Asian females are susceptible to this type of lung cancer, especially if they are smokers[2] . There is a silver lining however, those with adenocarcinoma tend to have a better prognosis than those with any other type of lung cancer. The five-year survival rates approach 85% for patients under the age of 30 if it’s in its first stage, which Ke is (American Cancer Society). Dr. Islas was surprised when Ke began to cry. He checked her medical history and noticed her grandmother had also been recently diagnosed with adenocarcinoma of the lung.

Dr. Islas delicately informed her that the five-year survival rate for those over 30 is approximately 10%. However, if her grandmother’s cancer is in its early stages the five-year survival rate can be as high as 35-40% (American Cancer Society, 2). In addition, this type of cancer is more likely than other types of cancer to be contained in one area of the body. It takes years for the tumor to grow and become metastatic cancer, unlike other forms of lung cancer. This means it’s not as aggressive as other forms of lung cancer. The doctor asked if her grandmother had displayed any symptoms.

The doctor was not surprised by the symptoms Ke’s grandmother displayed: coughing, shortness of breath, wheezing, and chest pain are common symptoms for those who have had the disease for a long time. Many doctors misdiagnose adenocarcinoma as pneumonia because of the indiscernible symptoms. Adenocarcinoma of the lung can appear pneumonic because this type of cancer typically begins in cells that secrete mucosal substances (American Cancer Society). The excess mucus production causes symptoms that mirror pneumonia. Dr. Islas could tell that Ke was feeling better. When patients have knowledge about their disease they feel more powerful, in control, and less scared. After all, knowledge is power. Dr. Islas continued educating Ke about her adenocarcinoma.

Dr. Islas informed Ke that approximately 40% of lung cancers are adenocarcinomas (American Cancer Society, 2). Adenocarcinomas are a type of non-small cell lung cancer that typically develops in the outer peripherals of the lungs. Ke’s mass was detected because the mass in her lung was forming the classical glandular patterns:


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Glandular Patterns of Adenocarcinoma of the Lung
Adenocarcinoma of the lung has a strong hereditary component compared to other types of lung cancer (American Cancer Society). The most common cancerous mutation that is passed down through generations is a mutation in the EGFR gene. Since Ke’s grandmother has the cancer as well, the doctor thinks it’s probable that the grandmother passed her EGFR mutation down to Ke. Her doctor continued, “Ke, this is not bad news - we caught your cancer early, it has not yet metastasized. Treatment should be short, simple, effective, and without complications. If you wish to discuss the various treatments I can meet with you tomorrow.” Ke made an appointment on her way out.


Treatment

The most popular surgeries for a resection are thoractomies or median steronomies. A thoractomy is when the entire interior of the chest is exposed so surgeons can operate on the mass first hand. A median sternotomy is similar to a thoractomy but instead of exposing the whole chest the surgeon will slice through the sternum and use cameras to eradicate the mass. These types of surgeries are expensive and invasive. However, they are effective (60% and 78%, respectively) and highly recommended for those in the late stages of adenocarcinoma (American Cancer Society). However, Ke’s doctor believes these surgeries are too risky and unnecessary for someone with stage one adenocarcinoma. Instead he suggests an effective alternative: VATS (American Cancer Society).


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Adenocarcinoma Surgury

For those in stage 1 or 2 of adenocarcinoma a less invasive procedure can be done: video-assisted thoracic surgery (VATS). VATS allow surgeons to remove the cancerous mass without exposing the patients chest cavity. This option is preferred because it is less painful, invasive, and limits the amount of bacteria that could enter the patients’ compromised lungs. Ke does not like the idea of surgery so she asks what other treatments is available. Dr. Islas informs her about chemotherapy and radiation therapy. Chemotherapy is a type of medicine that slows the progression of cancer (American Cancer Society, 2). Radiation therapy is a procedure that uses lasers to target and shrink the cancerous mass (American Cancer Society, 2). However, these types of treatments are painful, expensive, involve long recovery times, and have many unwanted side effects such as nausea and hair loss. Her doctor continues to recommend VATS because, unlike chemotherapy and radiation therapy, the side effects of the surgery are minimal and short-lived. VATS is also extremely effective with a 78-89% success rate.

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Video - Assisted Thorascopic Surgery

Ke then asked about clinical trials. Although Dr. Islas loves clinical trials, he does not want to recommend Ke for them because they are experimental and are reserved for those with advanced cancer. They can also can have terrible side effects, long recovery times, and can be painful and/or expensive. Dr. Islas believes VATS is clearly the best option for Ke. Ke agrees to follow the doctor’s recommendation and is about to undergo VATS. This treatment will allow Ke to live past 85% the 5-year survival expectancy (American Cancer Society). If all goes well she will live a long healthy life and pass away from non-cancer related natural causes.

Molecular Basis

While in the pre-op waiting room, Ke Xu asked her doctor to describe the molecular basis of her cancer. Dr. Islas complies because he knows knowledge relaxes Ke. Dr. Islas explained that cigarettes cause mutations by altering DNA segments. Specifically, he explained that there are many G to T alterations that trigger lung adenocarcinomas[3] . The increased rate of these changes, called missense mutations, can be observed in Figure 1. The prevalence of G to T transversions is as high as 30% in smokers’ lung cancer but as low as 12% in nonsmokers’ lung adenocarcinomas (Imielinski). This demonstrates a positive correlation between smoking and lung cancer. Specific types of mutations can lead to specific processes that cause cancer. In lung adenocarcinomas, these mutations typically initiate two common cancer characteristics: sustaining proliferative cell growth signaling and resisting cell death (Imielinski). The high contribution of these hallmarks are depicted in Figure 2:

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Figure 1. Mutation Rates of Lung Adenocarcinoma (Wikimedia)


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Figure 2. Mapping the Hallmarks of Lung Adenocarcinoma (Wikimedia)

Resistance to cellular death refers to the inactivation of cellular processes that normally trigger cell death. This happens when there are mutations on genes that hinder cellular growth suppression. This is analogous to having no breaks in your car; no matter how many times you step on the break, the car will not stop. Resistance to cellular death occurs in 74% of patients with lung adenocarcinoma (Imielinski). The gene TP53 is the main gene whose gene products hinder the growth of cells. 51% of patients with lung adenocarcinomas experience a loss of function from the TP53 gene (Imielinski). TP53 normally signals cells to stop their growth and division cycles if there is a mutation. If the DNA cannot be repaired, then TP53 tells the cell to stop growing and triggers cellular death. Without this breaking mechanism, cells can grow uncontrollably and become tumors. However, it his hard to treat loss of function mutations with drugs. Therefore, scientists look to the gain of function mutations to treat lung cancer[4] .
A gain of function mutation causes cancer by sustaining proliferative cell growth. Sustaining proliferative cell growth refers to the process of uncontrolled cell division, which occurs in 55% of lung adenocarcinoma patients (Imielinski). This happens when a mutation occurs in an oncogene, which is a gene whose gene products promote the growth of cells. When the mutation occurs, the oncogenes are not regulated. This process is analogous to a stuck accelerator in a car: even when you take your foot off the accelerator the car keeps going faster and faster. Thus the genes constantly produce proteins that code for cellular growth and division. The main genes in lung adenocarcinomas that cause this uncontrolled cellular growth are KRAS and EFGR (Imielinski). The high prevalence of these genes in cancer patients can be observed in Figure 1. About 26% of patients with Ke’s cancer have a mutation in their KRAS gene while 10% of patients have the EFGR mutation. The rest of the mutations that contribute to adenocarcinomas are so minimal they are not targeted for therapy[5] . KRAS and EFGR genes normally cause cellular growth and division at a normal rate. However, the cancerous mutations on these genes cause them to constantly produce growth factors, which make the cells grow and divide uncontrollably.

Dr. Islas believes Ke Xu has the EFGR mutation. He believes this because the mutation has a hereditary component and her grandmother has lung adenocarcinoma as well. Thus Dr. Islas describes the EFGR cancer-causing pathway. The pathway that is interrupted in this EFGR gain of function mutation involves tyrosine kinase receptors (RTKs). When these receptors are bound to growth factors, a signaling cascade is initiated that signals the cell to grow and divide. These steps can be observed in the image below. In the first step the RTKs bind to the membrane. Secondly, they bind to a partner because it takes two receptors to bind to a growth factor. In this case the growth factor is EGF (epidermal growth factor). Finally, the receptors bind to the growth factors that cause the cell to grow. In cancer cells, this happens constantly.


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The Normal Function of Receptor Tyrosine Kinase

While other types of cancer normally involve angiogenesis (vascularization of tumors) and metastasis, lung adenocarcinoma patients experience this only 15% and 28% of the time, respectively (Wikimedia). This means sustaining growth proliferation and resisting cell death are the primary hallmarks of lung adenocarcinomas.
There have been many targeted therapies developed that treat oncogenic genes. The medication Erlotinib, coupled with Gefitinib, has demonstrated success in the treatment of the EGFR mutation with a 28% progression free survival rate[6] . Erlotinib specifically targets the EGRF tyrosine kinase receptor to hinder the growth-signaling cascade. “In lung cancer, erlotinib has been shown to be effective in patients. Overall survival, progression-free survival and one-year survival are similar to standard second-line therapy (docetaxel or pemetrexed). Overall response rate is about 50% better than standard second-line chemotherapy” (Wikimedia). Although rashes, diarrhea, loss of appetite, and fatigue are side effects of the combination therapy, the success rate outweighs the negative side effects (Wikimedia). However, this is recommended for patients who have passed stage I lung adenocarcinomas. This is because a surgery is more effective for treating the primary tumor than drugs are. The doctor also does not want to prescribe this drug because it is expensive and patients rapidly develop resistance. For Erlotinib, more than half the patients typically develop resistance 8-12 months after treatment (Wikimedia). This is because the EGFR kinase domain mutates and the drug can no longer bind to the receptor. If the drug can no longer bind then it cannot stop uncontrolled growth signaling (Wikimedia). However, combination therapy involving the drug mentioned previously, Gefitinib, normally eliminates this resistance. This means patients can be treated longer than 8-12 months, which increases the progression free survival rate to 28% when it was formerly 18% (Wikimedia). Ke wishes to take this medication after her VATs surgery to make sure every cancerous cell is eliminated.


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Ke Xu Recovering in Post-Op

Ke is currently recovering in the post-op room. The VATs surgery was a success: her cancer was completely eradicated. Ke was diagnosed with adenocarcinoma of the lung three months ago via a bronchscopy, a minimally invasive procedure in which a surgeon uses a scope to observe the inside of the lung (Imielinski). Her doctor determined her cancer was in stage 1, which approximates an 85% 5-year-survival rate (American Cancer Society). Since the VATs surgery was a success, which it is 75-89% of the time, she most likely beat the cancer. Just in case the surgery did not remove all the cancerous cells, Ke is taking the combination Erlotinib and Gefitinib oral medication. This combination therapy increases progression free survival rate by 28% (Wikimedia). This medication is especially effective for Ke since it targets the EGFR mutation Ke inherited from her grandmother (American Cancer Society). The medication specifically targets the EGRF tyrosine kinase receptor to hinder the growth-signaling cascade. Although Ke does not necessarily need the medication, she is taking them to be safe. After all, her family left everything behind in China so Ke could live a long, happy, successful life. After this experience, Ke finally knows what kind of doctor she wants to become: a surgical oncologist. Her surgical oncologist left her with these final words, “Ke, please never smoke a cigarette again – cancer is scary and we’ve got to respect that. Thankfully, your surgery was a success and with the combination of Erlotinib and Gefitinib oral medication I doubt you will ever have to fight this battle again. Now go home and celebrate your good health with your family.”



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    "What Is Non-small Cell Lung Cancer?" American Cancer Society, n.d. Web. <http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer>.
  3. ^ Imielinski, Marcin, Alice H. Berger, Peter S. Hammerman, Bryan Hernandez, Trevor J. Pugh, Eran Hodis, Jeonghee Cho, James Suh, Marzia Capelletti, Andrey Sivachenko, Carrie Sougnez, Daniel Auclair, Michael Lawrence, Petar Stojanov, Kristian Cibulskis, Kyusam Choi, Luc De Waal, Tanaz Sharifnia, Angela Brooks, Heidi Greulich, Shantanu Banerji, Thomas Zander, Danila Seidel, Frauke Leenders, Sascha Ansén, Corinna Ludwig, Walburga Engel-Riedel, Erich Stoelben, Jürgen Wolf, Chandra Goparju, Kristin Thompson, Wendy Winckler, David Kwiatkowski, Bruce E. Johnson, Pasi A. Jänne, Vincent A. Miller, William Pao, William D. Travis, Harvey Pass, Stacey Gabriel, Eric Lander, Roman K. Thomas, Levi A. Garraway, Gad Getz, and Matthew Meyerson. "Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing." Cell. U.S. National Library of Medicine, n.d. Web. 15 May 2015. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557932/>.
  4. ^ "LUAD - Lung Adenocarcinoma Back." TumorPortal. N.p., n.d. Web. 15 May 2015. <http://www.tumorportal.org/tumor_types?ttype=LUAD>.
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