NSCLC

__**Aperçu: **__ //** Paul Kalanithi died in March of 2015 and is remembered by his loving family and beautiful daughter, Cady. Paul understood the meaning of life and while he was a dreamer, his feet were set in reality. “Our patients’ lives and identities may be in our hands, yet death always wins. Even if you are perfect, the world isn’t. The secret is to know that the deck is stacked, that you will lose, that your hands or judgment will slip, and yet the struggle is to win for your patients. You can’t ever reach perfection, but you can believe in an asymptote toward which you are ceaselessly striving” (4). **//

__** The Neurosurgeon: **__

Paul Kalanithi was on a pursuit to uncover the meaning of life, and was a true inspiration. When deciding what to pursue, Paul was intrigued with Biology but was unsure if he wanted to commit his life to studying this further. He coupled a BA in Human Biology with an MA in English Literature, his first love, and found the perfect balance in his education at Stanford University. After graduation, still unclear of his future, he went to the University of Cambridge and earned an MPhil in the History and Philosophy of Science and Medicine. It was after this that he decided to pursue a degree in medicine at Yale University. He stated that “medicine would allow me the chance to find answers that are not in books, to find a different sort of sublime, to forge relationships with the suffering, and to keep following the question of what makes human life meaningful, even in the face of death and decay” (4). After completing medical school, where he met his wife, Lucy, he entered a six-year long neurosurgery residency at Stanford University. In his memoir, //When Breath Becomes Air//, Paul explained that the basis of medicine is delayed gratification. Because he worked with patients whose conditions were subject to change at any given moment, Paul couldn’t worry about the long term. He simply had to come to terms with the fact that anything could change in the blink of an eye, and worrying about the future beyond lunch was impossible (4).

Paul’s story is intertwined with personal intimacy and professional detachment. As a neurosurgeon, part of his job involved removing tumors from patients’ brains. He saw cancer through a professional lens and thought of the disease as being selfish: that it didn’t care about what it was doing to the human body. This perspective motivated him to heal his patients as quickly and efficiently as possible. “Before operating on a patient’s brain, I realized I must first understand his mind: his identity, his values, what makes his life worth living, and what devastation makes it reasonable to let that life end” (4). Paul often learned more about his patients’ tumors from them because they did most of the research allowing him to take a humanistic approach to surgery. Paul had a professional understanding of what patients were facing in their daily lives, but never experienced it personally. He asked himself questions like where does one determine and accept that treatment may no longer be in the patient’s best interest? When does a doctor set his ego aside and think about this disease from the patient’s perspective? Paul had been on the professional side of this operating table for six years before he would soon lay on the very same table.

At 36 years old, just after his wife became pregnant with his daughter, he was diagnosed with lung cancer (4). To say Paul was devastated was an understatement; he immediately visualized all the potential scenarios and in all of them he didn’t recover (4). Paul received a poor prognosis, but was determined to make the most of the remainder of his life. Knowing his life would change forever, Paul began to understand the life of a patient. He had a new understanding of the importance of quality of life, especially knowing that he would be unable to see his daughter grow up. **Paul had to understand his own mind, uncover his identity, reassess his values, and discover what made his life worth living in order to accept the devastation that made it reasonable to let his own life end.**

__** The Cancer: **__



Paul had Stage IV, non-small cell lung cancer (NSCLC) which was EGFR positive ([|3]) (Figure 1). Around 90% of all lung cancers are NSCLC which subtypes are adenocarcinoma, squamous cell, and large cell ([|6]). Paul did not mention which subtype he had, but I am inferring that he had adenocarcinoma. This is cancer of the “mucus producing and secreting glandular cells in the lungs” ([|8]). Non-small cells are responsible for producing mucin proteins, which are the molecular basis of mucus ([|9]). Most cells show “an overproduction of secreted and transmembrane mucin proteins” ([|9]). As a result, gas exchange in the lungs is decreased due to the increased volume of mucus in the lungs ([|9]). This buildup covers the capillary beds within the alveoli preventing gas exchange. Patient’s symptoms of a persistent cough or wheezing are indicative of the damage of lung tissue caused by the over-proliferation of mucus ([|9]).



Adenocarcinoma makes up 40% of all lung cancers in the United States, and the most common mutation in this type of cancer is in the EGFR gene (20% of all adenocarcinoma mutations) ([|6]). EGFR (Epidermal Growth Factor Receptor) is a transmembrane protein and its activation initiates a signal transduction cascade that promotes tumor-cell proliferation and migration ([|5]). I am inferring that Paul was not a smoker as he was a healthy and active individual, other than enjoying the occasional Scotch. Finally, from his memoir Paul mentions using the drug, Erlotinib (Tarceva), which is commonly used to treat EGFR positive NSCLC as his first-line treatment ([|7]). Figure 2 demonstrates that the incidence for EGFR positive NSCLC is more common in Asians, females, non-smokers, and those with adenocarcinomas; Paul fulfills three out of four of these risk factors (13).

Using the TNM Staging system, Stage IV indicates that the cancer has metastasized, and is “a tumor of any size that has either grown into the space between the lungs, heart, large blood vessels near the heart, the windpipe, and the tube connecting the throat to the stomach, backbone or carina. In addition, two or more separate tumor nodules are present in different lobes of the same lung” ([|1]). To confirm this diagnosis, Paul underwent chest x-rays, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) scans, and other various diagnostic tests to assess his cancer progression (4). In relation to other types of lung cancer, Stage IV is the most severe and has the lowest survival rates ([|6]). People with this particular severity and type of lung cancer do not live very long. Sadly, only 1% of patients survive 5-years after diagnosis ([|2]).

When trying to piece the puzzle together, it’s difficult to truly understand why Paul got cancer, especially since he had a 1 in a 1000 chance of receiving such a diagnosis. **The paradox that an individual’s reward for living a long life is cancer, is untrue for Paul; at 37 years, his professional life was just beginning when his breath became air.**

__** Molecular Basis: **__



Paul’s Stage IV NSCLC EGFR cancer epitomizes the **sustained proliferative signaling and growth hallmark**. EGFR is a “transmembrane receptor for membranes of the epidermal growth factor family of extracellular protein ligands” (11). EGFR activates the RAS/RAF/MEK/ERK pathway which plays an important role in “regulating various cellular functions of proliferation, mortality, and differentiation” (Figure 3) (11, 12). In cancer cells, EGFR acts as an oncogene, where it is activated and subsequently overexpressed, and leads to dysregulation of critical cellular functions.

The “EGFR gene mutation (EGFR Positive) was discovered in 2004 and it can be considered as the first predictive biomarker in lung carcinoma” (12). In EGFR Positive NSCLC, EGFR is overexpressed on the cell surface membrane (Figure 3). The incidence for EGFR Positive NSCLC is more common in Asians, Females, Non-Smokers, and those with Adenocarcinomas; Paul fulfills three out of four risk factors (13). Molecular testing is used to determine the specific mutations in EGFR; the more positive the result, the worse the prognosis.

When the ligand binds (EGF or TGFα), EGFR forms dimers with two identical molecules (homodimers) or two different molecules (heterodimers) with other growth factor receptors, usually from the HER2 family (12). This is dependent on the “autophosphorylation of the intracellular domain and the activation of downstream signaling pathways” (12). Upon activation, these pathways lead to “cell proliferation, metastasis, and migration” (14). Experiments in mice demonstrated that having a mutation in EGFR is correlated with sustained EGFR signaling, which is required for tumor growth (13).



Mutations in EGFR “are usually heterozygous with the mutant allele also showing gene amplification, making it an oncogene” (18). The most common mutations are in the tyrosine kinase domain portion of EGFR and specifically in exons 19-21 (Figure 4) which consist in point mutations (either in-frame small deletions or insertions) (12). “Around 90% of the mutations are either a group of in-frame deletions in exon 19 (codons 746-750) and/or a single point mutation in exon 21” (L858R); a “missense mutation resulting in the switch from leucine to arginine” (13) which both modify the tyrosine kinase domain and result in “hyperactivation of downstream pro-survival signaling pathways” (20). Around 43% of mutations are missense in exon 21 (13), while 48% of mutations are exon 19 deletions. Exon 19 insertions, which occur in around 1% of EGFR mutations, include the insertion of 6 amino acids in the kinase domain. Additionally, exon 20 (codons 767-774) insertions which account for around 4% of EGFR mutations occur “within the loop that follows the C-helix of the kinase domain of EGFR” ([|19]).



The recurrence of mutations encompassed in the tyrosine kinase domain demonstrates that the ATP binding site is not being affected (Figure 4 and Figure 5). Therefore, an inference can be made that these mutations are presumably in the active site portion of the tyrosine kinase domain. **These mutations indicate that the tyrosine kinase domain autophosphorylates, but mutations prevent regulation of the domain (it is unable to turn itself off), thus amplifying the signaling cascade and leading to constitutive downstream activation. This promotes tumorogenesis as the cancer cells are unregulated.**

__** Treatment: **__

According to the National Comprehensive Cancer Network (NCCN), the preliminary work-up and diagnosis for EGFR Positive NSCLC involves evaluating lung capacity and lung function (pulmonary function tests), the presence of any nodes around the bronchial tubes (bronchoscopy), presence of any invasive cancer surrounding the lymph nodes (pathological mediastinal lymph node evaluation), a PET or CT scan, and a brain MRI ([|23]). Mediastinal lymph nodes are found in the area between the chest and lungs, surrounded by the breastbone, spine and lung ([|24]). In addition, Paul underwent molecular testing as it is recommended because it discerns the specific mutations and leads to better understanding the treatment and outcomes for patients (12). With a five-year survival rate less than 1% ([|25]), the prognosis is poor. Surgical resection is no longer an option as his cancer has metastasized. With metastatic cancer, systemic chemotherapies are usually the best option, however targeted therapies have been proven effective for EGFR positive NSCLC.



An inference can be made that Paul’s EGFR positive mutation was a sensitizing mutation. A sensitizing mutation is a somatic activation mutation, which indicates increased activity of the EGFR receptor. Evidence that around 90% of patients with EGFR positive mutations having either an Exon 19 deletion or L858R in the tyrosine kinase domain bolsters this. Sensitizing mutations are more receptive to first-line treatment with drugs under the class of epidermal growth factor receptor inhibitors like Erlotinib, Gefitinib, or Afatinib ([|23]). “Tyrosine Kinase activity is inhibited reversibly (Erlotinib and Gefitinib) or irreversibly (Afatinib) due to the competition of these drugs with ATP molecules for binding sites in the C-terminal domain of the receptor” (26). This then results in decreased activation of EGFR and the respective signaling cascade (Figure 6) (12). By preventing downstream signal transduction and activation, the TKI’s “interfere with important aspects of tumor viability which lead to reduced proliferation, survival, and angiogenesis of cancer cells, by promoting their apoptosis by increasing their sensitivity to the toxic effects of chemotherapy and radiotherapy” (26). EGFR-TKI’s cross the blood-brain barrier and can effectively be used for small metastasis in patients (26). The benefit of these drugs is that they can be used alone without chemotherapy as a neoadjuvant therapy ([|16]). The side effects of these drugs, particularly Erlotinib include: “skin problems, diarrhea, mouth sores, and loss of appetite” ([|16]).

When Erlotinib binds to EGFR, it reversibly binds to the ATP binding site and prevents the signal cascade initiation because of the phosphotyrosine residue created in EGFR (15). This leads to better regulation in cancer cells and prevents them from proliferating and differentiating. Erlotinib can be used as a first, second, and third line treatment option. First-line treatments are used for patients “whose cancer has spread to other parts of the body and has a sensitizing mutation in EGFR”. As second or third line treatments, this is used for “advanced-stage NSCLC in patients whose cancer has spread or grown after receiving at least one round of chemotherapy” ([|27]). In addition, it is important to note that for advanced NSCLC, these drugs are not used simultaneously with chemotherapy ([|27]). The likely reason is due to the levels of toxicity present when used in tandem, and since every patient’s threshold is different, it is imperative to be cautious.

A study performed indicated when analyzing the tumor size, 65% of patients who took Erlotinib had their tumors shrunken or even disappeared as opposed to 16% of patients who just received chemotherapy (carboplatin and paclitaxel) ([|27]). This study further illustrated that 86 patients (n=174), median progression free survival with Erlotinib was 10.4 months as opposed to 88 patients who just received chemotherapy whose median progression free survival was 5.2 months ([|27]). Findings from other clinical trials have indicated that with a sensitizing EGFR mutation, that there is “an increased efficacy of TKI’s treatment determining and improvement of progression-free survival” (12). While other studies have also demonstrated that EGFR-TKI’s have significant improvements in progression free survival, overall survival shows no significant difference with EGFR-TKI’s in comparison to standard chemotherapy (30). This is important to note moving forward with designing new treatments that target overall survival.

However, one such clinical trial demonstrated that combining EGFR inhibition with Erlotinib and radiotherapy in a Phase III trial improved the five-year overall survival for 45% (211) of patients compared to 36% (213) of patients receiving just the radiotherapy (29). The median overall survival for patients with Erlotinib + radiotherapy was 49.0 months while just radiotherapy was 29.3 months (29). The main side effect of Erlotinib is a skin rash (acneiform rash) which did not appear to be worse than just radiotherapy alone (29). The reasoning behind this is that radiotherapy “enhances the effectiveness of Erlotinib by cytoreducing the tumor and creating a hypoxic environment” (29). This then indicates that by using systemic and local therapies, that this produces maximal effects as the tumor is now de-bulking and reducing in size (29). The “optimal timing of administering Erlotinib and radiotherapy has yet to be determined” (29). Research indicates that future trials must evaluate administering Erlotinib “before, concurrently, and/or following the radiotherapy component of treatment”(29). However, research must also evaluate the progression of the disease and come to conclusions about which stages of cancer would benefit from such treatment. With Stage IV NSCLC, this type of clinical trial is not best suited because of the combination of Erlotinib and radiotherapy.

However, most patients with sensitizing mutations, like Paul become resistant to TKI’s after about 8-16 months of TKI therapy ([|23]). After resistance has been built, radiation therapy is recommended for “local palliation or prevention of symptoms (pain, bleeding, obstruction)” ([|23] ). By targeting this therapy to isolated or specific metastatic areas, survival can be prolonged ([|23]). Paul’s oncologist stopped prescribing Erlotinib around 10 months after he started taking it, as his liver enzymes were too high and causing abnormalities in his gastrointestinal track (4). The next option was second line treatments. In his memoir, Paul articulates chemotherapy as a nightmare; his cocktail of drugs nearly killed him and sent him to the ICU (4). Paul’s chemotherapy probably consisted of platinum based chemotherapy as research has proven it to be an effective course of treatment for advanced stage NSCLC albeit the toxic side effects (30). A suggested alternative for Paul could have been to start his first-line treatment with Gefitinib instead of Erlotinib. While they are both essentially the same drug, research has specifically shown that after “failure of first-line Gefitinib, platinum-based combinations and taxane-containing regimens were both predictive factors for second-line therapy response” (30). In addition, “platinum-based combination regimens resulted in better overall survival than a single agent chemotherapy or Erlotinib” (30).

The future of treatment is to create a more holistic and personalized approach for each individual patient and their cancer. The “treatment of each cancer patient will be targeted according to genetic alterations present in the tumors—treating the right patient, with the right drug, at the right dose, and at the right time” (26). A new area of study has been using EGFR as a predictive marker. Research has shown that to achieve the best long-term survival, using EGFR as a predictive factor in NSCLC is critical (14). Determining EGFR mutations is important and can chart the course of treatment for patients. There are a variety of ways to do so, but a new technique, using liquid biopsies proves to be hopeful as it is able to assess molecular alterations in real time (12). Results have demonstrated that by using the liquid biopsy technique on EGFR, that this will “increase the fraction of lung cancer patients who might have access to TKI therapy” (12). In addition, this has the potential to become an alternative to “biopsy providing the identification of resistance mechanisms and information about tumor heterogeneity” (12).

Paul was becoming weaker by the day and succumbing to extreme weight loss, diarrhea, and a constant dry mouth (4). Soon after, his soft palate and pharynx died from dehydration (4). Paul was deteriorating. His oncologist advised Paul that the only thing he could do to consider any other possible treatments was to regain his strength (4). Paul understood that his only way into any sort of experimental trial was to become stronger in every way. When approaching third-line treatments, Paul’s only option was entering a clinical trial. Paul was arranged to enter a clinical trial, but his brain MRI and CT scans showed that his cancer was indeed worsening in not only his lungs but also evidence of metastases (4). A new tumor in his brain, leptomeningeal carcionomatosis, was found (4). Letopmeningeal carcinomatosis, which occurs in a round of 5% of patients with cancer, is a complication of cancer where the disease spreads to surrounding membranes of the brain and spinal cord (4). Paul’s median survival if it was treated was 2-3 months (4). **Paul died just weeks later.**

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