Mikael+Stovarsky

The Third-Quarter Life Crisis // Sometimes the best path is not treatment, but rather an intentional ignorance that allows for use to live life to the fullest. //  About one in seven men will be diagnosed with prostate cancer during his lifetime (1).

Myron W. “Mike” Johns was a 64-year old white man who worked as a part-time consultant residing in Bozeman, Montana with his second wife of sixteen years, Sharon. He had four children from his first marriage, who were all grown, living in various areas of the U.S., and had their own children. He loved to fish, hunt, play golf, ski, and fly. He had his very own Piper Commanche in which he flew around most of the west and Midwest of the United States for business and pleasure. He was very involved in and valued education, and worked for over twenty years in various forms of higher education as a professor and administrator, before starting his own nation-wide consulting business. He was the founder and president of Hospital Development Inc., which set up philanthropic foundations for hospitals. He received many honors and awards for his work including Outstanding Young Men of America, Outstanding Educators of America, Leaders in Education, Who’s Who in the West, and Who’s Who in the Midwest (2). Despite all this, Mike always found time to call his grandkids every Saturday, and keep up with his two favorite college football teams, the Montana State Bobcats and Wyoming Cowboys.

In 2001, during an annual physical exam, the physician found an abnormality in Mike’s digital rectal exam on the left side of his prostate and referred him to an urologist. The urologist ran some more tests that confirmed Mike and Sharon’s fears. Mike had prostate cancer. Apart from skin cancer, prostate cancer (specifically adenocarcinoma) is the most common cancer in American men (1). An adenocarcinoma is uncontrolled growth of the gland cells of the prostate causing growths around and on the prostate gland (3). Age is the primary risk factor of prostate cancer, though some with less aggressive cancers will never experience symptoms or a decreased lifespan. Strangely, prostate cancer most commonly occurs in African-American men and Caribbean men, who are twice as likely to die from prostate cancer than a white man. Yet, it is the opposite for Asian American and Latino men, as they are statistically less likely to develop prostate cancer than any other races (1). Although scientists have not yet determined why these men are less susceptible to prostate cancer, and the still ambiguous root cause of prostate cancer has also been allusive, I would suspect either traditional lifestyle and culture choices of these groups of men or even a heritable genetic marker that gives these races extra protection from this particular form of cancer.

There are statistical links that indicate an increased risk of developing prostate cancer if it runs in the family, especially if a father or a brother has it, but it still occurs predominately in men without any prostate cancer in their family history. The inherited mutated genes typically connected with prostate cancer include: BRCA1 and BRCA2, which code for proteins that repair damaged or mutated DNA before proliferation; and HOXB13, which codes for a transcription factor that acts as a tumor suppressor, keeping cells from growing and dividing uncontrollably (3). When these genes are mutated either by exposure to environmental mutagens, spontaneously during cell duplication, or even simply inherited as already mutated from a parent, the cell has less mechanisms to keep damaged cells from duplicating and creating more damaged cells, that also cannot control how often they duplicate – creating an uncontrollable tumor or lump of mutated cells that can eventually become cancerous if they spread to other parts of the body.

Some environmental risk factors have also been identified to increase a male’s risk of developing the mutations necessary for a prostate tumor to proliferate. A high-fat diet with an excess of meat and dairy and a lack of vegetables along with a sedentary lifestyle, excessive alcohol use and exposure to toxic chemicals, have been linked to increased instances of developing prostate cancer (1). I cannot help pointing out that these lifestyle “risk factors are not exclusive to prostate cancer, but are rather just “risk factors” of an unhealthy life and will increase likelihood of many kinds of sicknesses, from the common cold to obesity to cancer.

The prevalent and initial symptoms that point to prostate cancer include: problems and pain while urinating, blood in the urine and/or semen, and erectile dysfunction. Less commonly, if the cancer has spread to the bones, a tumor can manifest symptoms such as pain in the hips, back, and chest, and weakness or numbness in the legs and feet or complete loss of bladder control from the tumor pressing against the spinal cord (1). When the cancer is still in an early stage, it can usually be treated successfully using combination radiation and chemotherapy, but if the cancer develops to a point where it invades surrounding tissues, the cancer can become life threatening. Prostate cancer typically spreads to the lymph nodes, bones, lungs, liver or brain, causing the less common hip, back and chest pain. Today, the 5-year survival rate is almost 100% and the 15-year survival rate is 95% (1).

Beyond some tension, swelling, and headaches due to scoliosis, Mike had no symptoms of irregular urination, hematuria, or incontinence that are typically consistent with prostate cancer, which is indicative of an early stage or a less aggressive tumor. He presented in overall very good health, evidence of and by a healthy diet and active lifestyle; he was well nourished and developed, all his vital signs were stable, and his medical history was frankly boring, in the line of unremarkable. At the time, both of Mike’s parents were still alive and in good health at ages 90 and 88 and the family had no history of urological cancers. He was a pipe-smoker in his youth, had not smoked in over twenty years, but did partake in approximately 5 alcoholic beverages a week. This history means that despite his age, Mike’s risk factors were almost zero. To diagnose Mike’s case, the urologist performed a transrectal ultrasound, which involves a small probe that gives off sound waves that enter the prostate and echoes. The probe can sense these echoes and feeds that information back to a computer that generates a black and white image of the prostate. The urologist used this image to help him perform a biopsy, by inserting a thin, hollow needle into the prostate via the rectum and removing a small cylindrical core of tissue that can be observed under a microscope (1). The whole procedure only takes about 10 minutes and is practically painless.

Mike’s samples were sent to the MD Anderson Cancer Center in Houston, Texas, where they saw some areas of darker cells with a few recognizable glands but most of the tissue had few recognizable glands and cell invasion into the surrounding tissue consistent with a poorly differentiated carcinoma. These conditions are assigned numbers on a scale called the Gleason score. These numbers are associated with how consistent tumor cells are to normal prostate cells. A score of 1 is normal tissue and a score of 5 is abnormal. The numbers 2, 3, and 4 are assigned on the scale based on the differentiation of the cells and whether or not they have invaded surrounding tissue. Because most cancers have different areas with varying grades of progression, a tumor is assigned two numbers, the primary grade and the secondary grade. The primary grade refers to the dominant pattern seen, over 50% of the tissue, and the secondary grade refers to the pattern of less than 50% of the tissue but still more than 5%. As you can imagine, much of this is up to interpretation by the pathologist diagnosing the sample. The primary and secondary score are then added together as the Gleason score for the tumor (4). Mike’s sample was very poorly differentiated and was given a Gleason score of 7 (primary score: 4 + secondary score: 3)

After this original diagnosis, Mike and Sharon flew to Houston to receive treatment options at the MD Anderson Cancer Center. He was then given a second, full physical, the pathology report reviewed, and an extensive medical history taken. The final assessment resulted in a diagnosis of an intermediately aggressive T2a adenocarcinoma of the prostate. Prognosis: treatable.

__ How did Mike get Cancer? __
Mike and his doctors were not surprised about his diagnoses. After age 50, a man’s risk of being diagnosed with prostate cancer greatly increases, and his chances are six in ten of being diagnosed after age 65 (5). Age is a major risk factor in all cancers because of the natural accumulation of mutations over time and the shortening of DNA in cells that divide.

Mike’s doctors explained the basics of cancer cells like this. When a cell divides, it has to copy all of its DNA, if there is a mistake in the original or in the copy that is not fixed before this process is done, then that mutation is sustained in the two cells that eventually result. Most of the time, a mutation like this occurs in a part of the genome that doesn’t code for anything, or the mutation doesn’t change the overall message that the DNA is meant to code for, so nothing happens. But the more and more these mutations accumulate in cells that continue to divide, the more likely that later the DNA message will be changed. Just like in the game telephone, this alteration can be a change of one little word, but this one little word can have a great impact on the overall meaning. In the case of cancer cells, this mutated message allows the cell to grow, divide, and invade uncontrollably.

There are two main types of genes that, when mutated, tend to lead to cancer: tumor suppressor genes and oncogenes. Tumor suppressor genes are what are referred to as “two hit genes” meaning that they require at least two mutations, one in each allele of a gene, in order for the gene to no longer function correctly. Every cell has two copies of a gene, one from the father and one from the mother, each of which is referred to as an allele. Tumor suppressor cells code for proteins that, when DNA is damaged or the cell is not ready to divide, stop the cell cycle from continuing, or and induce cell death. So in order to “knock out” a tumor suppressor gene, both of the alleles have to be mutated or suppressed in such a way that they no longer code for the correct protein. In most cases, if only one allele is mutated the other allele can still be used. An oncogene only needs “one hit” to start the cell on a path to cancer. Oncogenes code for proteins that promote cell growth and cell division and a mutation in either allele of an oncogene that leads to more of these proteins than normal will cause the cell to grow and divide excessively.

Since Mike’s family had no history of cancer it was most likely that his cancer was caused by mutations acquired during his lifetime, rather than a mutated gene he would have inherited. There are hundreds of genes and proteins that control cell growth and any one of them or more than one of them could be causing Mike’s prostate cancer. Some of these possible genes are common in many cancers because of their heavy influence in the cell cycle. According to research done by the Trust Sanger Institute, two of said genes, TP53 and PTEN are the most common mutations in prostate adenocarcinomas (6).

TP53 is a tumor suppressor gene that has a heavy influence in the cell cycle and hence is often found mutated in cancer cells. TP53 codes for the transcription factor p53, which senses when there is damaged DNA and can trigger the appropriate cascades to tell a cell to stop growing, stop dividing, stop copying DNA, to repair DNA, or to trigger cell death (8). P53 is like a conductor of a symphony, it can hear the entire piece and every section, when it senses something is wrong, he can stop the rehearsal temporarily to fix the problem, but if the musical number is all together terrible, and certain sections simply cannot get their notes right, p53 can trash the song all together; it does this in the cell by controlling whether the cell cycle is simply paused to repair damaged DNA or if the repair is irreparable and induces cell death. P53 is unique among tumor suppressor cells because it exists as a tetramer, meaning the gene TP53 has to be transcribed and translated four times to make four proteins that all come together in a complex that functions as p53. Normally tumor suppressor genes need “two hits” in both alleles, but because of this tetramerization, if only one allele is mutated, p53 made of both mutated and normal protein can tetramerize (7). These kind of mixed p53s usually have a non-functional DNA binding domain; without being able to bind to DNA, p53 cannot do its job of inducting DNA repair and apoptotic proteins. Something as simple as one point mutation (one nucleotide change), which is what is common in prostate cancers, in the TP53 loci can lead to cells that can no longer stop themselves from dividing (9).

PTEN is another tumor suppressor gene that negatively inhibits the AKT/PKB signaling pathway (10). In simple terms, this pathway is activated when a growth signal is received on the cell surface, that receptor connects to a secondary protein, which in turn signals another protein, all the way down the chain until finally the message reaches a protein that can access DNA and start transcribing genes needed for cell growth. What is crucial about the AKT/PKB pathway is that the activation of AKT/PKB pathway gets amplified. If AKT is triggered, it is like a falling domino that knocks over many more than one other line of dominos, which also each knock over several other lines of dominos, creating a big, branching, domino tree. When AKT is activated indirectly by a growth signal it turns on several other pathways that all connect to other protein cascades which then eventually lead to cell processes needed for cell growth (11). Since PTEN inhibits the activation of AKT it is an extremely important protein in preventing a cell from dividing before it is ready or when it isn’t supposed to.

There are many other genes that have been strongly correlated with many types of cancers (i.e TP53, PTEN, RB, MYC, etc.) and it is very possible that the mutation of one of these genes could be the culprit in Mike’s lesions, but there are some mutated genes that have been more closely linked to prostate cancer specifically. Today, researchers are using this knowledge to create therapies that target prostate cancer cells specifically by tagging the cells with these specific mutations. Most of these mutated genes lay in regions of the genome that control androgen receptor expression or are some how integrated in a hormone induced signaling pathway (12).

The AR gene has instructions for a receptor protein that binds to androgens, hormones such as testosterone that are important for male sexual development. When one of these hormones enters the cell, it bind to an androgen receptor, and this unit travels into the nucleus and binds to androgen responsive genes on DNA. These genes code for proteins involved in the development of mature male characteristics as well as processes involved in hair growth and sex drive for both males and females (13). About 46% of mutations in the AR gene are amplification, meaning that a slip during replication resulted in multiple copies of the gene, and another 10% are point mutations that result in an increased amount of receptors in the cell (12). Both of these mutations end in an overexpression of the androgen receptor, meaning that when androgen does enter the cell, much more of it is able to bind to receptors and start turning on genes. The increased amount of gene product than the signal actually asked for is described as overexpression (Figure 1). Surprisingly, studies done at the Memorial Sloan-Kettering Cancer Center have found that mutations that simply amplify the number of androgen receptors were absent in localized prostate cancers. Their conclusion was that the onset of prostate cancer, mutations in the AR gene itself do not typically play a role. However, during treatment of the primary tumor, if such a mutation arose, this new cancer cell could be resistant to the treatment, evolving the cancer into a more advanced, resistant tumor (14).

In primary tumors, mutations in genes that encode for proteins that interact and regulate AR receptors are much more common (12). Of which the most common is point mutations in the FOXA1 gene, which codes for an array of transcription factors involved in cell growth and differentiation. Transcription factors promote and facilitate the transcription of a particular gene or gene type, i.e. AR receptor genes. If any FOXA1 transcription factor is overexpressed due to a gain-of-function point mutation, its presence in the cell increases proliferation in the presence of androgen (15).

SPOP, the gene that codes for speckle-type POZ protein, which has more recently been added to the list of commonly mutated genes in primary prostate tumors, affects about 15% of patients (16). Mutations in SPOP prostate cancers mainly occur in its protein substrate recruiting region and in its Cul3 binding domain (17). To researches at the Baylor College of Medicine, this suggested that the SPOP protein bound and modified something else. Their results concluded that the SPOP protein acted as an expiration date for the protein SCR-3, a steroid receptor coactivator. When SCR-3 is over expressed or amplified the cell receives more growth signaling than it should, the SPOP protein binds to SCR-3 to promote its degradation when it is no longer needed (17). If SPOP suffers a loss of function mutation that prevents this, SCR-3 cannot rapidly degrade on its own, and becomes over expressed in the cell (Figure 2), much like the food in your fridge if you never clean it out. SCR-3 is particularly crucial because it also is connected to the AKT/PKB pathway and even AR transcription activity (18).

These are just some of the most common mutations found in prostate cancer, but because prostate cancer occurs mostly due to age, there are a plethora of other genes that, when mutated, can lead to these lesions (6).

Today, there is extensive research being done that may lead to treatments targeting SRC-3 and androgen transcription factor genes that could reduce tumor size (17). Unfortunately, Mike’s doctors probably never exactly explained what kind of mutations he had that caused his cancer. In the early 2000s, genotyping a tumor for the purpose of treatment was still extremely expensive and only done for research purposes. Mike’s tumor was probably never sequenced, at least not for creating targeted treatments. Whatever gene had been mutated was irrelevant to Mike’s future.

__ Treatment Options: __
Mike’s doctor began to describe the next steps of this journey. Now that Mike had been diagnosed there were several available paths before them in terms of what treatment to follow.

** Observation: ** It is well documented that prostate cancer often never physically harms the patient; there are cases where men have died from some unrelated cause, never knowing they had advanced prostate cancer. Since treatment can lower quality of life, and increase a patient’s chance of relapse or having other cancers develop, sometimes the best road is simply to observe and keep a close eye on the tumor. If there is a low risk for metastasis, the spreading of the cancer to the rest of the body, and the patient shows not outward symptoms, there is no urgent need to treat. The question becomes, for all treatments, how far is the patient willing to go for a non-guaranteed benefit of surviving a few more years?

** Surgery: ** Surgery is a viable option for patients that are young and healthy enough to undergo an operation and whose cancer has not spread beyond the prostate (T1 and T2 classified tumors). The preliminary type of surgery performed is called a radical prostatectomy; the goal of this surgery is to completely remove the cancer from the body by removing the entire prostate, seminal vesicles, and even other surrounding tissue if necessary. This surgery can be done as an open surgery or as a laproscopic surgery using small incisions either made by the surgeon or with the assistance of a robotic hand (19). To have this intense of a surgery means weeks of recovery and all the risks that come with going under anesthesia and being cut open. There are also longer lasting side effects including erectile dysfunction and loss of bladder control. This surgery is recommended for men under the age of 65 because of the risks involved in open surgery and the correlated increased life span compared to men who used active surveillance. But in men older than 65 there is no such advantage. Since Mike was 64 and had a borderline intermediate tumor, though still under this age barrier, a surgery would only mean added discomfort for him without increasing his lifespan.

** Radiation Therapy: ** Radiation therapy uses high-energy rays that damage DNA, thus preventing any cells it is targeted at from growing and dividing. This type of treatment is open to all forms of prostate cancer and can be done on the prostate as well as the surrounding lymph nodes in a patient that has metastasized (19). There are two main types of radiation. The first is external beam radiation therapy (EBRT); this is done with a machine outside the body. First, the patient must undergo a simulation session where the treatment team scans and images the prostate and the areas around. They then use these images to determine the dosage, number and shape of the beams, and the number of treatment sessions. A computer program shapes the hardware in the radiation machine and the beams are aimed at the tumor with the help of ink marks or tattoos on the skin.

The second type of radiation is called brachytherapy, which involves placing radioactive seeds inside the prostate. The seeds are about the size of a grain of rice and can be delivered in either high or low doses. This treatment can also be combined with EBRT and hormone therapy (19). Side effects of this treatment are similar to that of surgery because they include erectile dysfunction and loss of bladder control due to the large amount of cell death from the radiation, but also include skin irritation in the treatment area and colon pain as collateral damage.

If radiation therapy fails, cryotherapy is another option. This treatment consists of freezing the tumors using argon gas flowing through needles into the prostate, killing the cancer cells. Many of the side effects of cryotherapy are unknown, but include erectile dysfunction and painful swelling. Because of this, it is done as an outpatient procedure only if radiation therapy does not work (19).

** Hormone Therapy: ** Hormone therapy, or androgen-deprivation therapy (ADT) and the various drugs used to achieve the desired outcome are still experimental in many ways and are constantly in new development. It began as a treatment for men whose cancer had already metastasized beyond the prostate, but has now expanded to enhance treatment for men with localized prostate cancer (21). As discussed in the molecular analysis of prostate cancer, prostate cells need the sex hormones called androgens to grow; in males the main hormone to stimulate this is testosterone. Testosterone is mainly produced by the testis but about 5-10% is produced by the adrenal gland (21). Hormone therapy stops the body from making testosterone or makes the testosterone non-functional. Without this growth signal to feed the cancer, the tumor cells will shrink and slow tumor growth for a time. This is accomplished either through surgical castration or an assortment of drugs. These drugs can lower the amount of testosterone in the body by targeting the production of testosterone to lower its abundance, or by stopping the testosterone from properly binding to the androgen receptors (22). Hormone therapy does not eradicate the tumor because of the high rate of mutation in cancer cells can bypass the need for growth signals and can eventually become androgen-resistant; but by slowing down the process this gives the patient more time to directly treat the cancer through radiation (19). The side effects of ADT are not severe, lack of sexual drive, impotence, anemia, weight gain, increased cholesterol, fatigue, and muscle loss; it does require careful monitoring to prevent androgen-resistance and depression (23).

Mike’s physician reviewed the clinical factors, including his Gleason score of 7 and his number of positive core biopsies to determine his recommended treatment. His main concern was the fact that since Mike was in such good health otherwise and had no outward clinical symptoms, that this disease, including the treatment, was likely to greatly impact the quality and duration of his life. Mike, Sharon, and the physician spent an hour discussing all the potential treatment options including surgery, radiation therapy, and hormone therapy. The physician recommended the current standard of care for a T2b tumor, which is external beam radiation therapy with hormone therapy and possible brachytherapy (20). Studies have shown that although combination hormone and radiation therapy only increases the 5-year survival rate by 4%, it increases the percent of men who avoided relapse after 5 years by 21% (21). Although this phenomenon isn’t completely understood by the scientific community, the leading theory is that the combination of radiation and ADT triggers the immune system in attacking the cancer cells as well, increasing the treatment’s overall effectiveness (21).

After about a month of consideration and conversation, Mike decided to pursue only EBRT, despite the increased risk of relapse without symptoms. His decision came from a concern about the lifestyle changes and the increased risk of diabetes and heart attacks from a rise in cholesterol that came with perusing ADT (24). Also, if he perused ADT now, if his PSA levels still after radiation indicating metastasized, he would not be able to use ADT as a treatment because the cancer would have become resistant. He began his treatment by undergoing an intense imaging session where he laid down inside a CT simulator in order for the planning team to customize his radiation, and he was given treatment tattoos to guide the placement of the radiation beam. His treatment would be given in 42 fractions, or sessions, each with 1.8 Grays (the measurement of radiation energy per unit of matter) adding up to a total dose of 75.6 Grays. This meant coming in a about five times a week for about 2 months, and laying down in a machine, all alone in a room, with only a technician next door to chat with. He would lay there 10 minutes while an invisible energy beamed into his lower abdomen, killing whatever it penetrated.

** Chemotherapy: ** There are other treatments that were not recommended for Mike’s case but are used in treating many men with prostate cancer. Some of these are less common or are still experimental.

Chemotherapy is recommended for men with advanced, metastasized prostate cancer, and can be in combination with hormone therapy, only if it was not used for initial treatment. However, the side affects are severe and include, fatigue, nausea, weakness, neuropathy, and fever. Chemotherapy uses drugs that interfere with DNA or other cell structures to kill cancer cells. Docetaxel and cabazitaxel are used to treat advanced prostate cancer and are injected into the vein where they travel through the blood stream to treat cancer throughout the body, which is why it is used more often in advanced, invasive cancers and not localized cancers such as Mike’s (19). The therapy is given in cycles with a few days of rest in between to allow the body to recover.

Radiopharmaceuticals are drugs that contain a radioactive substance. Radium-223 is used to prolong life expectancy of patients whose prostate cancer has spread to the bones. Radium-223 is similar to calcium so it travels to bone that has been damaged by cancer and kills the cancer cells nearby. This does lower white blood cell counts and so the risk for infection, bruising, bleeding, and fatigue are high (19). This treatment is only recommended for patients whose prostate cancer has spread to the bones. Unfortunately, once a cancer has metastasized, a the 5-year survival rate drops to about 28%, even with treatment.

// Less than a year after Mike finished his radiation therapy, his cancer relapsed with lymph node metastasis. His doctors recommended hormone therapy or chemotherapy, neither of which was likely to extend his life by more than a couple years, so he refused treatment for the sake of his quality of life. Mike had always been quick to say that, “ life is not about longevity. It’s about what you do with the time you have.” // //He passed away surrounded by his family on May 20, 2004 (2).// ** References: ** (1) "Prostate Cancer." //Prostate Cancer//. American Cancer Society Inc., n.d. Web. 25 Apr. 2016. .

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(16) Blattner, M., DJ Lee, and //et al.// "SPOP Mutations in Prostate Cancer across Demographically Diverse Patient Cohorts." //National Center for Biotechnology Information//. U.S. National Library of Medicine, n.d. Web. 17 May 2016.

(17) "Role of SPOP in Prostate Cancer." //Baylor College of Medicine//. Baylor College of Medicine, n.d. Web. 16 May 2016. .

(18) Zhou, Ge, and Yoshihiro Hashimotot, //et al.// "Role of the Steroid Receptor Coactivator SRC-3 in Cell Growth." //Molecular and Cellular Biology//. American Society for Microbiology, 30 July 2003. Web. 16 May 2016. .

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(21) Garnick, Mark B. "Hormone Therapy for Prostate Cancer - Harvard Prostate Knowledge." //Harvard Prostate Knowledge RSS//. Harvard University, 10 Mar. 2009. Web. 05 June 2016. <http://www.harvardprostateknowledge.org/hormone-therapy-for-prostate-cancer>.

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(25) Mills, Ian G. "Figure 1: Androgen Receptor Activity Reflects Autocrine and Paracrine Signalling, Copy Number Amplification and Signalling Crosstalk." //Nature.com//. Nature Publishing Group, 2014. Web. 09 June 2016. <http://www.nature.com/nrc/journal/v14/n3/fig_tab/nrc3678_F1.html>.