Neely,+Alison

Dear Ms. Martin,

I have received and analyzed your lab results, and it is with sincere regret that I must inform you that, along with your existing ovarian tumors, you have tested positively for cancerous cells in your abdominal lining, This means that your ovarian cancer has become invasive and is now classified as Stage III. I firmly believe that all of my patients deserve to know exactly what type of fight they are up against and why they may be in their current situation, so I wish to be entirely transparent with you when it comes to your diagnosis.

I realize that you have a family history of breast cancer, and that this was most likely the type of cancer you were concerned about developing. You have expressed some concern since your diagnosis that your daughter is at a higher risk of developing ovarian cancer, and if she should take any steps to decrease this chance. She should be aware of the symptoms of this cancer, and report them to her doctor is they do emerge, due to your diagnosis and the prevalence of breast cancer in your family. Use of oral contraceptives has been shown to decrease ovarian cancer risk. They can also increase risk of developing breast cancer because of the exposure to excess hormones. Given your family history of cancer, this drawback should certainly be taken into consideration. Women that are able to carry a child to term, especially before the age of 26, are also less likely to develop ovarian cancer in their lifetime. Both this trend and the decreased risk due to birth control use are due to a change in ovarian activity. Each time the ovary has to release an egg, it becomes more susceptible to cancer development, and both oral contraceptive use and pregnancy decrease ovulation frequency.

There are some more drastic measures that can be taken, such as performing a tubal ligation, otherwise known as having one’s “tubes tied,” or a hysterectomy. I would not advise either of these procedures though, as the benefits are not great enough to justify the operations without other medical reasons. Your lack of oral contraceptive use and the fact that you had children later in life may have contributed to your development of ovarian cancer. Please do not let these choices discourage you – anyone would have made the decisions that you did, and it is commendable that you made a conscious decision to avoid developing breast cancer.

This probably comes as a very frustrating diagnosis because you have had persistent symptoms for some time now, beginning with abdominal and back pains. It is neither your nor your physician’s fault that tests for ovarian cancer, such as pelvic exams and CT scans, were not carried out at an earlier stage. Abdominal pains of this sort could be due to illnesses as common as appendicitis, gastritis, or Celiac disease. It is difficult not to feel that the time taken for other tests as “wasted” time that could have been put towards treating your cancer at a less invasive stage. Unfortunately, this is the frightening and distressing reality of cancer, and we must deal with the current situation as best as we can.

Your records show that you previously had genetic testing due to your family history of breast cancer and, as you know, you have no mutation in the //BRCA1// or //BRCA2// genes, which can also contribute to the development of ovarian cancer. This tells us that your cancer most likely initiated from an acquired mutation, which often occur in either the //TP53// tumor suppressor gene or the //HER2// oncogene. Rest assured – you have done nothing wrong to cause your cancer to proliferate, it is simply the nature of the disease and the nature of our human biological processes.

Many women have been and will be in your position with a Stage III diagnosis. In fact, about 61% of ovarian cancers are diagnosed at this stage. Symptoms are not often extremely concerning until the cancer has delocalized and spread to other areas of the body, meaning it has progressed to Stage III. Figure 1. Progression of Ovarian Cancer

In your case, it spread to your abdominal lining. This was likely the cause of your extreme abdominal pain as well as the bloating that began soon after, because cancerous cells cause a build-up of fluids in the area. It was your extreme fatigue, that began to prevent you from going to work and then made it difficult to even get out of bed in the morning, along with your weight loss due to a decreased appetite that led to a pelvic exam and eventually brought you to my office. I know that this is not a place that you, or anyone, want to be, but I can assure you that all of my efforts are focused toward your full recovery.

That being said, your prognosis must be addressed. As I am sure you are aware, a cancer at Stage III must be treated immediately and aggressively. We will talk about this treatment in the future, as there are many important decisions that need to be made. Approximately 28% of patients who are diagnosed with this stage of ovarian cancer are able to survive for at least 5 years. This number may seem disheartening, but the sooner that we are able to start treatment and better understand the disease that we are fighting, the better your chances of survival will be.

I realize that the numerous treatment options available to you may be overwhelming and difficult to process, so I have detailed each method for you. We will make the decision about what will be the most effective treatment for you together, as you are the one who will live with the side effects as well as the after effects. More than one method is usually necessary to eradicate the disease, especially for a Stage III patient such as yourself. The traditional regimen includes both surgery and chemotherapy, and in some cases radiation and targeted therapy can be utilized. Nearly all of these processes come with significant side effects, so as the patient, you will need to make a decision as to which of these effects will be worth enduring for a fairly extended period of time. Your current options are the following:

** 1. Surgery ** Surgery will absolutely be required in your case. There are two main goals of surgical removals in ovarian cancers: staging and debulking. In the former, a full hysterectomy, or removal of the uterus, is performed, along with the removal of both ovaries and fallopian tubes. This surgery tells us how far the cancerous cells have spread, and how invasive the cancer has become in surrounding tissues. The second goal of the surgery, debulking, is very important in invasive cases such as yours. The main objective is to “optimally debulk” the cancer, or leave behind no tumors in the body that are larger than 1 centimeter in diameter. This could mean that a variety of organs, such as the colon, bladder, spleen, stomach, liver or pancreas may need to be partially removed. Surgery should be scheduled as soon as possible, so we can attempt to eliminate the existing cancerous cells that could lead to further spread of the disease.

** 2. Chemotherapy ** Chemotherapy is necessary in nearly all cases of epithelial ovarian cancers, and I would certainly suggest that we use it to fight your disease. Traditionally, a two-drug combination is used in chemotherapeutic treatments, which are given either through IV or injected directly into your abdomen, called intraperitoneal administration, every 3 to 4 weeks. The standard beginning regimen contains a platinum compound, such as cisplatin or carboplatin, and a taxane, such as Taxol or Taxotere. Platinum compounds are alkylating agents, and are able to affect tumor cells when they are not actively dividing. Taxanes, on the other hand, are plant alkaloids that are able to cause cell death when cells are undergoing active division. Given your Stage III case, I would recommend that you receive 6 cycles of primary chemotherapy, each lasting 3 weeks. On the first day you would receive only Taxol through IV; on the second, you would again be given Taxol intravenously, followed by cisplatin administered intraperitoneally. On the eighth day of the cycle, you would receive intraperitoneal Taxol, and would be given the rest of the 3-week cycle to recover from the treatments. As I am sure you are aware, there are difficult side effects that come along with chemotherapeutic treatments. You will most likely experience hair loss, nausea and vomiting, hand and foot rashes, mouth sores, and possibly a loss of appetite. There is also an increased risk of infection, due to a significant decrease in white blood cells, when undergoing chemotherapy. This means that you will have to avoid highly populated places that may expose you to illnesses. The shortage of both platelets and red blood cells caused by chemotherapeutic drugs will lead you to feel fatigued and bleed and bruise very easily. The rest period of each cycle will give you some relief from these effects, but your lifestyle will undoubtedly change due to chemotherapy.

** 3. Targeted therapy ** The only targeted therapy that would be worth considering is an angiogenesis inhibitor called Bevacizumab. Many targeted therapies focus on mutated //BRCA1// or //BRCA2// genes. You do not show a mutation in either of these genes, so these drugs would not be effective for your case. Angiogenesis, the process by which new blood vessels are created to support tumor cell proliferation, is contributing to the growth of your tumors. This drug binds to VEGF, which signals for new vessel formation. It has been shown to slow the growth of advanced epithelial ovarian cancers, and in some cases can shrink the existing tumors.

** 4. Radiation therapy ** This type of therapy uses high energy x-rays to kill cancer cells, and will be the most useful in the areas in your abdomen that the cancer has spread. Each x-ray exposure is very short, but is given 5 times each week for several weeks. You would most likely experience blistering and peeling of your skin, fatigue, nausea and vomiting from these treatments, but all of these are temporary and would slowly go away after you stop treatment.

** 5. Clinical trials ** There are many ongoing clinical trials that we can consider for your treatment. There is one that has specifically caught my attention recently, which is being sponsored by Gradalis. This treatment, called Vigil, would use your own cancer cells to create an immunotherapy that is personalized to your own Stage III epithelial ovarian cancer. This trial is specifically geared towards Stages III and IV ovarian cancer if 5 to 6 rounds of standard chemotherapy have not been effective. Their goal is to activate your immune system to specifically target your tumor cells, as well as to enhance your existing immune system functions in order to help you better fight the disease. If you chose to participate in the study, you would receive a vaccine of your own tumor cells that have been incorporated with a novel plasmid. This plasmid codes for GMCSF, a growth factor that promotes immune system function, as well as a short hairpin RNAi that inhibits transcription of TGF b immunosuppressors, which would also enhance the functioning of your immune system.

We will need to use multiple forms of treatment to effectively rid your body of its cancer. I would suggest that we schedule a surgery immediately so that we can debulk your existing tumors and better understand your disease. This should be followed by a primary chemotherapy treatment, and I recommend that we proceed with the aforementioned 6 cycles of Taxol and cisplatin given both intravenously and intraperitoneally. I would not suggest that we pursue the use of Bevacizumab, because its effectiveness is not agreed upon in the oncology community. It is possible that, along with inhibiting angiogenic growth, the drug is also blocking chemotherapy treatments from reaching the existing tumors. When you have had time to fully consider every option we will meet and put together a plan.

You may also want to research complementary and alternative methods of treatment, which can make your treatment process more comfortable. These might include managing pain with acupuncture or relaxing with yoga. Finding activities that can help you cope with your new, dramatically altered lifestyle will be vital to the success of your treatments.

It is very common for patients to want to better understand the treatment plan that has been outlined for them, so I have detailed the specific targets of the treatments and how exactly this regimen would help rid your body of its cancer.

Recent studies have shown that a large majority of ovarian carcinomas have a mutation in the TP53 gene, suggesting that the gene plays a large role in the development of ovarian cancers. TP53 is most active in causing cell-cycle arrest and inducing cell death through apoptotic signaling. It is very likely that your ovarian cancer cells must, then, be resisting these signals for cell death. The TP53 gene, when operating normally, senses cellular insults that could compromise cell functions, such as ionizing radiation, oncogenic signaling, and transcription blockages. The functional form of the gene transcribes a functional p53 protein. This protein, which usually induces the transcription of another protein called p21, binds to and inhibits the activities of cyclin dependent kinase complexes. These activated complexes cause the cell to enter the S phase of mitosis, when chromosomes are replicated. In this way, the p53 protein halts the cell cycle when DNA information is compromised or damaged. The transcription of the p53 protein occurs through an indirect response to DNA damage. Both the ARF and MDM2 proteins control the transcription of the p53 gene. MDM2 inhibits the formation of p53, but ARF inhibits MDM2 (see Figure 2). MDM2 is consistently active and keeps the level of p53 protein in the cell very low. When the cell senses excessive oncogenic activity, though, the ARF protein is produced. Through its inhibition of MDM2, the level of p53 in the cell rapidly rises. For the TP53 gene to be inactivated, as it has been in your tumor cells, something has to have gone awry in this inhibition pathway.

Figure 2. Inhibition and activation of p53 protein.

Reintroduction of wild-type functional p53 has been researched and implemented by multiple institutions. When functional p53 is present in the cells of mice in the studies, established tumors regressed and there was no negative effect on the surrounding normal tissue. These therapies have been successful in clinical trials, but have not been integrated into the standard of care for ovarian cancers, and are therefore not an extremely practical treatment option for you. Nearly every standard care cancer therapy targets the p53 pathway, however indirectly, because they cause significant damage to DNA. This damage in turn induce increased activation and stabilization of the p53 protein in your cells. There is some evidence that cancers whose cells have mutant p53 are more likely to become resistant to chemotherapies, and cancer cells with wild-type p53 are more sensitive to chemoradiation. Nonetheless, chemotherapy is an engrained part of the standard of care for your cancer, and targets the cellular activities that occur downstream from the p53 pathway.

The chemotherapy drugs I have chosen to treat your case of ovarian cancer act in several ways to inhibit uncontrolled growth in tumor cells. Taxol, or paclitaxel, is comprised of multiple drugs that fall into the classification of plant alkaloids. Vinca alkaloids and taxanes, derived from the periwinkle plant and Pacific Yew tree, respectively, are both antimicrotubule agents. They inhibit cell growth by blocking mitosis, through interference with microtubules. Microtubules are responsible for separating replicated chromosomes during mitosis. Podophyllotoxins and camptothecan analogs act as topoisomerase inhibitors. Topoisomerase molecules are necessary in transcription and replication of DNA, because it is a supercoiled molecule. A tremendous amount of tension builds up between DNA strands as the coils are compressed during transcription, so topoisomerase break and re-fuse the strands to allow them to unwind and release tension that would otherwise halt transcription and replication. Cisplatin, or Platinol, is a platinum compound that acts as an alkylating agent. It causes cross-linking between DNA nucleotides, which inhibits transcription and replication of DNA, because the strands cannot be separated for DNA polymerase to access nucleotide information. Platinum compounds are the most active when the cell cycle is in its resting phase. Rather than targeting specific genetic mutations that caused the development of my patient’s ovarian cancer, these chemotherapeutic treatments aim to stop the further proliferation of cells containing the mutant genes. By hindering DNA transcription and chromosome separation, the drugs stop the cell cycles, and therefore block cell proliferation.

There are likely significant changes in the methylation patterns of DNA in your cancer cells in comparison to your normal cells. It is very common for hypermethylation to be detected at the BRCA1 gene locus in patients that already have a loss-of-heterozygosity mutation in the gene. 10-15% of ovarian cancers develop at least in part due to this mutation, but the patient in question does not have such a mutation. Other genes suffering from loss-of-heterozygosity mutations in addition to hypermethylation may have a role in the development of ovarian cancers. The protein transcribed by the SFN gene acts as an inhibitor of the cell cycle when it is functioning normally. There is often hypermethylation present around its promoters in ovarian carcinomas, which block transcription of the resulting protein. This aids in allowing your cells with damaged DNA to proceed in the cell cycle, when they would otherwise enter cell cycle arrest or apoptosis pathways.

Cancer therapies targeting epigenetic changes in tumor cells have not been explored on the same level as those focusing on genetic mutations. The first hypomethylating agent that was approved by the FDA for neoplastic treatment was 5-azacytidine. The drug functions by deregulating methylation enzymes, and thereby reactivating the genes that had been obstructed by hypermethylation. This aids in returning the tumor cells to a more normal state of functioning. In clinical trials, and in practice, the drug has been shown to lead to remissions or clinical improvements in over half of the patients that received the treatment. This treatment could be very relevant to your case because your ovarian cancer did not develop due to a genetic BRCA1/2 mutation. Therefore, epigenetic changes are a very possible cause for the development of your disease.

I fully understand that this diagnosis comes as a shock to you and your family, and it will take some time to process this information and the lifestyle changes that will be necessary. Because of the invasive nature of your disease, it is extremely important that we discuss and implement your treatment options as soon as possible. Once we perform the initial surgery, we will be able to better understand your tumor progression. The sooner we are able to begin treatment, the more effective it will be in eradicating your cancer. The treatment regimen that I have outlined for you should cause your existing tumors to shrink and should prevent further tumor growth and metastasis, but only if we start administering the drugs promptly. Please let me know if you have any further questions regarding your diagnosis and treatment options. When you have had time to fully consider every option we will meet and put together a plan. I look forward to seeing you in the near future.

Yours truly, Alison Neely

**// APERÇU: //** While some ovarian cancers are caused by a heritable genetic mutation, most develop from mutations that occur simply by chance, outside of the patient’s control. This lack of control is the frightening reality of ovarian cancer – there is no object of blame, there is no absolution, the only option is to hope for effective treatment.