Endometrial+Adenocarcinoma

Endometrial cancer is a type of cancer that starts in the lining uterus. The cancer begins to form when normal healthy cells start to proliferate uncontrollably and form tumors. These tumors tend to form around the age of 60 years and will affect about 2 or 3 women out of 100 over the course of their lifetime. Most of the individuals who have endometrial cancer are diagnosed at earlier stages and have a very good prognosis. Also thanks to advances in modern medicine, more than 500,000 women are survivors of this cancer because of earlier detection and treatment. However, some women are not as lucky and catch their cancer a little later. We will look at the story of one such patient and learn about her cancer and how to treat it.

**The Cancer**
Mrs. Williams is a 66-year-old, African American from San Jose, California. She is happily married and has two daughters and five grandchildren. Mrs. Williams is enjoying retirement after working for 35 years as an elementary school teacher. She is 5’4’’ and 175 lb. Her medical history is significant for obesity, high blood pressure, type II diabetes, and late menopause at the age of 53. She also used estrogen replacement therapy without the use of any progesterone for relief from menopause symptoms. Mrs. Williams came into the office reporting abnormal bleeding from the vagina and lower abdominal pain. After performing an endometrial biopsy by inserting an instrument through the vagina and cervix into the uterus to collect tissue sample from the inner lining, the results came back positive for endometrial cancer.

Endometrial cancer is the most common cancer of the female genital tract in the world, and is also the most common type of uterine cancer. Though the exact cause of endometrial cancer is unknown, it is believed that increased levels of estrogen may play a role in the onset of endometrial cancer. Estrogen is responsible for stimulating the body to build up the lining of the uterus, and progesterone is responsible for stimulating the thinning of that lining. Postmenopausal women are unable to shed the extra endometrial lining. Since Mrs. Williams has been using estrogen replacement therapy for menopausal relief without the use of progesterone, the increased levels of estrogen could have caused the overgrowth of the endometrial lining in her uterus and might have led to the onset of her endometrial cancer. Mrs. Williams’ history of obesity may have also added to the elevated levels of estrogen because fatty tissue in women continually produces large amounts of estrogen. Her history of high blood pressure and diabetes are also risk factors, but it may be because it is associated with her obesity. Also, Mrs. Williams’ history of late menopause increased her risk of endometrial cancer. This longer period of fertility allowed for prolonged estrogen production. The abnormal bleeding Mrs. Williams reported is normal for endometrial cancers as 9 out of 10 uterine cancers cause bleeding. In early stages of this cancer, the only symptoms patients are able to notice are bleeding as the cancer advances it can cause abdominal pain.

Endometrial cancer at stage I is first found only in the surface layer cells of the endometrium, the inner lining of the uterus. Depending on the patient, the cancer can continue to grow to varying depths in the myometrium, the muscle layer of the uterus. Stage II occurs when the tumor spreads from the uterus into the supporting connective tissue of the cervix. At this stage the cancer is still isolated within the uterus. When the cancer progresses to stage III, four different scenarios can occur. In stage IIIA the cancer continues to spread from the endometrium to the myometrium then finally to the outer surface of the uterus called the serosa and/or to the fallopian tubes and ovaries. In this stage the cancer has not yet spread to the lymph nodes or distant sites, this is also seen in stage IIIB cancer. The only differences between A and B is instead of the cancer spreading to the serosa, it has spread to the vagina and parametrium, which are the tissues surrounding the uterus. In the final two types of stage III, C1 and C2, the tumor is growing within the body of the uterus. The tumor may have also spread to other surrounding tissues, but not the bladder or rectum. This occurs at a later stage. Both C1 and C2 affect immune system cells. C1 spreads to the pelvic lymph nodes while C2 spreads to the lymph nodes around the aorta.

In the last stage of the cancer, stage IV, the cancer has finally spread to the inner lining of the rectum or bladder and may have also spread to nearby lymph nodes. The uterus is wedged in between the rectum and the bladder so once the cancer has spread through the width of the myometrium and serosa it can then grow into both the bladder and rectum. The second type of stage IV is defined by the spread of cancer into distant sites—distant lymph nodes, the upper abdomen, the omentum (tissue connecting the stomach and other abdominal organs), bones, and lungs.

Mrs. Williams was diagnosed with grade III endometrial adenocarcinoma, which tends to be the most aggressive form of the cancer. Growing and spreading rapidly through the body, the disease has a poorer prognosis. Her cancer has spread from her uterus to some nearby tissues, but has not yet reached the inside of the bladder or rectum. It has also spread to the pelvic lymph nodes but not around the aorta or distant sites. According to the International Federation of Gynecology and Obstetrics system, Mrs. Williams has stage IIIC1 endometrial adenocarcinoma. The five-year prognosis for patients with this type and grade of cancer is 57%. However, “the mortality rate of African American women is nearly twice as high as that of all other racial groups.” Women’s limited financial resources, lack of health insurance, and mistrust of the health care system may delay them from seeking medical attention. This makes it more likely for these women to have a more advanced disease at the time of diagnosis. Cancers that have progressed to later stages are harder to treat and have a poorer prognosis. Even though the prognosis for African American women does not seem very promising, some patients pass away from different causes lowering the statistic. Furthermore, this statistic was calculated 6 years ago, and since then improvements in treatments have been made and the current five-year prognosis may be even higher than reported. However, recurrence of the cancer is possible and usually happens within the first 3 years after diagnosis. Since this certain type and grade of cancer is a high-risk disease, there is a higher chance of recurrence. About 40% of recurrences are found in areas near the original tumor.

Although Mrs. Williams is not well versed in molecular biology and higher sciences, she is very interested in learning about her disease. She would like to have a full understanding of what changes have occurred in her body that led to her acquiring this cancer. I referred Mrs. Williams to a medical geneticist to help her understand her disease.

=**Molecular Basis**=

Endometrial cancer is not usually acquired through heredity, only about 10% of cases are caused in this way. The other 90% of patients acquire the cancer due to sporadic events. Each patient’s cancer is different but most arise in a similar way sharing the same characteristics. These shared characteristics are brought on by epigenetic, genetic, and environmental factors. Epigenetic changes in patients are one of the biggest influences that drive the progression of endometrial cancer. Unlike genetic changes that bring about cancer through mutations in the DNA, epigenetic changes affect gene expression rather than the DNA itself. In endometrial cancer, the epigenetic changes patients usually exhibit are the change in methylation status of CpG islands. CpG islands are within our DNA and influence the status of the promoters of genes. They can then control transcription initiation and chromatin configuration. In patients with endometrial cancer many of these CpG islands are hypermethylated, which inhibits transcription of these genes following the CpG islands. Genes commonly inhibited are important tumor suppressor genes such as //PTEN//, //MLH1//, //RASSF// //1A//, and //APC//.

The CpG island associated with // PTEN //is found to be hypermethylat d in up to 83% of patients with endometrial cancer. // PTEN // encodes a protein with tyrosine phosphatase function. Just the loss of // PTEN // can send cells down many different pathways to acquire the cancer. // PTEN //has phosphatase activity, which can negatively regulate the PI3K-d AKT signaling pathway by dephosphorylating PIP3 to generate PIP2 to block the PI3K signaling cascade. If // PTEN // function was lost, PI3K would be activated by a receptor tyrosine kinase and phosphorylate PIP2 to generate PIP3 which would then phosphorylate Akt. The activated Akt can then also activate the mTOR, which can lead the cell down two different pathways both regulating the cell cycle. The first pathway mTOR activates leads to the proliferative cell growth signaling and inducing angiogenesis, which are both fundamental hallmarks of cancer. mTOR activates S6 kinase by phosphorylating the protein, leading to enhanced translation ribosomal proteins and production of hypoxia-inducible factor-1a. The hypoxia-inducible factor-1a is responsible for inducing angiogenesis. The cancer can metastasize on a greater scale because now it has its own blood supply constantly bringing it nutrients to allow it to grow even larger. The second pathway mTOR activates is through phosphorylating 4E-binding protein 1, which promotes dissociation of this complex allowing initiation of factor-4 subunit E to increase translation of cell cycle regulators such as cyclin D1. Increased translation of cell cycle regulators will allow the cell to progress through the cell cycle, bypassing the G1/S checkpoint, and inhibits apoptosis. With the loss of // PTEN //function, patients face high chances of acquiring cancer because of the many different pathways the cancer can crop up from.

Researchers are now hoping targeted therapies will provide even better results than the current standard of care treatments. However, targeted therapies are not widely used to treat patients with endometrial cancer at the moment and are still being reviewed. One drug currently being tested is temsirolimus. This drug is used in targeted therapies to treat renal cancer, however, it has shown to inhibit growth in diverse tumor cells, which is why researchers are considering it as a possible treatment for endometrial cancer. This antitumor drug targets mTOR in the PI3K-AKT pathway by forming a complex with a FKBP12 to inhibit the activation of mTOR. FKBP’s are a family of proteins that have prolyl isomerase activity. FKBP12 can convert normally //trans// isomers of peptide bonds into //cis// isomers.

After temsirolimus is introduced to the body, it is then converted into rapamycin. Temsirolimus is actually an analog of rapamycin and is considered to be a pro-drug, which is a biologically inactive compound that can be metabolized in the body to produce a drug, for rapamycin. Rapamycin binds to FKBP12, which then dimerizes with mTOR and allosterically inhibits its kinase activity. Rapamycin may be necessary for continued dimerization of FKBP12 and mTOR so that mTOR is inhibited indefinitely. However, this is simply speculation, as I could not find sufficient evidence for the role of rapamycin and FKBP12. Temsirolimus only inhibits one subpopulation of mTOR proteins, specifically mTORC1, which regulates both pathways mentioned earlier. When temsirolimus inhibits mTORC1, the cancer cells will no longer be able to grow, proliferate, induce angiogenesis, or inhibit apoptosis. With one single drug, if it works, we will be able to inhibit many of the hallmarks of this cancer.

Looking at part of the molecular basis of endometrial cancer, we can tell that the cancer is not caused by mutations in the DNA but from changes of the area surrounding patients’ DNA. The risk of developing endometrial cancer can be lowered significantly by making changes to our diet. Our dietary choices affect our genome’s epigenetic instability, which can lead to the development of cancer. Folic acid and vitamins B2, B6, and B12 play a central role in carbon metabolism that provides a methyl group for DNA methylation. Low levels of these methyl donors have been found to induce promoter hypermethylation. This seems to be counterintuitive because one would think that lower levels of methyl groups would promote hypomethylation instead of hypermethlation. One way to combat this is including phytoestrogens, found in soy and soy products, in your diet. Asian populations and western vegetarian populations have been associated with reduced risk of incurring endometrial cancer because they include phytoestrogens in their diet. The phytoestrogens are believed to inhibit cell growth, angiogenesis, and induces apoptosis in cancer cell lines by modulating epigenetic events. Including soy into your diet may help to reduce your risk of developing endometrial cancer. Of course leading a healthy lifestyle is easier said than done. Problems such as obesity and diabetes, which also increase the risk of developing endometrial cancer, are felt throughout the country and have been for quite awhile. However, striving to lead a healthier lifestyle will not only decrease your risk of developing endometrial cancer, but many other cancers as well.

Targeted drugs such as temsirolimus are not ready to be used in treating patients. Also, i ncluding soy in Mrs. Williams diet after she has been diagnosed with stage III endometrial cancer will be of no help to her. A much more direct and common approach will be taken to treat Mrs. Williams.

=Treatment=

Endometrial cancer is usually caught in the first or second stages of the disease as it is most often diagnosed as a result of patients’ concern when they experience abnormal bleeding. Since it is usually easily detected, screening for endometrial cancer is unnecessary for asymptomatic women. However, women who are at a high risk for endometrial cancer are recommended to have annual screening with an endometrial biopsy. The procedure is performed by inserting an instrument through the vagina and cervix into the uterus to remove tissue samples from the endometrial lining. Some risks associated with this procedure result in discomfort, bleeding, infection, and rarely, uterine perforation. Transvaginal ultrasounds can also be used to screen for the cancer and is less invasive than endometrial sampling. For this screening a sonogram is taken of the uterus and surrounding tissues to check for tumors.

Mrs. Williams has stage IIIC1 endometrial adenocarcinoma. The standard of care for this particular stage of endometrial cancer is first performing a hysterectomy followed by chemotherapy. The hysterectomy is the main treatment for endometrial cancer. The operation removes the uterus and cervix either through an incision in the abdomen or through the vagina. However since Mrs. Williams has stage III, a radical hysterectomy, where the tissues next to the uterus and the upper part of the vagina is also removed, is performed. There are many different ways to operate, but the laparoscopic approach is recommended for Mrs. Williams for the shortest recovery time. In this approach, small incisions are made in the abdomen to insert tubes enabling the surgeon to view the inside of the abdomen and pelvis. Small surgical instruments can be inserted into the tubes and controlled by the surgeon to perform the surgery. Although not part of the hysterectomy, removal of the pelvic lymph nodes and a bilateral salpingo-oophorectomy, which is the removal of the ovaries and fallopian tubes, can also be done through laparoscopy. At this point in the surgery, most of the cancer, if not all, has been removed. A pelvic washing of the pelvic cavities and abdomen with saline salt water will be sent to the lab to check for remaining cancer cells. This entire procedure will be done with Mrs. Williams sedated using general anesthesia.

The radical hysterectomy is the primary treatment for Mrs. Williams and chemotherapy is used after to lower the risk of recurrence of the cancer, and it also kills the remaining cancer cells. After Mrs. Williams recovers for two to three weeks she can then start the adjuvant chemotherapy. She will receive combination chemotherapy including the drugs cisplatin, doxorubicin, and paclitaxel. Cisplatin is considered an alkylating-like drug because those types of drugs directly damage cell’s DNA to induce apoptosis. However, the drug is actually platinum based. It creates crosslinks in the DNA by binding platinum complexes to it. This causes the cell to activate DNA repair mechanisms, but the crosslinking of the DNA leaves the cell unsalvageable and apoptosis is triggered. The drug doxorubicin inhibits topoisomerase II from resealing the unwound DNA double helix during replication by stabilizing the complex. As a result, the cancer cells can no longer grow and multiply. Paclitaxel is a mitotic inhibitor and arrests the cell cycle in metaphase. It binds to the    b subunit of tubulin, hyper-stabilizing the microtubule structure, which takes away tubulin’s dynamic instability. This impairs cells in many ways because microtubules are used as a transportation highway for the cell and they are also very important in mitosis. Therefore, paclitaxel can inhibit cells from replicating. Each drug combats cancer cells in a different way. Since Mrs. Williams’ cancer has progressed to stage III, her cancer cells have had a while to differentiate and accumulate various mutations that allow them to proliferate uncontrollably. Therefore, to successfully eradicate all of the cancerous cells, the three different chemotherapy drugs must be used to combat the different cancer cells. The first day of treatment Mrs. Williams will receive doxorubicin and cisplatin intravenously. On the second day of treatment paclitaxel will be given intravenously and on days three through twelve she will receive a different drug, filgrastim, as a shot. Filgrastim is not a chemotherapy drug, but it is given during chemotherapy to reduce risk of infection. This regimen will be repeated every three weeks for six to seven cycles.

Removing patients’ pelvic lymph nodes can often lead to patients getting a condition called lymphedema. The lymphatic system consists of lymph vessels and lymph nodes. The lymph vessels transport fluid containing protein, water, fats, and wastes to the lymph nodes to be filtered out. Consequently, when the pelvic lymph nodes are removed, fluid can build-up in the legs resulting in abnormal swelling. There is nowhere for it to go. There is no cure for this condition, but it can be treated with therapy, and once it develops it may be uncomfortable and sometimes painful. Side effects associated with chemotherapy include nausea, vomiting, loss of appetite, mouth and vaginal sores, and hair loss. Other common side effects are infection, bleeding or bruising after minor cuts or injuries, and fatigue. These symptoms are caused by low white blood cells, platelet counts, and red blood cells respectively. Also each drug given during chemotherapy can cause different side effects. Doxorubicin can damage the heart muscle over time. Cisplatin can cause kidney damage, and both cisplatin and paclitaxel can cause nerve damage, which may cause numbness, tingling, or even pain in the hands and feet. Most of these side effects will stop once the treatment ends, but some can be long term. Clinical trials have shown patients treated with surgery followed by the three-drug regimen of adjuvant chemotherapy had a response rate of 57%. The progression-free survival statistic measures how long patients were able to live with the cancer, without it progressing. For this particular treatment the time frame was 8.3 months. The overall survival of patients treated with this regimen was 15.3 months. However, given the toxicity and limited efficacy of this certain treatment, Mrs. Williams may not feel comfortable continuing with the current standard of care option. We can look at some clinical trials that may offer better results.

One clinical trial Mrs. Williams is eligible for is being offered at Palo Alto Medical Foundation-Gynecologic Oncology. This particular clinical trial is studying if metformin hydrochloride helps paclitaxel and carboplatin work better in cancer cells. Metformin hydrochloride is not a chemotherapy drug, but it is used to treat patients with diabetes mellitus. The drug increases insulin sensitivity and enhances peripheral uptake by cells, which is caused by improved insulin binding to insulin receptors. Researchers are hopeful that metformin will also increase cancer cells’ sensitivity to paclitaxel and carboplatin. The increased uptake of these drugs will likely promote efficient and effective treatment. The drug carboplatin is also a platinum drug like cisplatin and treats cancer in a similar way but it produces less side effects. The clinical trial is trying to determine whether the drug metformin hydrochloride helps paclitaxel and carboplatin to work better by making cancer cells more sensitive to the drugs. Participating patients receive either the third drug or the placebo.

All participating patients will receive treatment intravenously. Every patient will be administered paclitaxel over three hours and carboplatin over thirty minutes on day one. They will also receive either the metformin hydrochloride or placebo on days 1-21 depending on which experimental group they are in. The treatments are given every 21 days for six courses. Researchers are primarily measuring the progression-free survival and overall survival time periods afforded to patients from this clinical trial. Therefore, we are currently unable to determine the effectiveness of this treatment. Patients who choose this treatment option do so knowing there is no guarantee of results.

I recommend Mrs. Williams to enroll in this clinical trial because it may offer her better results than the current standard of care for her disease. She should first undergo the radical hysterectomy then receive the clinical trial chemotherapy. The current standard of care adjuvant chemotherapy offers at best a 15.3 month overall survival. This clinical trial may increase Mrs. Williams’ overall survival rate and may be less toxic to her system. Since only two drugs will be used, Mrs. Williams will suffer less from side effects caused by the drugs. This course of action seems best for Mrs. Williams, and if she agrees we can start as soon as possible.

Mrs. Williams is in a tougher position than most women who are diagnosed with endometrial cancer because she is one of the few to be diagnosed with stage III. However, the clinical trial she is eligible for offers her a much better prognosis than the current standard of care. Also for future patients diagnosed with later stages, the targeted therapies seem to be a promising alternative treatment that will help to save the lives of many other women like Mrs. Williams. Being diagnosed with endometrial cancer is not a death sentence, and as our understanding of the cancer grows, so will the amount of patients’ lives will be saved.

=Aperçu =

Although the clinical trials seem promising, we can only assume that my patient has a short time left, and I want to encourage her to live the rest of her life fully.