Ductal+Carcinoma

**Patient Name:** Joanna Kathleen Smith **DOB:** 01/25/1960 **Date of Diagnosis:** 04/02/2015

**Type of Cancer:** Breast Cancer
 * Ductal Carcinoma
 * Stage IIA


 * Other Information: ** Married, son age 20

__**Joanna's breast cancer**__  A women’s breast is made up of 15 to 20 lobes, which are made up of even smaller lobules. Inside of these lobules there are groups of tiny glands that produce milk. The breast milk that is produced in these glands flows to the nipple through tiny tubes called ducts. Ductal carcinoma is classified by the presence of cancer cells growing in the lining of these ducts. Ductal carcinoma is the most common type of breast cancer affecting 8 of every 10 women diagnosed with breast cancer.  Similar to any type of cancer, early detection is key in helping treat and prevent the spread of cancer throughout the body. Women ages 50 to 74 are recommended to have a screening mammogram every two years. Using x-rays, a screening mammogram takes two images of each breast. A radiologist then examines these black and white x-ray images looking for any mass or abnormalities in each breast. Joanna has received yearly screening mammograms since the age of 45 because breast cancer persists in her family on her father’s side. Joanna’s grandmother died of ductal carcinoma in 1966 at the age of 67 and her aunt was diagnosed and treated for ductal carcinoma and died in 2012 at the age of 87 from complications during an unrelated surgery. Although ductal carcinoma runs in her family, Joanna and her aunt are not genetically predisposed to this cancer. Both Joanna and her aunt have normal functioning BRCA1 and BRCA2 genes. Although women with mutations in these genes have a higher risk of developing breast cancer, mutations in these genes account for fewer than 10% of all breast cancers.  Once screening results determine the size and extent of cancer cells in the breast, ductal carcinoma is classified as one of four stages. From stages 0 to IV the size of the tumor and the extent of spreading cancer cells to surrounding tissues and lymph nodes increases, making it more difficult to kill or surgically remove all cancerous cells. Joanna’s breast cancer has been classified as stage IIA. At stage IIA, either no breast cancer cells are found in the lymph nodes but a small tumor is found in the duct lining of the breast, or breast cancer cells are found in 1 to 3 lymph nodes and either no tumor or a small tumor is found in duct lining of the breast. During Joanna’s yearly screening mammogram, a tumor 1.5 centimeters across was discovered in the duct lining of Joanna’s left breast and cancer cells were present in surrounding breast tissue. An enlarged underarm lymph node was also discovered and through a needle biopsy more cancer cells were discovered in this lymph node. With treatment, patients diagnosed with stage II breast cancer have an estimated 84.6% survival rate after 5 years.

 __**Risk factors**__  In numerous studies of breast cancer and race, Caucasian women have the highest risk of developing breast cancer compared to other races. Joanna is of English and Irish decent which is just one of the risk factors that may have contributed to the development of breast cancer. Joanna also became pregnant and gave birth to her son when she was 35 years old. Because of her pregnancy at an older age, this also may have contributed to her development of breast cancer. When women give birth to a child they have an increase in risk of breast cancer for several years followed by a long-term reduction in risk. Already at an older age when giving birth to her son, her risk for breast cancer was even greater the first several years after her pregnancy which is when the breast cancer may have begun to develop. After the birth of her son, Joanna also decided not to breastfeed. While this is a personal decision and does not necessarily contribute to the development of breast cancer, studies have shown that breastfeeding may lower the risk of breast cancer the longer and more consistent one breastfeeds.

 Over a woman’s lifetime, she produces different levels of estrogen beginning at the start of her first menarche up until menopause. Estrogen production only pauses when a woman is pregnant. When a woman is pregnant she misses 9 consecutive periods and during post-natal breastfeeding, menstruation occurs less often. Because a woman is menstruating less often, less estrogen is produced in the ovaries. Joanna’s first menarche came relatively early; at the age of 10, and at the age of 55 she has not begun menopause meaning that her body is still producing high levels of estrogen. Joanna’s cancer is ER+/PR+ meaning that her cancer cells over express estrogen and progesterone receptors on their cell surface. Pathologists test for these hormone receptors using IHC (immunohistochemistry). It is estimated that 80% of all breast cancers are estrogen-receptor positive and 65% of estrogen-receptor positive cancers are also progesterone positive. Because Joanna is positive for these receptors and has a long menstrual history, the estrogen produced in her body has helped drive the growth of the cancer cells. Estrogen and progesterone have the ability to bind to these receptors and initiate a cascade of events that lead to cell growth and division increasing the number of cancerous cells.

 IHC is also used to test for HER2 receptors (human epithelial growth factor receptors). In normal cells, there are two copies of the gene that encode for HER2 receptors. Once bound by the growth factor, HER2 receptors control the growth, division, and repair of normal breast cells. In 20-30% of breast cancers the gene coding for HER2 receptors is over expressed meaning there are many more HER2 receptors than there normally should be. With too many HER2 receptors, breast cells grow and divide uncontrollably. An IHC score of 3+ means that cancer cells have many HER2 receptors and the cancer is HER2 positive. A HER2 positive cancer is a more aggressive cancer with a higher rate of recurrence. Joanna’s IHC was below 3 and therefore she is HER2 negative.

 __**Molecular Basis** __  The different pathways leading to the development of invasive ductal carcinoma are unique to each individual. The sequence of events before all breast cancers become invasive does follow a similar progression though. One of the earliest detectable signs of breast cancer is irregular cell growth resulting in atypical ductal hyperplasia (ADH). Next, breast cancer develops into ductal carcinoma in situ (DCIS) lesions, a not yet invasive form of cancer and ultimately progresses to invasive ductal carcinoma. Joanna’s breast cancer was caught at an early phase and luckily has not metastasized, or spread to other organs throughout the body, but still exemplifies a number of the hallmarks of cancer.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> Along with staging, breast cancer can also be graded based on the how similar breast cancer cells are to normal breast cells by measuring gland formation, nuclear features, and mitotic activity. Grade 1 cancer cells look slightly different from normal breast cells and grow in a slow organized manner. Grade 2 cancer cells do not look like normal breast cells and grow somewhat faster than normal. Grade 3 cancer cells look very different from normal breast cells and grow very quickly in an unorganized manner

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> Table 1. Molecular Subtypes of Ductal Carcinoma <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> Breast cancer tumors may also be classified as one of four molecular subtypes: luminal A, luminal B, basal-like, or HER2 positive. To test for these subtypes of breast cancer, the biotech industry has developed many assaying procedures. Two tests that work similarly in testing for subtype include the PAM-50 Breast Cancer Intrinsic Classifier assay and OncotypeDX. These tests use a reverse transcription polymerase chain reaction (RT-PCR) assay that uses the gene product levels of 15-50 genes thought to be inherent to the molecular subtype. It categorizes individual cancers into the molecular subtype to which they are most similar. The MammaPrint test, requiring fresh tissue specimens because of its microarray-based platform, also includes an option to test for molecular subtype. After administering a MammaPrint test, Joanna’s breast cancer has been classified as luminal A. Approximately 40% of breast cancers are luminal A, making this subtype much more common than the other three.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> As mentioned before, ER/PR positive breast cancers over express genes encoding for these estrogen and progesterone receptors and therefore their numbers are drastically increased. While the number of gene alterations in breast cancer is vast, one amplified gene has been identified that is responsible for coding for estrogen receptors. ESR1, located on chromosome 6, encodes for this ligand-activated receptor. Once bound by a ligand, the estrogen receptor undergoes a conformational change and forms a homo- or hetero-dimer. The dimer then binds to a specific DNA sequence known as the estrogen response element (ERE) and transactivates gene expression in response to estrogen. The amplification of this gene is responsible for the increased number of estrogen receptors present in Joanna’s breast cancer cells. Amplification is one example of chromosomal aberrations that contribute to genomic instability, one of the enabling characteristics of cancer.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> In over 30% of invasive breast cancers, the PI3K pathway is altered either through mutation, amplification or both. Phosphoinositide-3 kinase (PI3K) is made up of a regulatory subunit, p85, and a catalytic subunit, p110. P13K is activated when a growth factor or ligand binds to a specific receptor tyrosine kinase. When active, p85 and p110 initiate a phosphorylation cascade that leads to protein synthesis and proliferation as shown in Figure 5. A gain of function mutation most commonly found in three “hot spots,” resulting in single amino acid substitutions: E545K and E542K in exon 9 and H1047R in the kinase exon 20, lead to the continual expression of subunits p110 and p85 without inhibition enhancing downstream signaling of cell proliferation.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> Evading growth suppressors is another hallmark of cancer that embodies breast cancer. The cell cycle of growth and proliferation is driven by cyclins and cyclin-dependent kinases (CDKs). By themselves, CDKs are inactive and must have their respective cyclin subunit to be active for example, cyclin D1. Cyclin D1 competes with CDK inhibitor, p16INK4A for heterodimerization with CDKs. When cyclin D1 is bound, it activates the CDKs, which then phosphorylate RB, releasing E2F and initiating gene transcription, leading to cell cycle progression. When p16INK4A is bound, the CDK is inactive and therefore cell cycle progression is halted. In 50% of breast tumors, p16INK4A showed total loss of expression or reduced expression. The loss of expression of p16INK4A may be due to a deletion, methylation, or more rarely a mutation.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> At the molecular level, breast cancer develops along highly variable pathways. Testing for molecular subtype as well as sequencing the breast cancer cell genome highly personalizes treatment for every patient. Although two patients may have the same stage II ductal carcinoma, their treatments are not the same due to that specific pathway in which their cancer developed.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> media type="youtube" key="mT74IWGN2bA" width="392" height="219" align="right"<span style="font-family: Arial,Helvetica,sans-serif;">__**Treatment**__ <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;">For Joanna's stage II invasive ductal carcinoma, a mastectomy is the recommended treatment. A total mastectomy is the surgical removal of all breast tissue excluding the chest muscles under the breast. The surgery takes approximately 1 to 2 hours and the patient is given general anesthesia before. The surgeon makes an oval-shaped incision and detaches the breast tissue from the skin and chest muscles so it can be removed. Some possible side effects from the mastectomy include pain, swelling, and scarring. A mastectomy may also cause stiffness, tiredness, and crawly sensations as the nerves in this area heal. In one study, women who had undergone a mastectomy alone had a 79.9% survival rate after 10 years <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;">.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;">Because cancer cells were found in Joanna’s underarm area, an axillary lymph node dissection is another recommended treatment. During this lymph node surgery around 10 lymph nodes are removed from Level I below the armpit, Level II in the armpit, and Level III below the collarbone for extra precaution. During the mastectomy, these lymph nodes will be removed through the same incision. The most serious side affect of axillary lymph node dissection is swelling due to buildup of lymph and is called lymphedema. Lymphedema may be a permanent side effect but has been reported by women as bothersome but not disabling <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;">. Receiving general anesthesia for the mastectomy and axillary lymph node dissection may also cause a sore throat, vomiting, confusion, and muscle aches.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;"> After further discussion with Joanna, I have recommended she undergo breast reconstruction. The surgeon will perform a skin-sparing mastectomy in order to save as much of the breast skin and perform the breast reconstruction immediately. A skin sparing and total mastectomy only differ in the amount of breast skin removed, both remove all breast tissue under the skin. During the skin-sparing mastectomy, only the nipple, areola, and some skin around the biopsy sight will be removed. Having a skin-sparing mastectomy decreases scarring and gives the breast a more natural shape. There are three ways in which breasts can be reconstructed, with implants, flaps, or both. Breast implants are usually small bags filled with salt water, silicone gel, or both and are placed under the breast muscle. An expander may be placed under the skin to help stretch out the muscle and skin until the implant will fit in place. Some possible side effects of implants include pain, scar tissue or tissue death. Using tissue from the belly area, butt, or under the shoulder blade; flaps, are another form of breast reconstruction. Flaps can either stay attached and slide over to the breast area or can be completely removed from the body and sewn into place. Some possible side effects of flaps include tissue death, lumps from death of fat, and muscle weakness that may cause a hernia. Breasts can also be reconstructed using both implants and flaps to more precisely match the shape and size of the other breast. During breast reconstruction, the nipple can also be replaced using tissue from the vulva, thigh, or other nipple or a fake nipple can be made. Joanna has decided to undergo her skin-sparing mastectomy and reconstruct her breast with implants. In general, women spend one to two nights in the hospital following surgery and returning to regular activities may take four to five weeks or longer. Breast reconstruction has become increasingly popular with 46% of women undergoing breast reconstruction in 1998 to 63% in 2007.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;"> Because Joanna's breast cancer is is ER/PR positive, her treatment will include hormone therapy using the drug, tamoxifen. Because breast cancer cells exhibit the first hallmark of cancer in sustaining proliferative growth signals, tamoxifen works to inhibit these growth signals, specifically those initiated by estrogen. In order to prevent estrogen or progesterone from binding to its receptors and initiating a cascade of events that lead to cell proliferation, tamoxifen works by blocking the binding sites of ER/PR receptors. By binding to these receptors itself, tamoxifen blocks the reception of the estrogen message and therefore hinders estrogen-induced growth. Tamoxifen is able to bind to estrogen and progesterone receptors because chemically, tamoxifen looks very similar. As shown in Figure 4, tamoxifen holds the same structure and chemical composition of estrogen only differing in an extra carbon chain.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;"> Tamoxifen is a highly effective drug not only for its inhibitory actions but in mimicking the effects of estrogen in other parts of the body as well. Throughout the body, estrogen is a vital chemical substance that not only affects the uterus and breasts but the bones also. Along with vitamin D, calcium, and other hormones, estrogen helps in building bone and preventing bone loss. Through numerous studies of the drug, tamoxifen appears to act like estrogen in bone cells, providing the proper signals for bone maintenance.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;"> Unlike ER/PR positive cancers, ER/PR negative cancers are not fueled by hormones like estrogen. These cancers are most commonly fueled by overexpression of the epidermal growth factor receptor (EGFR). Tamoxifen works exclusively by binding to estrogen and progesterone receptors and is not capable of binding to epidermal growth factor receptors making it an ineffective treatment for cancers that are ER/PR negative. There are several drugs though that are undergoing clinical trials that inhibit EGFR, but have yet to be proven effective.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;"> Tamoxifen is taken orally in pill form and is taken every day during treatment. Tamoxifen should be taken for five years, and after the five years Joanna’s menstrual status will be assessed to see whether she is still premenopausal or not. If she is still premenopausal, it is recommended that Joanna take tamoxifen for another five years. If she becomes postmenopausal after five years, it is recommended that Joanna either continue taking tamoxifen for another five years or switch to an aromatase inhibitor for five years. Women taking tamoxifen for five and ten years show a significant decrease in risk of recurrence with a 25% and 21% recurrence risk respectively. The possibly side effects for tamoxifen include many symptoms of menopause like hot flashes, weight gain, hair thinning, and fatigue. Tamoxifen also has two serious possible side effects including cancer of the uterus and blood clots. Aromatase inhibitors also may cause bone weakness. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;">Chemotherapy is often used for stage II cancers when the tumor is larger than 5cm across. Chemotherapy helps kill the tumor cells, making it smaller and easier to remove during surgery. Because Joanna’s tumor is 1.5cm across, chemotherapy is not needed, but radiation therapy may be suggested. While the results of the skin-sparing mastectomy will ultimately dictate whether radiation is needed, if any cancer cells are still present in the lymph nodes or area around the edge of surgical margin, radiation therapy will be recommended. Radiation therapy uses high-energy rays to kill cancer cells and usually begins three to four weeks after surgery. External beam radiation therapy (EBRT) is the most common type of radiation therapy used for Stage II breast cancers. Before EBRT, a CT scan is administered to take images of the breast and plan the precise shape and dose of high-energy rays. The highly focused beam targets the area with cancer cells for two to three minutes causing DNA damage, which either kills the cells or prevents further growth. Some possible side effects of radiation therapy include red, dry, itchy skin and tiredness <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;">.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;"> Ultimately, our hopes are that after the mastectomy, all cancer cells will have been removed but it is very likely that cancer cells still may be present. Radiation therapy, as well as hormone therapy for the next five years will <span style="font-family: Arial,Helvetica,sans-serif;">greatly hinder the continued group of cancerous cells. Once the results of the surgery are determined there are still many options for Joanna but we will take it one step at a time keeping Joanna’s best interests and health our priority.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;"> __**Update**__

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt; line-height: 1.5;"> Throughout Joanna’s life the possibility of developing breast cancer has always been at the back of her mind. Maintaining a healthy lifestyle and scheduling regular mammograms could not prevent the disease, which Joanna tried so rigorously to evade. Her efforts were not for nothing though. Joanna’s mastectomy was a success with very few cancer cells present after the surgery. Joanna underwent one round of radiation therapy and I am happy to report that she is now cancer free. Because of the precautionary measures Joanna took, her cancer was caught at an early phase, which gave her a promising prognosis. Today, Joanna is prescribed tamoxifen to be taken regularly in her continual fight to prevent reoccurrence. Joanna is also in the process of deciding whether or not to undergo a mastectomy of her right breast as an extra precautionary measure.

//Aperçu: Hormone receptor positive breast cancer, like Joanna's, has the incredible ability of taking advantages of it's "resources." From her first menarche around 11 to 13 years old up until menopause at around 50 years old, a woman produces high levels of estrogen throughout her body. Over a woman's lifetime, that's a lot of exposure to estrogen and breast cancer, which is overwhelmingly most common in women, has found a way to use all that estrogen to fuel its own growth.//