Sarah+Craven

= Breast Cancer and Pregnancy =


 * The Cancer**

Amidst a time of joy and celebration – a new baby with another on the way! – comes news of a debilitating, intrusive, unwanted kind of growth. A kind of growth that is starkly opposed to the warm, snuggly, lovable growth of a baby. In June of 2002, my aunt Jordonna Craven is diagnosed with stage III infiltrating (invasive) ductal carcinoma at 38-years old. She has no family history of breast cancer, and her diagnosis comes during her third pregnancy. Craven is a physically fit mother, who possesses a strong support network of friends and family. She is an avid crocheter, and around the time of her diagnosis she takes up knitting as well. I have fond memories of Aunt Jordonna, without hair, but certainly not without a fighting spirit, teaching ‘8-year-old me’ how to knit. She has a passion for children, and before her recent transition to becoming a full-time mom, she worked with children with special needs and their families.

Infiltrating ductal carcinoma characterizes about 80% of all breast cancers, and it starts in the milk duct of the breast and grows to invade surrounding fatty breast tissues (1). The milk duct is a tube which carries milk from the lobules (milk producing sacs) to the nipple (2).Once the cancer becomes invasive (breaks through the basement membrane into surrounding breast tissue), it can easily reach the lymph nodes. Lymph vessels carry nutrients, like oxygen, to the cell tissue, and lymph nodes are a vital part of part of the lymphatic system which filter out the waste material that may be suspended in lymph fluid (3). As a stage III breast cancer at diagnosis, Craven’s cancer has spread to tissues and lymph nodes immediately nearby the breast tissue, but has not metastasized into secondary tumor sites (4). According to the American Cancer Society, the 5-year survival rate for stage III breast cancer is 72% (5).

Craven’s diagnosis comes while she is 11 weeks pregnant with her third son, and almost immediately before the diagnosis, she had weaned her second son off of breast milk, which presents a unique set of possible contributing factors. Craven’s cancer is estrogen receptor positive (ER-positive) and progesterone receptor positive (PR-positive), meaning her breast cancer cells contain receptors for estrogen and progesterone hormones, and the hormones subsequently aid in the growth of the cancer cells.

It is normal for estrogen and progesterone to drop from their normal levels during lactation in order for the milk-producing-hormone prolactin to be produced, whereas during early pregnancy estrogen and progesterone levels spike dramatically (7). In the transition from breastfeeding to pregnancy, Craven’s female sex hormones have thus been on a recent roller coaster, and the dramatic spike of estrogen and progesterone levels in the transition may have aided in the development of her cancer. Additionally, changes in breasts during breastfeeding and pregnancy, such as breast swelling, asymmetry, soreness, or sensitization of the nipple, can also be signs of breast cancer (8,9). The overlap in the signs of pregnancy versus breast cancer may have made it more difficult for Craven to detect potentially harmful changes in the breast pointing to cancer. One study published by //Obstetrics and Gynecology// journal demonstrated that women who have breast cancer while pregnant have higher death rates compared to breast cancer patients who are not pregnant (10).The difficulty in detection of cancerous breast abnormalities during pregnancy likely means that breast cancer is often more progressed in pregnant patients, which may account for the higher death rate in pregnant breast cancer patients.

Breast cancer can also be characterized by its status of the HER2/neu growth promotion protein. Breast cancers which have an over abundance of the HER2/neu protein are called HER2-positive (11). Expression of a HER2-positive phenotype is associated with an increase in production of VEGF and thus upregulation of angiogenesis (12). The increased expression of the angiogenic hallmark of cancer makes HER2-positive breast cancers more aggressive than HER2-negative phenotypes. Craven’s cancer is HER2-negative, meaning it is it less apt to growing and spreading than its HER2-positive counterpart. Thus, from the accepted standpoint of HER2/neu protein expression, Craven’s risk of metastasis and death due to her cancer is lessened.

At 38-years old at the time of diagnosis, Craven’s age constitutes a risk factor. Craven is considered a young breast cancer patient; according to an article from //Seminars in oncology,// “approximately 7% of women with breast cancer are diagnosed before the age of 40 years...and younger age [is] an independent predictor of adverse outcome” (13). I hypothesize that young age may be correlated with negative outcome because women do not typically start to get mammograms, nor must they generally worry about the possibility of breast cancer, until they are 40 or older. Thus, breast cancer in women under 40 may be more progressed and/or aggressive, because women are least apt to self-check, and are unlikely to have already received mammography screening. Not only does Craven’s age make her prognosis worse, but the potential side effects of treatment – like infertility, psychosocial issues and bone loss – have more time to manifest themselves in younger women (13).

Craven maintains a treatment plan which implements chemotherapy in the midst of her pregnancy, because studies have shown that chemotherapy poses no harm to the baby once the mother has entered her second trimester of pregnancy (14). Craven puts her baby first at all times, and due to the risks surgery and radiation pose to the child, she avoids both of these forms of treatment until after she gives birth. Eventually, a mastectomy becomes a necessary course of treatment, so her baby is induced about two months early (and is, miraculously, a healthy boy!). As a result of her mastectomy, 31 lymph nodes were removed from Craven’s breast and surrounding area, and all 31 were positive for cancer. Although such a large mass was removed through surgery, it is likely that positive lymph nodes were left behind, so the cancer could still spread. The abundant, aggressive spread of Craven’s cancer to the lymph nodes may have been amplified by her young age and pregnancy, and foreshadows the metastases to the liver and bones that eventually manifest themselves.


 * The Molecular Basis of the Cancer**

The cunning capabilities of Craven’s cancer enable it to modify normal cells’ regulatory pathways, which causes continued cell growth and subsequent invasion. Craven's pregnancy at the time of diagnosis makes her even more determined to fight the sleuthing pathways of cancer in every manner possible. According to COSMIC database, tumor protein p53 (TP53) gene is mutated in approximately 30% of ductal carcinoma breast cancer cases, and p hosphoinositide-3-kinase ( PIK3CA) gene is mutated in about 20% of ductal carcinoma cases (15). The TP53 gene codes for p53 transcription factor, which senses primarily internal factors in order to determine whether the cell should go through the cell cycle or induce apoptosis or cell senescence. If p53 senses too much pressure, the protein will bind DNA and initiate production of pro-apoptic factors. However, in mutations of p53 in cancer cells, the DNA binding domain is typically the mutated area, so p53 can no longer bind DNA and regulate the cell cycle. Thus, cancer cells exhibit loss of function mutations in p53 in order to avoid its tumor suppressing function.

PIK3CA, on the other hand, regulates cell proliferation and survival and is an activator of cell signaling cascades (17). As a result, cancer cells often exhibit gain of functions in PIK3CA so that cell proliferation is constitutively turned on. PIK3CA also regulates invadopodia formation in breast cancer cells (18). Invadopodia break down the cell matrix, bulge out from the the endothelial cells and break through adherens junctions into the stroma; this makes them central in cancer cells’ ability to invade and metastasize (18). For breast cancer patients, a mutation in PIK3CA can therefore be doubly harmful because it targets two hallmarks of cancer: sustaining proliferative signaling and enabling metastasis and invasion. Interestingly, TP53 and PIK3CA are not typically both mutated in a single ductal carcinoma patient (19). Since TP53 and PIK3CA affect different hallmarks of cancer, it’s not entirely clear why they aren’t often both mutated. Both genes’ strong influence on cell processes may simply mean that a mutation in one is more than enough to express cancer characteristics and enable further mutations. For example, resisting cell death through a p53 mutations could mean that a cancer cell does not need to turn on constitutive cell proliferation through a PIK3CA mutation. Through the p53 mutation, the cancer cell is already able to avoid cell cycle arrest and can continue to grow.

Although Craven’s ductal carcinoma is not HER2-positive, the overexpression of HER2 receptor protein is commonly exhibited in ductal carcinoma patients, and is associated with more aggressive cancers. A variety of external growth factors bind to three of the four members of the family of human epidermal growth factor receptors (HER1, HER3 and HER4), but HER2 itself does not bind ligands (20). After binding a ligand, the HER receptors may then respond by dimerizing and inducing cellular signaling pathways via intracellular tyrosine kinase activity (20). Since HER2 does not bind ligands itself, it must be bound to one of the other three receptor monomers in order to induce signaling. HER1, HER3 and HER4 receptors have highest dimerization affinity for the HER2 receptor (20). Additionally, the cellular signaling pathway induced by a dimer containing HER2 is stronger and more prolonged than dimers without HER2 (20). An upregulation of HER2 means more, intensified and longer dimerization and signaling. Furthermore, increased HER2 presence is also associated with the upregulation of angiogenesis (12). In angiogenesis, hypoxia inducible factor (HIF) senses low oxygen environments and signals vascular endothelial growth factor (VEGF) to create new blood vessels around the hypoxic environment. Thus, cancer cells with upregulated angiogenesis possess better blood flow around them, which gives them more of the nutrients they need for growth. Contrary to the typically valid belief that HER2-positive breast cancer is a disadvantage due to its ability to constitutively turn on signaling pathways, in Craven’s case, the HER2-negative status may actually be a disadvantage. Since the only safe treatment option during her pregnancy is chemotherapy, decreased blood flow around Craven’s tumor due to decreased angiogenesis may make her cancer less responsive to chemotherapy.

Craven’s cancer is both ER-positive and PR-positive, meaning the presence of estrogen and progesterone hormones aid in the growth of her cancer cells. Estrogen and progesterone diffuse through the plasma membrane by themselves and subsequently bind their receptors, which exist inside the nucleus (21). The receptor-hormone complexes then bind to the DNA and act as transcription factors for the expression a variety of genes, including genes regulating cell growth (21). This process occurs in normal breast cells, but its occurrence in cancerous cells means that those dangerously mutated cells can proliferate using female sex hormones. There are two types of estrogen receptors, known as ER α and ERβ, which are structurally similar in their DNA binding domains and ligand binding domains, but vary towards the amino-terminus. The form of estrogen known as 17 β-estrodiol (E2) is the most abundant female sex hormone, and the type with the largest effect on both classes of estrogen receptors (22). Both types of ERs have large ligand-binding domains, making them able to bind a wide variety of aromatases, even if the ligands aren’t incredibly similar to estrogen’s structure (22). This variability in types of ligands makes it easier to synthesize estrogen inhibitors for ER-positive breast cancer treatment. However, since so many ligands can bind to the ERs, unwanted chemicals may bind ERs in normal breast cells, inhibit endocrine signaling and potentially cause cancer (22). Craven’s estrogen and progesterone levels would have dramatically dropped while she was breast-feeding, and then spiked once she became pregnant with her next son. Especially if the ER-positive/PR-positive cancer cells were already present before her pregnancy, the striking sex hormone increase during pregnancy could act as a green light for the proliferation of Craven’s cancer cells. Due to this expression, it is imperative to find ways to either decrease the levels of these female sex hormones, inhibit the hormones from binding the receptor, or downregulate the receptor presentation itself.


 * Cancer Treatment Options**

Cut, poison, burn. The words that describe cancer treatment may sound more representative of torture, but combatting cancer aims to use this aggressive trio to torture the cancer, not the patient. Yet, determining the proper course of treatment for a cancer patient can be devastatingly difficult, especially in light of potential serious side effects which may manifest themselves (even years after the treatment itself occurs). In order to determine the proper course of treatment for breast cancer patient Jordonna Craven, the cancer will first be staged clinically, and then evaluated more thoroughly through pathological staging. Clinical tests include blood tests, liver function tests, and imaging tests--diagnostic bilateral mammography, ultrasound, breast MRI (23). Pathological staging examines parts of the tumor (removed through surgery) under a microscope to characterize HER2 status, hormone receptor status, and whether the cancer has spread to the lymph nodes. HER2 status and hormone receptor status can be evaluated using immunohistochemistry. For example, for estrogen receptors, if at least 1 out of every 100 cancer cells exhibits estrogen receptors (as determined by staining for the receptor), the cancer is labeled ER-positive (23). The lymph node biopsy, using either final needle aspiration (samples a group of cells) or a core biopsy (removes a larger amount of tissue) enables pathologists to evaluate whether the cancer has spread to the lymph nodes, and if so, to what extent (23).

After assessing the extent of the cancer, doctors will determine whether the patient should undergo chemotherapy before surgery (23). Craven’s cancer has already moved to too many regional lymph nodes to do surgery first, so neoadjuvant therapy will be performed with a goal of reducing the extent of the cancer before surgery so that most of the cancer is removable through surgery (23). The risks of surgery and radiation are high during pregnancy, but chemotherapy is safe because it cannot penetrate the placenta and affect the baby once the pregnancy has reached the second trimester. Luckily, Craven is therefore able to follow the recommended standard of care even amidst her pregnancy.

The preferred chemotherapy regimen for Craven’s cancer is four 14-day cycles of A/C (doxorubicin + cyclophosphamide), followed by four 14-day cycles of paclitaxel (23,24). There are no current targeted therapy options, because most target HER2 (i.e. trastuzumab) or are not approved until the cancer has metastasized (i.e. lapatinib). Doxorubicin is a systemic chemotherapy that intercalates between DNA/RNA base pairs. It stabilizes the topoisomerase/DNA complex so that topoisomerase cannot do its job of removing DNA supercoils, meaning DNA cannot be replicated and cells cannot undergo mitosis (25). Cyclophosphamide also is a systemic chemotherapy, but it is an alkylating agent that binds to DNA, prevents replication, and initiates cell death (26). The second part of the chemotherapy regimen is another systemic drug called paclitaxel. Paclitaxel is a taxane, meaning it prevents microtubule disassembly and subsequently stops cell division (27). As systemic chemotherapy treatments, doxorubicin, cyclophosphamide and paclitaxel are unable to solely target the breast cancer cells. They target all actively dividing cells, like the stomach lining, skin cells and red blood cells. As a result of the overarching effects, side effects such such as hair loss, nausea, vomiting, low blood counts, fatigue, joint pain, and mouth sores are common (28,29,30). In rarer instances, blood cancer may develop due to the chemotherapy, and doxorubicin can also interfere with the heart’s ability to pump blood effectively (28,29). Despite the miserable side effects, I still believe the A/C treatment followed by paclitaxel is necessary. At the moment, it is the standard of care for a HER2-negative, receptor-positive patient. The 5 year survival rate for stage III breast cancers is 72%, which suggests that this treatment works for patients like Craven (5). The serious, long-term side effects are much rarer, so the fight to live now should be at the forefront of one’s mind, even in the midst of draining short-term side effects.

For stage III breast cancer, a total mastectomy is typically recommended, especially when the cancer has spread significantly to the lymph nodes (23). A mastectomy is the removal of all breast tissue, as opposed to a lumpectomy, where only the tumor is removed. Doctors may assess how well the cancer responded to the initial chemotherapy, and then determine if a mastectomy is the proper course of treatment (23). In Craven’s case, the mastectomy is avoided during pregnancy with the desire to decrease tumor size through neoadjuvant therapy and to decrease surgery-associated risks during pregnancy. As a result, in order to ensure the surgery occurs in the proper time frame after chemotherapy ends, Craven’s baby is induced about 2 months early.

For Craven, the surgery also includes axillary lymph node dissection, in hopes of removing all lymph nodes where the lymph from the tumor drains. Her cancer has spread through levels I and II lymph nodes, to level III lymph nodes, which are under her collarbone. The surgery removes all three levels of lymph nodes.

After surgery, adjuvant radiation therapy may be administered to the patient. Depending on the extent of the tumor post-surgery, radiation can target the whole breast and may also target the chest wall and infraclavicular, supraclavicular, and internal mammary lymph nodes (23). Doctors focus strongly on reducing the amount of healthy tissue that is hit by radiation beams by implementing techniques such as CT-guided radiation therapy, intensity modulated radiation, brachytherapy and respiratory breathing techniques in the patient (24). CT is especially recommended when regional and internal mammary lymph nodes are a target of radiation, due to their proximity to important internal organs.

Since Craven’s breast cancer is ER-positive and PR-positive, female sex hormones will be targeted through endocrine therapy in order to stop the proliferation of her cancer cells. After chemotherapy, surgery, and potentially radiation, a typical course of treatment for a premenopausal, hormone receptor-positive patient puts her on tamoxifen. Tamoxifen is an antiestrogen which works to block estrogen from binding to its receptor, so the hormone-receptor complex subsequently cannot bind DNA and initiate transcription of genes involved in cell proliferation (32). Tamoxifen is considered a targeted therapy, because it is focuses on a specific characteristic of the cancer; however, it still has an effect throughout the body, since noncancerous cells’ estrogen receptors will be impacted by the presence of tamoxifen as well. The course of treatment may also include ovarian ablation, which is either surgery to remove the ovaries or treatment so that progesterone and estrogen are no longer produced in the ovaries (23,24). A premenopausal patient takes tamoxifen for 5 years, and her menopausal status will then be evaluated by testing the levels of estrogen and/or follicle-stimulating hormone in her blood (23,24). If the patient has become postmenopausal while taking tamoxifen, she may then begin taking an aromatase inhibitor, such as letrozole, which stops the production of estrogen in postmenopausal women (23,24). The choice to go on tamoxifen may be a tough decision for a premenopausal woman, because it means that she will go through menopause early and can no longer have kids.

Craven’s cancer treatment regimen occurred from 2002-2006; since then, not much has changed in the standard of care for a stage III, PR-positive, ER-positive, HER2-negative invasive ductal carcinoma patient. There are an abundance of clinical trials working to better cancer-killing abilities and to decrease the side effects of cancer treatment. Participation in clinical trials would be difficult for Craven, because the unknown consequences could threaten the health of her baby. One promising area of study is the use of allogeneic natural killer (NK) cells in order to attack the cancer cells. Allogeneic NK cells come from a donor, not the patient, which may mean that the cancer has not learned to evade these cells’ immune response, like it has of the patient’s own NK cells (33). In order to lessen any unwanted response in the patient due to the introduction of donor NK cells, the NK cells may be preconditioned or combined with chemotherapy (33). Current clinical trials focus on using allogeneic NK cells that come from related donors or that maybe be genetically modified to be more effective (33). This more natural approach to cancer treatment could be better suited to targeting the cancer cells and decreasing debilitating side effects. After Craven’s pregnancy and after the metastasis of her disease, I would recommend participation in clinical trials using allogeneic NK cells, since the current standard of care is not as efficacious as hoped.


 * Conclusion/Aper ç u**

After a fierce battle against the relentless bombardment that is cancer, Jordonna Craven died in February of 2006. Despite cancer's most vicious efforts, however, the image of my aunt "the cancer patient" is not the one that remains with me. Rather, it is her infectious smile, wholehearted love of her family, warm laugh, willingness to teach, and go-getter attitude. Sure, cancer is physically shameless. Cancer is agonizingly Machiavellian in its ability to slip through the cracks of the body's innate checks and balances. Yet, cancer cannot penetrate the root of our being, nor can carcinogens mutate our memories of loved ones. The insatiable disease has no control over our attitudes, and try as it might, cancer. cannot. conquer. everything.

__//**In Loving Memory of Jordonna Craven**//__



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