Running head: EFFECTS OF AROMATASE INHIBITORS ON THE BONES OF BREAST CANCER PATIENTS

Transcription

1 Running head: EFFECTS OF AROMATASE INHIBITORS ON THE BONES OF BREAST CANCER PATIENTS Effects of Aromatase Inhibitors on Bones of Postmenopausal Female Breast Cancer Patients Final Paper Submitted to Kennesaw Mountain High School by AWESOME KMHS STUDENT Kennesaw, GA May 2016

2 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 1 Abstract Breast cancer is the most common form of cancer found in women. Out of all the breast cancer diagnoses each year, almost 50 percent are postmenopausal patients with estrogen and progesterone receptor positive cancer. By using a type of hormone treatment called an aromatase inhibitor, oncologists block these hormones and cut off the nourishment that feeds the growth of the cancer. In other medical situations, this has decreased bone mineral density. This study aimed to determine the effect of hormone therapy on bone mineral density of postmenopausal breast cancer patients and their risk of a skeletal related event occurring. I implemented a quantitative cohort study to conduct this research. In this study, I used a sample of 22 patients based on menopause and cancer receptor status. I utilized a paired t-test to compare the average baseline and post-baseline spinal and femoral bone mineral densities of the postmenopausal breast cancer patients. The spinal paired t-test showed a statistically significant difference (p = 4.02E-07) in the baseline and post-baseline bone mineral densities. The femoral paired t-test also showed a statistically significant difference (p = ) in the baseline and post-baseline mineral densities. The statistical significance of both spinal and femoral t-tests indicated that the aromatase inhibitors cause a significant increase in bone demineralization. Increased bone demineralization also leads to an increased occurrence risk for a skeletal related event. I recommend conducted further research with a larger, randomized sample and examining alternative or preventative care. The doctor should conduct a risk-benefit analysis with the patient to determine if the risk of bone demineralization is greater than the benefits of decreased cancer growth.

3 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 2 Acknowledgements Thank you to Dr. Raul Oyola and his team at the Marietta office of the Northwest Georgia Oncology Centers for allowing me to learn under their care and providing assistance over the course of this research. Thank you to my research and internship teacher, Ms. Chelsea Sexton, and my magnet coordinator, Dr. Kelly Ingle, without whom I would not have been able to have this opportunity. I would also like to thank Cool Chica, Dapper Dude, Kooky Kid, Excellent Editor, Excited Elephant, Jovial Jester, and Marvelous Man. Without the advice and edits from this group of people, I would not have been able to prepare a well-written paper. Thank you to all who have helped guide and assist me through this research process.

4 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 3 Table of Contents Chapter 1: Introduction... 5 Statement of the Problem... 5 Purpose of the Study... 6 Research Question... 6 Hypotheses... 6 Significance of the Study... 7 Definition of Key Terms... 7 Summary... 9 Chapter Two: Review of the Literature Breast Cancer Breast Cancer Treatment Estrogen and Progesterone Receptors Hormone Therapy Bone Mineral Density Summary Chapter 3: Research Method Research Question Hypotheses Research Methods and Design Population Sample Materials/Instruments Data Collection, Processing, and Analysis Assumptions Limitations Delimitations Ethical Assurances Summary Chapter 4: Findings Results Evaluation of Findings Summary Chapter 5: Implications, Recommendations, and Conclusions Implications Recommendations Conclusions... 27

5 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 4 References Appendix A: Informed Consent Appendix B: Data Table Appendix C: Spine Statistics Appendix D: Femur Statistics Appendix E: Spine Assumptions Appendix F: Femur Assumptions... 37

6 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 5 Chapter 1: Introduction The American Cancer Society expects that, within the United States, there will be approximately 1,700,000 new cancer diagnoses in 2016 (American Cancer Society, 2016). Out of these new diagnoses, approximately 247,000 cases will be breast cancer in females (American Cancer Society, 2016). Though it only results in 7% of all cancer deaths, breast cancer is the most common form of cancer found in women (National Cancer Institute, 2015). A woman is more likely to develop osteoporosis from breast cancer treatment than die from the cancer itself (National Cancer Institute, 2015). Statement of the Problem In certain breast cancer diagnoses, a patient's cancerous tissue displays an increase in either estrogen receptors, progesterone receptors, or both, leading to rapid cell growth (National Cancer Institute, 2015). To combat this, oncologists use a hormone therapy treatment of aromatase inhibitors to stop cancer growth by blocking these receptors (Fabian, 2007). The effects of hormone therapy are equivalent to what happens in women during their postmenopausal stage. The aromatase inhibitors suppress aromatase enzyme activity, which interferes with the production of hormone receptors (Fabian, 2007). The hormones detected by these receptors help maintain and develop female sex characteristics, bone growth, and the menstrual cycle (National Cancer Institute, 2015). However, just like post-menopause, this induced depletion results in osteoporosis, a major side effect, found during a dual-energy x-ray absorptiometry (DXA) scan (Durling, M., & Perez, 2009). Diminishing bone density increases the risk for skeletal related events (SREs) including pathological fractures and spinal cord compressions (Chin, Fleshner, Saad, & So, 2012). Therefore, increased demineralization of bones leads to osteoporosis, which increases the probability of a SRE occurring.

7 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 6 Purpose of the Study The purpose of this quantitative cohort study is to determine if there is a statistically significant difference in the degree of bone demineralization of postmenopausal breast cancer patients before they start aromatase inhibitors compared to 2 years after the start of the aromatase inhibitor. Aromatase inhibitors block estrogen and progesterone hormones in breast cancer patients to block stimulation of cancer cell growth (National Cancer Institute, 2015). Adversely, hormone blockage due to aromatase inhibitors can potentially cause a decrease bone mass leading to osteoporosis (Bosco, 2012). Researches have yet to determine the extent of this bone damage. This study aims to determine if aromatase inhibitors cause a major increase in bone demineralization leading to increased risk for SREs. Research Question Q1. How does hormone therapy affect the bone mineral density of postmenopausal breast cancer patients and their risk of a SRE occurring? Hypotheses H1. The use of aromatase inhibitors changes the rate of bone demineralization of postmenopausal breast cancer patients and, in turn, increases their risk of a SRE occurring. H10. There is no statistical difference in demineralization of the bones of postmenopausal breast cancer patients when comparing a baseline and post-baseline bone density, indicating no increased risk of an SRE occurring. H12. There is a statistical difference in demineralization of the bones of postmenopausal breast cancer patients when comparing a baseline and post-baseline bone density, indicating no increased risk of an SRE occurring.

8 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 7 Significance of the Study Breast cancer is a form of cancer that affects about 12% of women in the United States (American Cancer Society, 2016). Approximately 80% of these cases are either receptor positive for estrogen, progesterone, or both (Ratini, 2015). The risk of breast cancer occurrence increases with age, which is why almost 46% of breast cancer cases are in females 65 years of age and older (American Cancer Society, 2016). Most women reach menopause between the ages of 45 and 50 (Todd, 2015). Aromatase inhibitors block hormones in estrogen and progesterone receptor positive postmenopausal women (National Cancer Institute, 2015). Oncologists prescribe aromatase inhibitors to postmenopausal women because premenopausal women create too much aromatase in the ovaries for the inhibitors to block them effectively (National Cancer Institute, 2015). Therefore, almost half of all breast cancer patients are postmenopausal and on an aromatase inhibitor without knowing the extent of bone damage risk. This study examines if the extent of bone demineralization caused by aromatase inhibitors changes the risk of an SRE occurring. The results indicated by this study will help facilitate further research into alternative medicines or preventative care. If the damage is extensive, doctors may be reluctant to use aromatase inhibitors in postmenopausal breast cancer patients. Furthermore, the patients themselves will be able develop a better understanding of the effects of aromatase inhibitors on their bones. This study will prompt patients to reconsider their decisions on whether or not to take the treatment. Definition of Key Terms Breast Cancer. Breast cancer is uncontrollable cell growth in the breast ducts or lobules of one or both breasts due to a gene mutation (American Cancer Society, 2016).

9 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 8 Estrogen. Estrogen is sex hormone found in males and females, transported through the blood that protects bone health (Tulane University, 2014). Progesterone. Progesterone is a sex hormone found in males and females, transported through the blood that protects bone health (Tulane University, 2014). Hormone Receptors. Hormone receptors are proteins that pick up cell growth signals carried by hormones through the bloodstream (American Cancer Society, 2016). Endocrine System. The endocrine system consists of all the hormone-producing glands that regulate sleep, mood, sexual function, growth and development, and metabolism (Zimmermann, 2014). Aromatase. Aromatase is an enzyme that produces estrogen and progesterone in ovaries and tissues (National Cancer Institute, 2015). Aromatase Inhibitors. Aromatase inhibitors are drugs that block aromatase enzyme activity, effectively decreasing estrogen and progesterone in the body (National Cancer Institute, 2015). Osteoporosis. Osteoporosis refers to the loss of bone mass due to malfunctioning osteocytes which results in a lack of new bone creation and maintenance failure of existing bones (Mayo Clinic, 2014). Dual Energy X-Ray Absorptiometry (DXA) Scan. A DXA scan uses an x-ray to measure bone loss to diagnose osteoporosis (Kaye, 2014). Skeletal Related Event (SRE). A SRE is a pathological fracture or spinal cord compression that can occur on any bone (Chin et al., 2012). These most commonly occur in the hips (Chin et al., 2012).

10 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 9 Pathological Fractures. A pathological fracture is a bone fracture that occurs due to a bone-weakening disease such as osteoporosis, infections, and tumors (Cluett, 2016). Menopause. Menopause is a natural process that occurs in women, usually in their 50s, 12 months after their last menstrual period (National Institute on Aging, 2013). Menopause ends fertility and menstrual cycles and begins symptoms of hot flashes, sleeps deprivation due to emotion, lowered energy levels, and may trigger feelings of anxiety, sadness, or loss (National Institute on Aging, 2013). Post-menopause. Post-menopause is the indefinite time after the twelve months of menopause, where menopausal symptoms ease and estrogen and progesterone levels decrease (National Institute of Aging, 2013). Summary Out of the potential 247,000 female breast cancer diagnoses in 2016, about half will be postmenopausal with estrogen or progesterone positive receptors (American Cancer Society, 2016; National Cancer Institute, 2015). The standard treatment of aromatase inhibitors has shown to decrease bone density and may lead to osteoporosis (Bosco, 2012). These weakened bones and osteoporosis leads to an increased occurrence risk of SREs (Chin et al, 2012). This quantitative cohort study aims to determine if aromatase inhibitors cause a major increase in bone demineralization leading to increased risk for SREs. This study will help examine if the extent of bone demineralization caused by aromatase inhibitors changes the risk of an SRE occurring. The results indicated by this study will help facilitate further research into alternative medicines or preventative care.

11 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 10 Chapter Two: Review of the Literature Breast cancer is the most common form of cancer found in women (National Cancer Institute, 2015). The risk of getting breast cancer increases with age; therefore, older women are more likely to get it compared to younger women ("What Is," 2015). As a woman becomes menopausal and postmenopausal, her risk of getting osteoporosis also increases (Campbell, 2012). Studies have shown that hormone therapy, a breast cancer treatment, is a possible risk factor for osteoporosis and osteoporosis-associated skeletal related events (SREs) (Barad et al., 2005; National Cancer Institute, 2015). Breast Cancer Breast cancer and cancer tumors occur when breast cells grow at an uncontrollable rate (American Cancer Society, 2016). Cells become cancerous when a mutation occurs in critical genes (American Cancer Society, 2016). These genes, whose normal role is to regulate and maintain healthy cells, cause cells to divide uncontrollably and produce similar mutated cells to form a tumor (American Cancer Society, 2016). The breast. The breast consists of milk glands called lobules and ducts that carry the milk from the lobule to the nipple (National Cancer Institute, 2015). Surrounding these glands are tissues made of fat tissue, lymph nodes, connective tissue, and blood vessels (National Cancer Institute, 2015). Breast cancer is commonly located within the cells of the ducts, as well as the lobule cells or other breast tissue, but can spread to the surrounding tissue (National Cancer Institute, 2015). Non-invasive breast cancer. Non-invasive breast cancer occurs when cancer cells are inside the ducts, but have not spread outside to tissues or other regions ("What Is," 2015). Noninvasive breast cancer is also termed pre-invasive breast carcinoma or ductal carcinoma in situ

12 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 11 (DCIS), where "in situ" means "in place" ( What Is, 2015). The cancer cells remain "in place" within the ducts ( What Is, 2015). Non-invasive breast cancer has the ability to become invasive ( What Is, 2015). Invasive breast cancer. Oncologists characterize invasive breast cancer as cancer that spreads from the ducts or lobules to the surrounding tissue (National Cancer Institute, 2015). Invasive breast cancer occurs when the cancer cells within the ducts or lobules spread to nearby breast tissue through the bloodstream or the lymphatic system ( What Is more, 2015). Breast cancer primarily invades the axillary lymph nodes, located in the underarm, before any other part of the body ( What Is, 2015). If a breast cancer becomes increasingly invasive, as seen in advanced stages, the cancer cells are able to spread to other parts of the body, such as the brain, lungs, and liver, through a process called metastasis ( What Is, 2015). If rapid cancer cell growth reoccurs, new tumors may form resulting in metastatic breast cancer ( What Is, 2015). Breast Cancer Treatment Breast cancer has various treatment methods, including the most common treatments for breast cancer: surgery, chemotherapy, and radiation (American Cancer Society, 2016). Oncologists administer treatment in two ways: local therapy and systemic therapy (American Cancer Society, 2016). Local therapy treats cancer at the tumor site and does not affect the rest of the body (American Cancer Society, 2016). Systemic therapy involves treatment sent through the bloodstream, effectively reaching any cancer cells in the body (American Cancer Society, 2016). Systemic therapy is the standard of care for breast cancer (Ioannidis, Mauri, & Pavlidis, 2005). Surgical treatment. Doctors perform one of three surgeries that may eradicate breast cancer: breast conserving surgery, total mastectomy, or modified radical mastectomy (National

13 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 12 Cancer Institute, 2015). Breast conserving surgery, also known as a lumpectomy or partial mastectomy, removes the normal and cancerous tissue and sometimes part of the chest wall lining or lymph nodes (National Cancer Institute, 2015). A total mastectomy, or a simple mastectomy, occurs when the cancer spreads to the point where the entire cancerous breast needs removal and may lead to the removal of some under arm lymph nodes (National Cancer Institute, 2015). A modified radical mastectomy will eradicate the entire cancerous breast plus many underarm lymph nodes, chest muscle lining, and parts of the chest wall muscles (National Cancer Institute, 2015). Radiation treatment. Radiation therapy uses high energy X-rays to kill the cancer cells or stop their growth (National Cancer Institute, 2015). There are two types of radiation: internal radiation and external radiation (National Cancer Institute, 2015). Internal radiation uses needles, seeds, wires, or catheters to place radioactive substances by or in the cancer (National Cancer Institute, 2015). External radiation, used to treat breast cancer, occurs through machines outside the body (National Cancer Institute, 2015). Chemotherapy. Chemotherapy is the use of drugs to halt the growth of cancer by killing its cells or stopping cell growth (National Cancer Institute, 2015). Doctors use either an IV, port, or a pill to administer chemotherapy, depending on a patient s situation (American Cancer Society, 2016). Chemotherapy can enter the body in various locations. Systemic chemotherapy is an oral pill or a shot injected into a vein or muscle to disperse the drug through the bloodstream (National Cancer Institute, 2015). Regional chemotherapy places chemotherapy drugs within a body cavity or organ or disperses the drugs into the cerebrospinal fluid (National Cancer Institute, 2015). Drug placement within a certain region helps to target the chemotherapy to specific areas of the body and decreases risks of affecting other parts of the body (National

14 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 13 Cancer Institute, 2015). When pathologists identify the specific type of cancerous cells, oncologists are able to use targeted therapy to customize treatment to the specific type of cancer (National Cancer Institute, 2015). This type of treatment reduces the risk of harming normal, healthy cells (National Cancer Institute, 2015). Adjuvant vs. neoadjuvant therapy. Adjuvant and neoadjuvant therapy include radiation, chemotherapy, and targeted therapy (National Cancer Institute, 2015). Adjuvant therapy is treatment administered after surgery to increase the chances of remission (National Cancer Institute, 2015). Neoadjuvant therapy is treatment used to treat cancer before surgery. Clinical trials show that neoadjuvant treatment reduces the size of breast tumors in postmenopausal women, thus reducing the amount of surgery required (National Cancer Institute, 2015; Ioannidis, Mauri, & Pavlidis, 2005). Studies also show that neoadjuvant therapy is equivalent to adjuvant therapy based on overall survival and disease progression (Ioannidis, Mauri, & Pavlidis, 2005). Estrogen and Progesterone Receptors Hormones are chemical messengers sent through the bloodstream to reach their targets (National Cancer Institute, 2015). In women, endocrine tissues and ovaries create the hormones estrogen and progesterone (National Cancer Institute, 2015). These hormones help maintain and develop female sex characteristics, bone growth, and the menstrual cycle (National Cancer Institute, 2015). Estrogen and progesterone can also nourish cancer cells, resulting in the growth of hormone-sensitive (or hormone-dependent) breast cancer (National Cancer Institute, 2015). This type of breast cancer contains proteins called hormone receptors (National Cancer Institute, 2015). When the estrogen and progesterone interact with the receptors, they lead to the stimulation of cell growth (National Cancer Institute, 2015). Oncologists conduct biopsies of the

15 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 14 cancer by removing samples of tumor tissue to evaluate the cancer (National Cancer Institute, 2015). A biomarker test on the tissue samples helps assess estrogen receptors (ER) and progesterone receptors (PR) (Cimino-Mathews & Zheng, 2015). If the receptors are present, oncologists categorize the cancer as estrogen receptor-positive (ER-positive) or progesterone receptor-positive (PR-positive) (National Cancer Institute, 2015). If a patient has ER- or PRpositive breast cancer, oncologists will treat the cancer with endocrine therapy (Cimino-Mathews & Zheng, 2015). Professionals suggest that patients with breast cancer test for ER and PR in both the primary stages and retest in recurrences and metastasis because the ER and PR status has the ability to change (Cimino-Mathews & Zheng, 2015). Hormone Therapy To treat cancers that are ER- or PR-positive, oncologists use a form of treatment called hormone therapy (National Cancer Institute, 2015). Hormone therapy blocks the body's ability to produce hormones (National Cancer Institute, 2015). In the case of breast cancer, hormone therapy blocks the production of estrogen and progesterone to slow or stop the growth of cancer cells (National Cancer Institute, 2015). Hormone therapy is highly effective and relatively nontoxic (Cimino-Mathews & Zheng, 2015). Aromatase inhibitors. Aromatase is the enzyme that the body uses to make estrogen in the ovaries and tissues (National Cancer Institute, 2015). The hormone therapy drugs that block aromatase enzyme activity are aromatase inhibitors (National Cancer Institute, 2015). Aromatase inhibitors block the conversion of androgens to estrogens, suppressing plasma and tissue estrogen levels (Bosco, 2012). Oncologists prescribe aromatase inhibitors to postmenopausal women because premenopausal women create too much aromatase in the ovaries for the inhibitors to block them effectively (National Cancer Institute, 2015).

16 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 15 Bone Mineral Density As healthy women enter menopause, estrogen depletion causes a loss in bone mass (Campbell, 2012). Women can lose up to 40% of their endosteum and 10% of their periosteum within the first ten years following menopause, increasing the risk for fractures (Campbell, 2012). Barad and others show that post-menopausal survivors of breast cancer are more likely to have low bone mineral density (BMD), but not to the extent of osteoporosis, in comparison to other women of the same age (2005). A decrease in bone mineral density increases the risk of developing fractures or other skeletal related events (Bosco, 2012). Osteoporosis. The depletion of estrogen by aromatase inhibitors leads to bone demineralization (Bosco 2012). Increased demineralization results in possible osteoporosis (Bosco, 2012). Osteoporosis refers to the loss of bone mass due to malfunctioning osteocytes which results in a lack of new bone creation and maintenance failure of existing bones (Mayo Clinic, 2014). Bones are made of a hard outer shell and the inside shaft made of compact bone (Cancer, 2014). The inside contains protein, calcium, and other minerals (Cancer, 2014). The compact bone, made of smaller bone pieces called struts, allows blood vessels and bone marrow to flow through the bone (Cancer, 2014). Osteoporosis develops when the struts begin to thin or disappear, allowing the bone to fracture more easily, and usually goes undiagnosed until a fracture occurs, commonly in the back, due to degradation of cartilage and disks in the spine, and the hip and wrist which are common impact areas when you fall (Cancer, 2014). Detection. Breast cancer patients have a dual energy x-ray absorptiometry, DXA, scan done before beginning hormone therapy and have a follow up scan done two years after the start of the treatment (National Institute of Health, 2015). A DXA scan finds the mineral density of bones, compares that density to an established baseline, and produces a T-score, which is the

17 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 16 number of units a bone density deviates from the established average (National Institute of Health, 2015). Researchers established that a T-score between -1 and +1 signifies normal bone mineral density (BMD) for a healthy adult (National Institute of Health, 2015). As the T-score and BMD decreases, the risk for a SRE occurrence increases (National Institute of Health, 2015). A T-score of -2.5 or lower indicates a diagnosis of osteoporosis with the osteoporosis (National Institute of Health, 2015). The severity of osteoporosis increases as the T-score decreases (National Institute of Health, 2015). The DXA scan also reveals the actual bone mineral densities in g/cm² (National Institute of Health, 2015). Strengthening the bone. To prevent osteoporosis, oncologists combine bisphosphonates or denosumabs with aromatase inhibitors (Bosco, 2012). Bisphosphonates inhibit bone resorption, while denosumabs inhibit key pathways in the vicious cycle of bone metastases (Pavlakis, Stockler, & Wong, 2012). Studies show that bisphosphonates and denosumabs reduce the risk of developing SREs and delays the time to SREs in women with bone-metastasized breast cancer (Pavlakis, Stockler, & Wong, 2012). Doctors also recommend taking calcium and vitamin D supplements to strengthen bones (Campbell, 2012). Summary The American Cancer Society defines breast cancer as cancerous cells located in either the duct, lobule, or breast tissue of one or both breasts (2016). Cancerous cells occur when genes that should regulate and maintain healthy cells mutate and allow cells to grow uncontrollably leading to a tumor (American Cancer Society, 2016). When the cancer stays within the duct or lobule, a cancer is non-invasive ( What Is, 2015). Once the cancer spreads to surrounding tissue, it becomes invasive ( What Is, 2015). Breast cancer treatment is either systemic or local and includes surgery, radiation, and chemotherapy (American Cancer Society, 2016). Radiation,

18 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 17 chemotherapy, and targeted therapy can be neoadjuvant or adjuvant (National Cancer Institute, 2015). Biopsies and biomarker tests characterize some breast cancers as estrogen or progesterone-positive, resulting in the need for an aromatase inhibitor prescription (National Cancer Institute, 2015). Aromatase inhibitors block the estrogen that feeds the growth of cancer cells (National Cancer Institute, 2015). A possible side effect of the hormone therapy is bone loss resulting in osteoporosis (National Cancer Institute, 2015). To strengthen bones, patients can take calcium and vitamin D supplements along with bisphosphonates or denosumabs (Bosco, 2012; Campbell, 2012). Chapter 3: Research Method In estrogen or progesterone receptor positive breast cancer, oncologists use hormone therapy in the form of aromatase inhibitors to prevent estrogen and progesterone from stimulating cancer cell growth (Fabian, 2007; National Cancer Institute, 2015). Estrogen and progesterone are sex hormones that strengthen bone in both men and women (Tulane University, 2014). Blocking these hormones causes malfunctions in osteocyte creation and maintenance, leading to a decrease in bone density (Mayo Clinic, 2014). Increased demineralization of bones leads to osteoporosis, which increases the probability of a SRE occurring. This study aimed to determine if there is a statistically significant difference in the degree of bone demineralization of postmenopausal breast cancer patients on aromatase inhibitors as compared to other patients not on aromatase inhibitors; leading to a change in the occurrence risk of a SRE. This chapter will introduce the what, when, whom, and how I will be conducting this study. Research Question Q1. How does hormone therapy affect the bone mineral density of postmenopausal breast cancer patients and their risk of a SRE occurring?

19 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 18 Hypotheses H1. The use of aromatase inhibitors changes the rate of bone demineralization of postmenopausal breast cancer patients and, in turn, increases their risk of a SRE occurring. H10. There is no statistical change in demineralization of the bones of postmenopausal breast cancer patients when comparing a baseline and post-baseline bone density, indicating no increased risk of an SRE occurring. H12. There is a statistical change in demineralization of the bones of postmenopausal breast cancer patients when comparing a baseline and post-baseline bone density, indicating no increased risk of an SRE occurring. Research Methods and Design I will conducted a quantitative cohort study. Cohort studies are studies used in medical research that investigate the relation between risk factors and health outcomes. Through the utilization of a baseline and repeat bone density scan, the cohort study allowed me to observe the bone mineral density changes in bones of breast cancer patients prescribed aromatase inhibitors. I can then compared the baseline bone density and the post-baseline bone density to determine significant changes. The observational design of this study allowed me to follow changes in bone density without interfering with what the medication was doing. The design and research method of this study allowed the study to be highly reliable because all measures are consistent by using the bone mineral densities given by the DXA scan results. The internal validity of this study is relatively high because all the subjects used the same equipment for testing and measuring and a professional radiologist interpreted the test results. However, the study was

20 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 19 susceptible to a lower internal validity because the extent of interference of other medications and non-preventable events is unknown. Population The Marietta office of the Northwest Georgia Oncology Centers has approximately 1,000 post-menopausal breast cancer patients on aromatase inhibitors, which was my population pool. I had a limited population because I did not have research privilege at any other locations or hospitals to expand my search. A limited population restricted my sample size and in turn decreased external validity of the study because the study became less generalizable to a larger population. Sample The sample group was from the patient population of the Marietta office of the Northwest Georgia Oncology Centers. As I did not have unlimited access to these patients, I utilized a convenience sample for my study. To be a viable candidate a patient must fit the criteria of a postmenopausal breast cancer females that have been on aromatase inhibitors for a minimum of two years and have a baseline and post-baseline bone density scan conducted. As patients come in for follow-ups and consults, I evaluated the diagnosis and treatment of each patient to see if they are a viable candidate based on the patient profile that I built. I ignored all subjects that did not fit the criteria for the study. The sample size was 22, even though the minimum sample size of a quantitative study should be 100 to decrease data variations. As stated above, a smaller sample size lowered my external validity. The sample size represented the post-menopausal breast cancer patients on aromatase inhibitors at the Marietta office of the Northwest Georgia Oncology Centers, but could not represent a larger population outside the context of my study.

21 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 20 Materials/Instruments I used the baseline and post-baseline DXA scan reports that the office performed to monitor a decrease in bone density due to age. Historically, oncologists determined bone density by analyzing bone biopsies of the femur during a fracture treatment surgery (Alhadithi et al., 2010). However, the radiologic DXA scan is a scan on the non-fractured hip, or femur, and lumbar spine (Alhadithi et al., 2010). Studies show that the DXA scan is 20.2% more valid and reliable than the bone biopsy (Alhadithi et al., 2010). Data Collection, Processing, and Analysis I collected data by looking at DXA scans and noting the baseline and post-baseline bone mineral densities. The DXA scan results included a t-score and a bone mineral density. I utilized the bone mineral densities to determine statistical differences because the densities are more accurate than the t-scores. Data processing by means of a paired t-test, helped to compare the average baseline bone density of aromatase inhibitor patients to an average post- baseline bone density of the same subjects. A statistically significant change in the bone densities of the subjects would indicate that the aromatase inhibitors change the rate of bone demineralization that is already going on in our bodies due to aging. Assumptions I assumed that all bone density scans received had a low amount of machine error to the point where it is not significant. I also assumed that at this point in the treatment process, the only treatment related medication the subjects should be on is the aromatase inhibitor and that no other medication is affecting the bone density. Another assumption that I made is that the different stages of breast cancer and different types of breast cancer has no effect on the results of the study. The paired t-test I used to test my statistical significance needed to meet three

22 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 21 assumptions: (1) no pseudoreplication, (2) independent individuals, and (3) normality of population differences. The bone density of one person cannot affect the bone density of another person; therefore, no pseudoreplication occurred. A histogram or normal probability plot determined the normality of the population differences. A randomized sampling from the population was also an assumption of this test ("Test Assumptions," n.d.). However, I forwent this assumption, as I am limited to a convenience sample. I was able to omit this assumption because it was the only way I could acquire data. Limitations My limitations were that my sample size was reliant on convenience and therefore could only represent the Marietta office of the Northwest Georgia Oncology Centers. I was also limited to my control over the medication. I was not qualified to prescribe medication and control treatment plans; therefore, any extraneous events related to medication and treatment plans was out of my control. This decreased my external validity because I could not accurately determine if something other than the aromatase inhibitors was significantly affecting the bone mineral density; and because my sample size was so small, this study could not support any other population outside my study population. Delimitations My delimitations included my subject profile that patients must be postmenopausal women with breast cancer, on aromatase inhibitors for a minimum of two years prior to the study. I did not be considering any patients that did not fit the subject profile for the study. A minimum of two years post-baseline was a requirement because according to the guidelines set by the American Cancer Society, for breast cancer patients on aromatase inhibitors, two years after the start of the medication, oncologists should conduct a post-baseline scan for optimal

23 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 22 results (2016). Therefore, if I had pulled patients for my sample that were on the aromatase inhibitor for less than two years, they would not have had a post-baseline DXA scan for me to compare to the baseline DXA scan. Ethical Assurances The HIPAA nondisclosure was in affect throughout the entire study. The International Review Board reviewed and approved a research application outlining this study along with the attached informed consent form that all viable candidates received. The subjects name did not appear on any of the results presented within this paper or in a teaching environment. At the end of the study, I disposed of all patient results in Shred-It bins located in the Northwest Georgia Oncology Center office building. Summary By comparing bone density scans, I aimed to determine how hormone therapy affects the bone mineral density of postmenopausal breast cancer patients and their risk of a SRE occurring. I used a quantitative cohort study by observing changes between the baseline and post-baseline bone density scans. I pulled my sample at convenience from the patient population of postmenopausal breast cancer females on aromatase inhibitors at the Marietta office of the Northwest Georgia Oncology Centers by determining if patients fit my subject profile. A viable subject must have fit the criteria of a postmenopausal breast cancer female that had been on aromatase inhibitors for a minimum of two years and had a baseline and post-baseline bone density scan conducted. I analyzed the data by determining the change between the two bone mineral densities of the DXA scans. Using a paired t-test, I compared the average baseline bone density of aromatase inhibitor patients to an average post-baseline bone density of the same subjects. I assumed that machine error is negligible and that other medication or a patient s

24 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 23 cancer stage did not affect the results. My patient population limited me to the post-menopausal breast cancer patients on aromatase inhibitors at the Marietta office of the Northwest Georgia Oncology Center. All subjects must have fit the criteria stated in the subject profile. I did not include patients that do not suit the profile. The study had relatively high internal validity, low external validity, and high reliability, attributed to consistent measurements, a small sample size, and unknown results of extraneous factors such as other medications. Chapter 4: Findings According to the National Cancer Institute, hormone therapy blocks estrogen and progesterone receptors so that the hormones cannot continue nourishing the cell (2015). However, in other medical situations, blocking these receptors has led to increased fragility of the bone due to demineralization (Campbell, 2012; National Cancer Institute, 2015). Increased fragility of the bone allows an increased risk for SRE s such as hip and wrist fractures (Bosco, 2012). The purpose of this study was to identify if the hormone therapy resulted in a significant change in bone loss that would affect a patient s risk of an SRE occurrence. This chapter will present, evaluate, and synthesize the findings of this study. Results I rejected my null hypothesis, which stated that there is not statistical difference in demineralization of the bones of postmenopausal breast cancer patients when comparing a baseline and post-baseline bone density, indicating no increased risk of an SRE occurring. Utilizing Microsoft Excel software, I implemented a paired t-test, as displayed in Table 3 and Table 5, to determine statistical significance of the difference between the baseline and postbaseline bone densities of the spine and femur as indicated in Table 1. The spinal paired t-test p- value, as seen in Table 3, was 4.02E-07. The femoral paired t-test p-value, as seen in Table 5,

25 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 24 was Using and alpha value of 0.05, the t-test showed a difference between the baseline bone densities and the post-baseline bone densities of both the spinal and femoral bones. The three assumptions that I needed to meet for a paired t-test were: (1) no pseudoreplication, (2) independent individuals, and (3) normality of population differences. The bone density of one test subject can have no influence upon the bone density of another test subject; therefore, pseudoreplication did not occur. The samples of the baseline and postbaseline bone densities for the femur and spine show a normal distribution as seen by the normal probability plots (Figures 3-6). Evaluation of Findings There is a statistical change in demineralization of the bones of postmenopausal breast cancer patients when comparing a baseline and post-baseline bone density, indicating no increased risk of an SRE occurring. The results of the paired t-test indicate a statistically significant decrease in bone mineral densities as seen in the baseline and post-baseline DXA scan results. These results are reliable because the data results given by using a DXA scan has shown to be 20.2% more effective and consistent than any other test (Alhadithi, Alkudiari, & Humadi, 2010). This study showed high internal validity through data that represents the bone densities of each subject and indicates the difference between the baseline and post-baseline bone densities. Current literature states that estrogen and progesterone depletion results in decreased bone mineral density; therefore, aromatase inhibitors, which block these hormones in postmenopausal breast cancer patients, should lead to demineralization of the bones (American Cancer Society, 2016; National Cancer Institute, 2015). This quantitative cohort study supports the literature, indicating a decrease in bone mineral density. The results indicated by this study

26 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 25 will help facilitate further research into alternative medicines or preventative care. Since a statistically significant decrease occurred in the spinal and femoral bone mineral densities, doctors may be reluctant to use aromatase inhibitors in postmenopausal breast cancer patients. Summary I rejected my null hypothesis that there would be no statistical change in demineralization of the bones of postmenopausal breast cancer patients when comparing a baseline and postbaseline bone density, indicating no increased risk of an SRE occurring. A paired t-test, determined the p-value of the spinal and femoral data, showing a statistically significant difference between the baseline and post-baseline bone densities of postmenopausal breast cancer patients. The results indicated by this study will help facilitate further research into alternative medicines or preventative care. Doctors may show increased reluctance due to the statistically significant decrease in bone mineral density due to the aromatase inhibitors. Chapter 5: Implications, Recommendations, and Conclusions Although almost half of all breast cancer patients are postmenopausal and estrogen and progesterone receptor positive, researchers have not yet determined the skeletal effects of the medications used to block these hormones (American Cancer Society, 2016; National Cancer Institute, 2015). Oncology literature has shown that estrogen and progesterone depletion leads to demineralization of the bones (National Cancer Institute, 2015). Therefore, the blockage of these hormones by aromatase inhibitors should lead to a decrease in bone mineral density. This study aimed to identify if the hormone therapy resulted in an abnormal change in bone loss that would affect a patient s risk of an SRE occurrence. Breast cancer is the most common form of cancer found in women (National Cancer Institute, 2015). The risk of getting breast cancer increases with age; therefore, older women are

27 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 26 more likely to get it compared to younger women ("What Is," 2015). As a woman becomes menopausal and postmenopausal, her risk of getting osteoporosis also increases (Campbell, 2012). Studies have shown that hormone therapy, a breast cancer treatment, is a possible risk factor for osteoporosis and osteoporosis - associated skeletal related events (SREs) (Barad et al., 2005; National Cancer Institute, 2015). By analyzing the average baseline and post-baseline bone mineral densities taken from the femur and spine of each patient, I was able to determine if there was a significant change in the bone mineral densities after the patients began taking the medication. The results of this study will lead to future alternative and preventative research along with heightened doctoral consideration of the side effects of the medication when recommending it to a patient. I selected patients based on convenience; therefore, my study lacks randomization and can only represent the Marietta office of the Northwest Georgia Oncology Centers. I maintained the confidentiality of all patients in this study as directed within the HIPAA nondisclosure agreement. This chapter will discuss the implications of the results and the recommendations based off these results and implications. Implications Within the quantitative cohort study, the results of the paired t-test conducted upon the collected data shows a statistical significance in the difference of the baseline and post-baseline bone mineral densities of postmenopausal breast cancer patients. Due to a small sample size, the study is not generalizable to a larger population, but is applicable to the patients within the sample. The collected data shows a decrease in bone mineral density between the baseline and post-baseline DXA scans of the femur and spine. This indicates that the aromatase inhibitors

28 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 27 decrease the bone mineral density of postmenopausal breast cancer patients. The significant demineralization points to an increase in the risk of an SRE occurring. The results indicated by this study will help facilitate further research into alternative or preventative medications and care. Doctors may be reluctant to use aromatase inhibitors in postmenopausal breast cancer patients once they see the significant amount of demineralization caused by the hormone therapy. Furthermore, the patients themselves will be able develop a better understanding of the effects of aromatase inhibitors on their bones. This study will prompt patients to reconsider their decisions on whether or not to take the treatment. Recommendations I recommend replicating this study with a larger, randomized sample that can be generalizable to a larger population. Future researchers should investigate alternatives to this medication that would not result in demineralization of the bones, along with preventative skeletal care. Oncologists should inform any patients on the medication about the results of this study so they are better equipped to make a decision on whether or not to take the aromatase inhibitor. Conclusions The results of this quantitative cohort study show a statistically significant difference between the baseline and post-baseline bone mineral densities of the spine and femur. The convenience sample utilized in this study is not generalizable to a larger population and therefore can only represent the subjects in the sample. This study provides evidence that aromatase inhibitors significantly decrease spinal and femoral bone mineral density correlating to an increase in the occurrence risk of an SRE. Furthermore, the results indicated by this study suggest instigating further research for alternatives or prevention. Doctors should take great care

29 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 28 when contemplating prescribing this medication. Doctors and patients should also conduct a risk-benefit analysis of the demineralization of the bones versus the significant decrease in cancer growth as indicated by previous literature (National Cancer Institute, 2015).

30 EFFECTS OF AIS ON THE BONES OF BREAST CANCER PATIENTS 29 References Alhadithi, R. H., Alkudiari, S. I.,& Humadi, A. (2010). Validity of the DEXA diagnosis of involutional osteoporosis in patients with femoral neck fractures. Indian Journal of Orthopaedics, 44(1), doi: / American Cancer Society. (2016). Cancer facts and figures Retrieved January 23, 2016, from American Cancer Society. (2016). What is breast cancer? Retrieved February 05, 2016, from Barad, D. H., Bassford, T. L., Chen, Z., Gass, M., Leboff, M. S., Lopez, A. M.,... Ritenbaugh, C. (2005). Osteoporosis and rate of bone loss among postmenopausal surviviors of breast cancer. Cancer, 104(7), doi: /cncr Bosco, D. (2012). Osteoporosis and aromatase inhibitors: Experience and future prospects. Clinical Cases in Mineral and Bone Metabolism, 9(2), Retrieved February 02, 2016, from Cancer, J.(2014). Perspectives in breast cancer. Breast Cancer Research and Treatment. Journal of Cancer, 5(6), doi: /jca.8693 Campbell, B. J. (2012, July). Healthy bones at every age. Retrieved February 05, 2016, from Chin, J., Fleshner, N., Saad, F., & So, A. (2012). Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: Incorporating new agents into clinical practice. Canadian Urological Association Journal, 6(6), doi: /cuaj.12149