MALE BREAST CANCER: BRIDGING THE GAP By Parker Pattschull A thesis submitted to the School of Radiologic Sciences in collaboration with a research agenda team In partial fulfillment of the requirements for the degree of MASTER OF SCIENCE IN RADIOLOGIC SCIENCES (MSRS) WEBER STATE UNIVERSITY Ogden, Utah December 15, 2023 THE WEBER STATE UNIVERSITY GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a thesis submitted by Parker Pattschull This thesis has been read by each member of the following supervisory committee and by a majority vote found to be satisfactory. ______________________________ Dr. Tanya Nolan, EdD Chair, School of Radiologic Sciences ______________________________ Dr. Laurie Coburn, EdD Director of MSRS RA ______________________________ Director of MSRS Dr. Robert Walker, PhD ______________________________ Christopher Steelman, MS Director of MSRS Cardiac Specialist 1 Table of Contents List of Tables ...............................................................................................................................2 List of Figures ..............................................................................................................................3 Abstract ......................................................................................................................................4 Dedication ..................................................................................................................................5 Introduction................................................................................................................................6 Purpose ......................................................................................................................................7 Methodology ..............................................................................................................................8 Review of Literature ...................................................................................................................9 Etiology & Epidemiology ..........................................................................................................9 Pathology ..............................................................................................................................12 Genealogy .............................................................................................................................13 Screening ...............................................................................................................................15 Diagnosis ...............................................................................................................................16 Staging and Prognosis ............................................................................................................18 Psychosocial dynamics ...........................................................................................................19 Mortality Risk Valuation .........................................................................................................20 Discussion .................................................................................................................................21 Conclusion ................................................................................................................................22 References ................................................................................................................................24 Appendix A ...............................................................................................................................27 Tables ....................................................................................................................................27 Appendix B ...............................................................................................................................30 Figures ...................................................................................................................................30 Appendix C ...............................................................................................................................36 List of abbreviations...............................................................................................................36 2 List of Tables Table 1. Relative Risk of Male Breast Cancer ............................................................................27 Table 2. ACR Appropriateness Criteria Evaluation of the Symptomatic Male Breast ................28 Table 3. SEER Data for Stage at Diagnosis .................................................................................29 3 List of Figures Figure 1. Race Descepencies Among Male Breast Cancer .........................................................30 Figure 2. Proportion of Male Breast Cancer Incidence and Mortality Cases by Age .................31 Figure 3. Male vs Female Mortality Rates.................................................................................32 Figure 4. Risk of Various Cancers Among Men Who are BRCA1/2 positive ...............................33 Figure 5. NCCN Genetic Testing Guidelines ...............................................................................34 Figure 6. Male vs Female pie chart comparison of stage at diagnosis ......................................35 4 Male Breast Cancer Abstract Male breast cancer (MBC) is a rare disease that often goes unnoticed, leading to advanced disease at diagnosis and a potential outcome of death. This paper explores the reasons behind delayed diagnosis and the lack of awareness surrounding male breast cancer. By conducting a comprehensive analysis of available literature and data, this study investigates several factors contributing to delayed diagnosis. Firstly, this paper examines the etiology and epidemiology of male breast cancer. This information provides us with populations of males at an increased risk. Prevalence and incidence rates of males with breast cancer are discussed, with evidence indicating an increase in recent years. Mortality rates are discussed as it is a significant reason for this research. Males with breast cancer have higher mortality rates than females. However, when considering the stage at diagnosis, the rates are relatively equal. Therefore, this thesis also explores the diagnosis and staging of male breast cancer, emphasizing the importance of early medical attention, and highlighting the impact of delayed treatment on mortality. By shedding light on the challenges associated with male breast cancer, this thesis aims to raise awareness, especially for specific populations, to improve the prognosis for men diagnosed simply by gaining a deeper understanding. 5 Dedication I dedicate this thesis to my daughter Nellie Rae Pattschull. “I’ll cheer your accomplishments, little and great, share all the proud moments you earn and create, be glad for your triumphs and joys, celebrate! and hope life's full of wonder for you. I love you for all that you are and will be, for everything good you have given to me. you make me the father I hoped I would be, my darling, my daughter, my world” 6 Introduction Breast cancer is a widely studied and well-recognized malignancy predominantly associated with the female population. In fact, breast cancer is the most common cancer among women.1 Rightfully so, the whole month of October is reserved for breast cancer awareness, from advertisements, pro sports leagues acknowledgments, local fundraisers, to local mammography clinics sending out yearly reminders. All of this is symbolized by a pink ribbon targeting women with visual clues to remind them of the importance of breast cancer screening. However, a less acknowledged aspect of breast cancer research and awareness revolves around the male demographic. Male breast cancer (MBC) is an underrepresented population demonstrating its own unique characteristics, risk factors, and barriers that necessitate specialized attention. The behavior of breast cancer in men is quite like that in women. Men typically exhibit a detectable lump, have similar types of tumor histology, and respond well to comparable treatments. Albeit the disease is similar, males typically are diagnosed at a later stage and have a higher mortality rate than their female counterparts. c So that begs the question, what is the reason, and what is the cause for that reason as to why males have a higher mortality rate than females? Previous literature on breast cancer is vastly comprised of female populations, while prior research on males does not typically have large sample sizes and/or is on a specific topic that does not consider the whole dynamic. For example, one study looks at the psychosocial dynamics of delayed seeking of medical attention. Until recently, there were limited recommendations for males to be screened or genetically tested. Males make up only 1% of all breast cancers, but when healthcare professionals are 7 faced with a higher mortality rate in a specific population, it is paramount to understand the root cause. This thesis compiles a number of aspects in the hopes of a stronger grasp of understanding MBC and highlighting the most at-risk individuals. Awareness and mortality rate ought to be inversely related. Purpose The purpose of this thesis is a comprehensive literature review of breast cancer in an underrecognized population. Although breast cancer is a highly studied cancer, there are limited studies that are directed at the nuances of male breast cancer. By exploring the unique factors associated with MBC, this investigation aims to shed light on the underrepresented challenges and considerations specific to males affected by this disease. The study seeks to bridge the knowledge gap surrounding MBC, emphasize the importance of early detection and tailored medical care, and advocate for increased awareness within the medical community and general population. Male breast cancer represents a distinct yet often overlooked aspect of breast cancer research and care. Despite sharing similarities with female breast cancer, MBC exhibits specific risk factors, presentation patterns, and outcomes that demand focused attention. The limited recognition of MBC contributes to delayed diagnosis and subsequently higher mortality rates. This study addresses the critical need to better understand the intricacies of MBC, including its unique etiological factors, screening recommendations, and other adventitious implications. This research intends to compile many works for a comprehensive general overview of male breast cancer in hopes gain more understanding. By delving into the distinct characteristics of 8 MBC, this research aims to provide valuable insights that can contribute to better medical practices, increased awareness, and ultimately improved outcomes for men affected by this consequential disease. Methodology This study constitutes a comprehensive review of literature surrounding male breast cancer (MBC). The research methodology involved an extensive exploration of various databases to gather relevant articles, studies, and statistical data. Databases searched included PubMed, the WSU Library, the National Library of Medicine, and Google Scholar. Additionally, specialized sources such as SEER (Surveillance, Epidemiology, and End Results), the American College of Radiology (ACR), the American Cancer Society, and the National Comprehensive Cancer Network (NCCN) were accessed to gather statistics and evidence-based recommendations. The search strategy aimed to encompass a wide range of publications covering male breast cancer while ensuring the inclusion of the most recent and pertinent studies available. The timeframe of the research was expansive due to the limited amount of male-specific research in this domain. The literature review spanned the past two decades predominantly, with the majority of references dated within this period. Two studies from 1998 and 1999 were included due to their relevance and significance in understanding MBC. The methodology aimed to synthesize and analyze existing information, aiming to address the gaps in understanding male breast cancer comprehensively. The focus remained on 9 drawing insights, understanding unique characteristics, identifying risk factors, and highlighting the disparities in MBC compared to its female counterpart. Review of Literature Etiology & Epidemiology • Cause The disease of breast cancer, including risks, symptoms, and treatment, are strikingly similar among men and women. However, there are several specifics related to men. Like with female breast cancer (FBC), age is the most significant factor with increasing risk. Typically, men have no identifiable risk other than age. Genetics plays a role in both men’s and women’s breast cancers, and it is proven that both sexes will have an increased risk if a first or second-degree relative has a history of breast cancer.2 Because male breast cancer is rare, the several unique differences that specifically raise risk in men should be a filter for whom we should advocate awareness. Increased risks among males include genetics, occupation, lifestyle, radiation exposure, and endocrine factors (table 1). Most notably, genetics and endocrine factors3. 15-20% of male breast cancer cases have a positive family history. BRCA2 is more common than BRCA1 for males. The male population has a 0.1% chance of developing the disease. To put it more into perspective, men who inherit BRCA1 mutations have a 1% chance, and those with BRCA2 mutations have a 6% chance. That’s 60 times higher than a male without BRCA2. Endocrine factors, on the other hand, are a range of conditions that can all be summed up as anything that causes excess estrogen stimulation. 10 This can range from congenital abnormalities to mumps to obesity and liver disease. All of which cause hyperestrogenism in men.3 Nothing is more specific to male breast cancer than Klinefelter syndrome. Klinefelter syndrome only affects males and blurs the lines between genetics and endocrine factors. It is a chromosomal condition that affects the X and Y sex chromosomes. Typically, females have the XX and males XY, but with Klinefelter syndrome, males have an extra X chromosome. The extra X gives them XXY and results in several symptoms, including reduced testosterone and increased estrogen.4 Coming second to BRCA2, Klinefelter patients have a 20 to 50-fold increased risk. The subset population of Ashkenazi Jews carry a high percentage of BRCA2 mutations. This ethnoreligious group has a population of 5.7 to 10million in the United States.5 Because of this, Ashkenazi Jews should receive increased advocacy. Due to MBC being a rare disease with a mortality rate, it is essential to seek out the males at higher risk and advocate for them. • Prevalence According to the American Cancer Society, 2800 new cases of male breast cancer will be diagnosed in 2023. Compared to the ~298,000 cases for females, this is consistent with the statistic that male breast cancer accounts for nearly 1% of all breast cancer cases. The prevalence of male breast cancer has seen an increase with population increase and an uptick in incidence rate.6 11 • Incidence The lifetime risk of a male developing breast cancer is roughly 1 in 833, compared to 1 in 8 in women. This equates to ~1% of all breast cancer cases, but the incidence of MBC is rising. According to Konduri et al., there was an increase in incidence from 7.2% to 10.3% between 2004-20147. In recent years, there has been an incidence rate increase of 0.5% per year.6 Within males, there is also a discrepancy between race and age. Non-Hispanic black and non-Hispanic white populations see a slightly higher incidence within the United States. 1.9 and 1.3 per 100,000 population, respectively (figure 1). The incidence with age increases directly up to 70-79 years. 60-69 has the highest incidence of 30.1% of all male breast cancer diagnosed in this decade (figure 2).8 • Morbidity An extensive study compared mortality rates of men vs. female breast cancer. A review of 1,800,708 females and 16,015 males diagnosed with breast cancer. The study looked at threeyear, five-year, and overall survival rates. For men, the overall survival rate was 45.8%, the 3year rate was 86.4%, and the 5-year rate was 77.6%. For women, the overall survival rate was 60.4%, the 3-year rate was 91.7%, and the 5-year rate was 86.4% (figure 3).9 This discrepancy is the basis for the question, “Why”? Why are survival rates for men lower than their female counterparts despite the cancer being similar? 12 Pathology It is important to understand the basic pathology of breast cancer as there is some variance in males compared to females. Breast cancer is first determined to be invasive or noninvasive. The true noninvasive breast cancer is ductal carcinoma in situ (DCIS). In situ means to be situated in its original location. Furthermore, ductal carcinoma refers to cancer in the breast's milk ducts. Everything else is invasive, meaning that the cancer has spread from its origin into nearby breast tissue or lymph nodes. DCIS is incredibly rare in men as they typically present with invasive carcinomas.10 The largest study on males with DCIS looked at 84 cases of pure DCIS and 30 cases of ductal carcinoma in situ associated with invasive carcinoma (DCISAIC). The study showed that pure DCIS was primarily low grade, whereas DCISAIC was more frequently high grade.11 We must understand why males rarely present with pure DCIS and are more likely to present with high-grade DCISAIC. When comparing the development of breast tissue between males and females, males generally only develop more central ducts. This is because terminal ductal lobule units (TDLU) only develop in the presence of estrogen. Moreover, if highgrade DCIS is only found in TDLUs, then there is a strong correlation between hyperestrogenism in males and high-grade DCIS. When looking at risk factors for males, outside of genetics, the large majority surround hyperestrogenism, thus proving that hyperestrogenism in males is a major risk factor. Following a biopsy, it is pertinent to know the hormone receptor status. These receptors are proteins that hormones bind to, which feed the cancer to grow and spread. Estrogen receptor (ER) and progesterone receptor (PR) are the two hormone receptors that require testing with invasive cancer. Results could be positive, negative, or a mix of positive and negative. Knowing 13 these results will guide the treatment process to include hormone therapy. Hormone therapy prevents the cancer from receiving these hormones and halts the growth and spread of cancer.12 Human epidermal growth factor 2, or HER2 is another factor necessary to test when someone presents with an invasive cancer. According to the American Cancer Society, approximately 15% of breast cancers have an abundance of HER2 proteins. HER2-positive cancers grow and spread more rapidly than HER2-negative cancers. The status of HER2 is important as therapies that target HER2 proteins can yield a favorable outcome. Having ER+, PR+, and HER2+ results are referred to as triple positive. Whereas triple negative implies ER-, PR-, and HER2-. Males are more likely to be diagnosed with positive hormone receptor status. ER+ is seen in 97.43% of men compared to women at 82.72%. PR+ follows suit with 91.63% in comparison to 72.46% in women. On the other hand, males are less likely to be ER2+ at 11.04% vs. 14.68% respectively.13 Knowing the makeup of a breast cancer is crucial in the treatment process. It is crucial to understand that therapies are tailored to the specific aspects of breast cancer. Genealogy Humans have genes that limit proliferation in order to control growth of normal tissue. By limiting the rate at which cells divide and grow, these genes reduce the risk of cancer. Humans have two breast cancer genes appropriately named, BRCA1 and BRCA2. Healthy BRCA1/2 genes are tumor suppressors.14 Problems emerge when one or both genes become 14 mutated. Most of the reported BRCA1 and BRCA2 mutations are characterized by deletions, insertions, nonsense mutations and splice variants that result in a truncated protein.15 Genetically, BRCA mutations are autosomal dominant. Having a dominant gene means that only one parent is required to pass on the mutation to future generations. With one parent having BRCA1/2 mutation, there is a 50% chance the offspring would inherit it. If, on the off chance, both parents have an autosomal dominant gene, the chance increases to 75%. Mutations of BRCA1/2 are uncommon. Approximately, anywhere from 1:300 to 1:800 are reported in general populations of both male and female.16 BRCA1/2 mutations have significant effects on cancer risk. Although uncommon, the inheritance rate is high and thus, knowing family history can be key to the detection of cancers early. The standard risk for a male to develop breast cancer is 0.1%. This risk goes from 0.1% to roughly 1.2% risk with BRCA1 by age 70. BRCA2 mutation has a more significant effect on risk, taking it from a 0.1% standard risk to a 6.8% risk by the age of 70. 17 Not only do these mutations increase the risk of developing cancer, but also the prognosis. Patients with BRCA1/2 mutations have worse overall survival rates and breast cancer severity score when compared to BRCAnegative cancers.18 Knowing the patient’s heritage plays an essential role in understanding the risk of BRCA1/2 mutations. The highest prevalence of BRCA1/2 is among the Ashkenazi Jewish population. The increased risk associated with this ethnic group is significant enough that descendants of Ashkenazi Jews meet the criteria for genetic testing. As stated, BRCA1/2 appears anywhere from 1:300-1:800 in the general population. Ashkenazi Jews show mutations of BRCA1/2 genes in as little as 1:40.19 15 To stress BRCA1/2 awareness for males even further, the following must be noted. When a female is diagnosed with breast cancer, only about 5-10% can be attributed to inherited gene mutations. Whereas with males, about 40% can be tied to inherited gene mutations.20 Recalling that genetic mutations increase risk and severity score, advocacy for male genetic testing is important. Males with BRCA1/2 mutations have a significantly greater risk to other cancers as well (Figure 4). Most noteworthy for men is a ~fivefold increase in the risk of prostate cancer. Equivalently with breast cancer, the prognosis of prostate cancer with BRCA2 mutation is worse than BRCA-negative.21 Screening The National Comprehensive Cancer Network (NCCN) has set forth guidelines for screening and genetic testing for both sexes. When it comes to genetics, the guidelines can be broken down to personal history of cancer and family history of cancer (figure 5). The NCCN list several recommendations for males to follow who are known, or likely, BRCA pathogenic positive. Beginning with general education of early signs and symptoms of cancer. At 35 years old, patients should receive self-exam training and education. At that age, yearly clinical breast exams are also recommended. Routine annual mammograms are advised for males who are BRCA2 positive at the age of 50 or 10 years earlier than the youngest family history (whichever comes first). The NCCN specifies BRCA2 positive, as BRCA1 carries a lower risk for male breast cancer.22 Important to note both males and females within the LGBTQ community are less likely to present for cancer screenings than non-LGBTQ communities.23 There must be recognition and 16 advocacy for transgender patients. Recommendations to follow are based on sex assigned at birth. Furthermore, the NCCN guidelines recommend annual screening for male-to-female (transfeminine) patients at age 40 who have been on hormone medications for greater than 5 years. The same guideline is suggested for female-to-male (transmasculine) who have not had a mastectomy.22 Diagnosis Symptoms of male breast cancer are similar to that of female breast cancer. Most commonly males present with a lump in one of the breasts. These lumps are more of a prominent symptom in males due to the relatively smaller size of the breast. Although, patients with a history of gynecomastia could have a lump that is falsely attributed to the gynecomastia. The other common symptoms of all breast cancer still apply; nipple retraction, nipple discharge, ulceration, and pain could all present themselves.2 The foremost noteworthy piece of MBC is the delay in which males seek medical attention. It is important to note that females may commonly be diagnosed asymptomatically due to routine annual screenings. Males do not receive routine mammogram screenings as it would be impractical to screen each person with such a low incidence. Because of this, a symptom must be noticed before any medical attention can be triggered. Several studies have looked at varying factors that cause the diagnosis delay, even when symptoms exist. For example, males may be unaware that breast cancer is possible. Psychosocial aspects have also 17 been studied. Even when consulting a physician, a painless lump may be discredited as something less intrusive. The American College of Radiology has set forth the ACR Appropriateness Criteria Evaluation of the Symptomatic Male Breast. Guidelines to follow when a male presents with symptoms of gynecomastia, an indeterminate palpable breast mass, or other symptoms concerning for breast cancer. Five variants are indicated and the appropriateness of imaging modality for each of the five.24 These five are listed below: Variant 1: Male patient of any age with symptoms of gynecomastia and physical examination consistent with gynecomastia or pseudogynecomastia. No imaging is recommended. Variant 2: Male younger than 25 years of age with indeterminate palpable breast mass. Ultrasound breast is usually appropriate. Variant 3: Male 25 years of age or older with indeterminate palpable breast mass. Diagnostic mammography and digital breast tomosynthesis is usually appropriate. Variant 4: Male 25 years of age or older with indeterminate palpable breast mass. Mammography or digital breast tomosynthesis indeterminate or suspicious. Ultrasound breast is usually appropriate when diagnostic mammography and digital tomosynthesis is indeterminate or suspicious. 18 Variant 5: Male of any age with physical examination suspicious for breast cancer (suspicious palpable breast mass, axillary adenopathy, nipple discharge, or nipple retraction). Diagnostic mammography, digital breast tomosynthesis diagnostic, and ultrasound breast are all usually appropriate with this category. Notice that MRI breast is deemed usually not appropriate with all variants (Table 2).24 One study examined all cancers and the effects of delayed treatment on mortality. Breast cancer, among all cancers, was included in this study. They evaluated the delay based on the time between diagnosis and treatment. They saw mortality rates increase with as little as a four-week delay. Although not explicitly studied on breast cancers, one could imagine that a male delaying medical attention or mismanagement could directly increase the mortality rate. The first step to beating cancer is a diagnosis, and we must proactively advise medical attention at the first sign of symptoms.25 Staging and Prognosis The delay of diagnosis in men results in a higher stage at diagnosis. The stages can be stratified into stage 0, I, II, III, and IV. The percentage of which males present with at diagnosis are 37% for stage I, 21% for stage II, 33% for stage III, and 9% for stage IV. 3 Accordingly to American Cancer Society SEER data, the percentage for each stage at diagnosis for females is as follows: 60-70% for stage I, 20-30% for stage II, 10% for stage III, and 5-6% for stage for IV (table 3). Breast cancer diagnosis is also commonly lumped into local, regional, and distant (metastatic) disease. Disease confined to the breast is considered the local stage. Regional stage refers to the spread to surrounding tissues and lymph nodes nearby. Distant stage is cancer that 19 has spread throughout the body to other organs and more distant lymph nodes. 26 Local equates to stage I, regional to stage II and III, and distant refers to stage IV (Figure 6). The outlook for breast cancer can be optimistic when discovered at an early stage. Stage 0 and I both have a 100% 5-year survival rate. Stage II still results in a favorable outcome of 93% survival rate. Stage III sees a drop to 72%. The cancer becomes less than favorable once it spreads systemically. Patients only have a 22% survival rate at stage IV. 27 Men have higher mortality rates, but when the stage at diagnosis is stratified, the survival rates are such: stage I has a survival rate of 75% to 100%, stage II is 50% to 80%, stage III is 30% to 60%, and stage IV is 20% to 30%. Research shows that males with breast cancer do not have significantly higher mortality rates than females with breast cancer when matched with various prognostic factors such as age, stage of disease, and grade. 28 Psychosocial dynamics Quantitative research is highly beneficial for its objectivity, large sample sizes, statistical analysis, and replication and verification. However, in the case of an under-recognized population, a qualitative study helps to understand the given population deeper. One study claims to be the only qualitative study on male breast cancer participants, and that study was published in 2020. Nguyen et al. conducted a study to explore men's experiences living with breast cancer. The study interviewed 18 male breast cancer patients. The interview consisted of 4 main categories: living with a "woman's disease," barriers, coping, and supportive care needs. The issues that stood out with the highest frequency included stigma, lack of awareness of the disease among HCP, and standard procedures that do not consider men. The participants 20 mentioned how they were not comfortable talking about their disease amongst peers as it made them feel it threatened their masculinity. Several participants were quoted expressing disappointment with the lack of knowledge their healthcare provider had regarding male breast cancer. Furthermore, the study remarked that some men were even wrongfully referred to see a plastic surgeon.29 This qualitative approach sheds light on the experiences males have with this disease. The issue of breast cancer being a woman's disease shines through. Mortality Risk Valuation The Environmental Protection Agency (EPA) estimates the dollar amount a population would be willing to pay for a reduced mortality risk. This estimate does not put a price on an individual’s life but instead uses benefit-cost analysis. They call this analysis mortality risk valuation. The EPA typically uses this when deciding on new environmental policies. Several factors can influence the mortality risk valuation. The EPA recognizes altruism amongst populations and knows that humans are more willing to pay more money to reduce cancer. They even call this a cancer differential when calculating the mortality risk valuation. Mortality risk valuation can directly relate to the cost of cancer. The underrepresentation of males in breast cancer trials is of concern, and there may be room for improving treatment options. 30 However, the cost of bringing a new cancer drug to market with FDA approval can be staggering. The cost can range from $314 million to $2.1 billion.31 Spreading awareness is relatively free compared to FDA new drug approval. The hope to reduce mortality rates among a considerably 21 small population could be costly. Nevertheless, if mortality rates can be reduced for free, even to the smallest degree, there is no excuse not to advocate for that. Discussion The disease process of breast cancer is similar between males and females. However, male-specific breast cancer is less researched and has higher mortality rates than female breast cancer. The lack of awareness, absence of preventive care in targeted populations, and delayed medical attention directly correlate with increased mortality among men. One could understand why routine screening for a disease with a low incidence rate is not feasible. The number of resources needed for every male to have a routine screening would create a burden on breast centers so large that not everyone could be serviced. This could lead to an increase in missed breast cancers; therefore, the benefits would not outweigh the disadvantages of males not having routine screenings. Thus, understanding the multifaceted dynamics and zeroing in on the highest-risk populations can improve patient care and outcomes. Klinefelter syndrome patients, Ashkenazi Jews, and males who have, or are likely to have, based on family history, BRCA2 mutations carry the highest risks. Being aware of the other factors that may cause hyperestrogenism is also important. Thankfully, the NCCN has recently established new genetic testing and screening guidelines among men known or likely to be BRCA pathogenic positive. This is a great start as it gives criteria for at-risk men and starts with thorough history taking to evaluate family history of BRCA-positive genes. This advocacy and education can raise awareness in at-risk men, leading to sooner medical attention and a better chance for a positive 22 outcome. But what about the males who do not meet the NCCN criteria for screening and testing or those who test negative for BRCA mutations? I believe this is where improving the stigma of breast cancer can provide benefits. As breast cancer awareness month, October is a fantastic reminder for females to receive their annual screening mammogram. However, there is little marketing towards males during this month. Pink-colored marketing gives a false stigma that breast cancer strictly affects females. More marketing could be created to include males. This marketing could advertise any of the aforementioned causes that increase the risk for male breast cancer and also debunk the stigma that males cannot be affected by breast cancer. While drug development costs can be substantial, advocating for increased awareness and early detection is a cost-effective strategy to potentially reduce mortality rates without imposing significant financial burdens. If more awareness shortens the time to seek medical attention, mortality rates could be lowered. Awareness will not cure cancer, but it may help save lives. Conclusion This thesis has comprehensively explored male breast cancer (MBC), a subject that has remained relatively underrepresented in the broader discourse on breast cancer. While breast cancer research has made significant strides, a crucial gap persists in understanding and addressing the unique challenges men afflicted with this disease face. The overarching purpose of this thesis has been to illuminate the nuanced aspects of MBC, ultimately advocating for increased awareness, early detection, and tailored medical care within both the medical community and the general population. 23 In conclusion, this thesis has provided a comprehensive overview of male breast cancer, emphasizing the urgent need for increased awareness, early detection, and tailored medical care. This research aims to improve medical practices, heighten awareness, and ultimately, better outcomes for this underrepresented and critically important population by delving into the distinct challenges and considerations specific to men affected by breast cancer. Male breast cancer, though often overlooked, deserves its place in the spotlight, and this thesis hopes to pave the way for further research, advocacy, and progress in the field. 24 References 1. Cancer Statistics - NCI. Published April 2, 2015. Accessed September 14, 2023. https://www.cancer.gov/about-cancer/understanding/statistics 2. Khattab A, Kashyap S, Monga DK. Male Breast Cancer. In: StatPearls. StatPearls Publishing; 2022. Accessed November 18, 2022. http://www.ncbi.nlm.nih.gov/books/NBK526036/ 3. Fentiman I. Male breast cancer: a review. ecancermedicalscience. 2009;3:140. doi:10.3332/ecancer.2009.140 4. Klinefelter syndrome. nhs.uk. Published October 18, 2017. 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JAMA. 2020;323(9):844-853. doi:10.1001/jama.2020.1166 27 Appendix A Tables Table 1. Relative Risk of Male Breast Cancer 28 Table 2. ACR Appropriateness Criteria Evaluation of the Symptomatic Male Breast 29 Table 3. SEER Data for Stage at Diagnosis Stage Male Female I 37% 60-70% II 21% 20-30% III 33% 10% IV 9% 5-6% 30 Appendix B Figures Figure 1. Race Descepencies Among Male Breast Cancer Incidence Per 100,000 Race/Ethnicity 2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 Hispanic Non-Hispanic Asian/Pacific Islander non-Hispanic American Indian/Alaskan Native non-Hispanic Black non-Hispanic White Non-hispanic black populations have more than double the risk factor than other race populations. 31 Figure 2. Proportion of Male Breast Cancer Incidence and Mortality Cases by Age, 2013-2017 Pie charts showing males are most commonly diagnosed between the ages of 60-69. Meanwhile, mortality rates indicate a direct proportion to increasing age and mortality rate. The old a male becomes, the less chance of survival. 32 Figure 3. Male vs Female Mortality Rates Survival Rate Male v Female 100.00% 90.00% 80.00% 70.00% 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% Male 3 year 86.40% 5 year 77.60% Overal 45.80% Female 91.70% 86.40% 60.40% 3 year, 5 year, and overall survival rates compared between the two sexes indicate males have less chance of survival at each interval. 33 Figure 4. Risk of Various Cancers Among Men Who are BRCA1/2 positive BRCA1/2 mutations are not only correlated with breast cancer but give significant increased risks to many other cancers as well. 34 Figure 5. NCCN Genetic Testing Guidelines Recommendations for who should have genetic testing done set forth by the National Comprehensive Cancer Network. 35 Figure 6. Male vs Female pie chart comparison of stage at diagnosis MALE Local Regional FEMALE Distant Local Regional Distant Male chart shows a larger slice for distant and regional breast cancer at diagnosis when compared to the female chart. Females chart largely indicates a higher amount of local breast cancer. 36 Appendix C List of abbreviations ACR: American College of Radiology BRCA1: breast cancer gene 1 BRCA2: breast cancer gene 2 DCIS: ductal carcinoma in situ DCISAIC: ductal carcinoma in situ associated with invasive carcinoma EPA: Environmental Protection Agency ER: estrogen receptor FBC: female breast cancer HER2: human epidermal growth factor 2 MBC: male breast cancer NCCN: National Comprehensive Cancer Network PR: progesterone receptor SEER: Surveillance, Epidemiology, and End Results TDLU: terminal ductal lobule units