Women with breast cancer in sub-Saharan Africa are commonly diagnosed at advanced stages. In Tanzania, more than 80% of women are diagnosed with stage III or IV disease, and mortality rates are high. This study explored factors contributing to delayed diagnostic evaluation among women with breast cancer in Tanzania.A qualitative study was performed at Muhimbili National Hospital in Dar es Salaam, Tanzania. Twelve women with symptomatic pathologically proven breast cancer were recruited. In-depth, semi-structured interviews were conducted in Swahili. Interviews explored the women’s journey from symptom recognition to diagnosis, including the influence of breast cancer knowledge and pre-conceptions, health seeking behaviors, psychosocial factors, preference for alternative treatments, and the contribution of culture and norms. Audio-recorded interviews were transcribed and translated into English. Thematic analysis was facilitated by a cloud-based qualitative analysis software.All women reported that their first breast symptom was a self-identified lump or swelling. Major themes for factors contributing to delayed diagnostic presentation of breast cancer included lack of basic knowledge and awareness of breast cancer and misconceptions about the disease. Participants faced barriers with their local primary healthcare providers, including symptom mismanagement and delayed referrals for diagnostic evaluation. Other barriers included financial hardships, fear and stigma of cancer, and use of traditional medicine. The advice and influence of family members and friends played key roles in healthcare-seeking behaviors, serving as both facilitators and barriers.Lack of basic knowledge and awareness of breast cancer, stigma, financial barriers, and local healthcare system barriers were common factors contributing to delayed diagnostic presentation of breast cancer. The influence of friends and family also played key roles as both facilitators and barriers. This information will inform the development of educational intervention strategies to address these barriers and improve earlier diagnosis of symptomatic breast cancer in Tanzania. Breast cancer is a disease that affects women and men worldwide, contributing to a substantial public health burden. It is estimated that 2.3 million new cases of breast cancer are diagnosed each year . Breast Sub-Saharan Africa is experiencing a growing cancer burden , 6. CancThe mortality-to-incidence ratio (MIR) for breast cancer in Tanzania is 0.5, indicating that half of all women diagnosed with breast cancer will succumb to the disease . While cThere is currently a lack of studies investigating the factors contributing to delayed diagnosis of breast cancer among Tanzanian women. A few survey-based studies have evaluated breast cancer knowledge and beliefs among Tanzanian women, the vast majority (>97%) of whom had no personal history of breast cancer , 13. To This qualitative investigation used an interpretive phenomenology design –16 to exIn this study, we took rigorous steps to ensure the trustworthiness and validity of our work. A detailed description of the inclusion and exclusion criteria, working environment, data collection process, and data analysis is provided below. All interviews were conducted by the same researcher who had dedicated in-depth coursework training in qualitative research, ensuring fidelity to the methodology.This study was conducted at MNH in Dar es Salaam, Tanzania. MNH is the teaching hospital affiliated with MUHAS. It is a national referral hospital with a 1,500 bed capacity and provides care for up to 2,000 outpatients per day. MNH is the largest referral hospital for cancer diagnosis in the country, equipped with a state-of-the-art radiology department with diagnostic breast imaging capabilities, and well-established medical, surgical, and pathology departments.Participants were recruited from June to September 2019. Patients with a histologically confirmed diagnosis of breast cancer who were actively undergoing surgical/oncologic management were recruited from the Radiology or Oncology Departments at MNH.All eligible participants were approached by the research assistant. Purposive sampling techniques were used to invite participants whereby all eligible participants visiting the clinic during the study period were consecutively recruited. Individuals who were too ill to participate in the interview were excluded. Patients who met the inclusion criteria and completed the written informed consent were enrolled. Participants were briefed about the study and were informed that their participation was voluntary with the right to withdraw at any time. Participants consented to participate in the study and for their interview to be recorded. Recruitment was done concurrently with data analysis and stopped once saturation was reached on key themes, with saturation defined as no longer finding new information adding to our understanding of the categories or coming to a point in the data collection where no new categories emerge , 17, 18.Interviews were conducted in a quiet private room at the hospital premises. Interviews were conducted in Swahili, the national language of Tanzania, and were all performed by a single research assistant with formal training in qualitative research methodology. A semi-structured interview guide was developed by the research team and piloted on three women before formal recruitment started. Interview questions focused on exploring the participant’s journey from the first recognition of breast signs and symptoms to diagnosis of breast cancer, including barriers and facilitators to timely diagnosis. Interviews delved into factors such as pre-existing breast cancer knowledge and pre-conceptions, psychosocial factors, health-seeking behavior, preference for alternative treatment, and the contribution of culture and norms.Demographic data of participants were also collected, including age, highest level of education, marital status, number of children, place of permanent residence, and distance and method of transportation to the local healthcare provider. Key medical information collected from the patients included the breast signs and symptoms, who detected the signs and symptoms, time between symptom onset and seeking of medical care, use of traditional medicine, breast imaging evaluations performed prior to being referred to MNH, and breast cancer risk factors, such as family history of breast cancer.Interviews were audio-recorded to ensure that all information as reported by participants was captured. The recorded interviews were then transcribed verbatim in Swahili and translated into English after each interview by a single research assistant (an intern physician). These transcribed interviews, both the Swahili and English versions, were subsequently reviewed for accuracy by the interviewer. Both individuals, the interviewer and the transcriber, had advanced proficiency in both Swahili (native language) and English. Interviews were performed until saturation was achieved on key themes (N = 12). This theoretical saturation point was defined as no longer finding new information adding to our understanding of the categories and no new categories emerging. In other words, we stopped data collection at the point where the women’s experiences became repetitive/redundant and further data collection became unnecessary , 17, 18.Patient characteristics, including socio-demographic data and breast symptoms were summarized with descriptive statistics. Qualitative analysis was performed using Dedoose, a cloud-based qualitative analysis coding application software. Transcripts in English were reviewed concurrently with the data collection to explore initial emerging issues to follow up in subsequent interviews, until saturation was achieved. Data were coded and analyzed using a thematic approach , 19, 20.Semi-structured interviews were conducted in a total of 12 women with histologically proven breast cancer. Each interview lasted for approximately 30 minutes. Mean age was 50 years (range 40–65). The most commonly reported highest level of education was primary school (42%) and secondary school (42%). The most common occupations were petty trader (25%) and peasant (25%). Most participants were married (58%) or widowed (17%). One participant had no children; the remaining 11 participants had children.All participants reported that their first breast symptom was a self-identified lump or swelling. Additionally, three women had associated breast pain and one woman had associated bloody discharge. Study participants’ characteristics are summarized in The main emergent themes from the participants’ accounts of their journeys from symptom recognition to breast cancer diagnosis were grouped as barriers and facilitators to timely diagnosis. These are summarized in Participants’ responses revealed six common barriers that contributed to delayed diagnosis.All participants admitted to recognizing a symptom, such as a lump or swelling in the breast, but most didn’t understand that it could be a sign of cancer. Many were initially not worried about the symptoms and decided to ignore it, believing it was not a serious condition.I thought that it was just a normal condition for a woman to feel a little problem. I had never thought the disease of cancer in my mind. I didn’t think that I can get such a thing…Probably it is a communicable disease, so getting such a disease would be difficult.” “I wasn’t knowledgeable when I saw the swelling and didn’t understand it.” “I never noticed it was cancer because I only saw something hard…So you are sick but you keep on working regarding it as a normal condition.” “Others were reassured by the absence of pain, unaware that breast cancers commonly present as painless palpable lumps.We didn’t take it seriously because it wasn’t painful. I continued doing my activities, you know how we neglect things … without knowing that the more we delay the more the problem worsens.” “I didn’t understand what it was, I didn’t understand it without the kids telling me to go to the hospital! I was just asking myself why was the area hard however there was no pain. Only later did I decide to get to the hospital.” “The problem is the knowledge, not being aware, not understanding something…You start questioning what it is and if it has no pain you might just ignore it.” “Participants reported seeking health care four months to two years later, after symptoms had progressed to more advanced stages. One participant was aware of self-breast examination, noticed a lump, and shared the information with her husband. Together they agreed to wait several months before seeking medical care.Participants described their struggle to get money so they could access health care, contributing to delays in diagnosis. After being seen by a primary health care provider, several participants had to mobilize to collect funds, through efforts such as family fundraising, to get enough money to receive the necessary diagnostic services. Some had to travel to zonal and referral hospitals for necessary diagnostic investigations and needed to find funds for travel and temporary accommodations.The doctor told me to have an ultrasound or x-ray so that they can give me a transfer to come [to MNH] to know what it is. Unfortunately, I didn’t have enough money so I had to return home… I knew the problem of cancer is a disease that is so scary in Tanzania or the world. It is the disease that is most feared, but to be honest, money was the greatest challenge”. “Since I was poor, I couldn’t manage the costs. I struggled to get money for the investigations.” (P09)“It was expensive because I was paying. So, there were high costs indeed. Moreover, taking into account the transport costs and food costs when you are away, in fact the expenses are high…You consider the fare from Tanga to Moshi, how to live there and you don’t have relatives there, now you can see. I was so late such that I was in bad condition. So the expenses to enable me to get the services there, to stay at a lodge, was a challenge.” “It took about one month and three weeks when my sister had all the money needed. Then I came to Muhimbili” “What are other reasons for the delay? Financial crisis, money has been a problem. Especially this time, it didn’t rain, so few was harvested. There was an option of selling cows, but they are not good-looking to sell due to lack of pasture and are sold at a cheaper price. And this place is too far, especially for two people it is really expensive.” “These struggles to gather funds for investigations contributed to delays in breast cancer diagnosis. Some expressed a sense of inevitability that those who are poor will suffer.The factors that lead to the delay, for instance for us peasants, it’s the monetary factor…They are just there, hopelessly waiting for God’s call, waiting for their death.” “When participants did seek medical attention for their breast symptom, several reported further delays in diagnosis due to barriers within the local health system. For example, some participants managed to get to their primary health care provider in a timely manner, but they were assured that the symptom was nothing worrisome.I noticed a small swelling. A small one here on the breast. So I went to the hospital, and the doctor that was there told me that it wasn’t a problem… Yes, so you become less worried and you proceed with your works and mind you it is a medical doctor who told me that it wasn’t a problem and I didn’t go to a traditional healer, I only went to the hospital for that.” “I felt like there is a swelling inside…When I arrived [at the hospital], the doctor examined me and told me that the breast doesn’t have threatening symptoms.” “Two participants visited their local healthcare provider and were given acetaminophen tablets for their breast lumps. Others were given antibiotics, further delaying diagnosis.I went to the district hospital and told them. They gave me medications, antibiotics, I took them but the situation didn’t change. It was still painful. I went again after I completed the dose, and they changed the dose they gave me another one.” “At the regional hospital they told me that it was an abscess, and because it didn’t show where it originated from then they decided to give me antibiotics. They gave me the medications, and after sometime I didn’t notice it turning out to be an abscess, so I went to Dodoma.” “Improper management and delay in diagnostic work-up may reflect to lack of knowledge among primary health care providers in the recognition and appropriate evaluation of breast symptoms. Further, most primary health care facilities lack biopsy capabilities, imaging equipment, and pathology services necessary to establish a breast cancer diagnosis. This necessitates referrals to zonal or referral hospitals for a diagnosis to be made. In many cases, participants reported difficulties in obtaining referrals, which further contributed to delays.There is a challenge how to get a referral. I don’t know whether it is that the doctor tried to treat and see what he will achieve but as a patient, you are suffering. You as a patient, you are deteriorating. I prefer if there were enough investigations, many hospitals and specialists, it would be helpful.” “There are areas where the health care providers did wrong…those doctors from the regional hospital, if they know that it is not their field, then they should not tamper with things that could cost somebody’s life, and they should make the referral system more official.” “Some participants faced delays in cancer diagnosis due to first seeking care from a traditional healer. One participant believed she was being bewitched so she went to a traditional healer first. Most who sought traditional medicine for their breast symptoms reported spending more than three months using these alternative treatments. Upon realizing that their symptoms were worsening, they later sought care at a medical facility.I was given local herbs that once I urinate the swelling would go, but there was no response so I went to the hospital and I was told that it is cancer.” “So, there was a medication that I was applying on that area, [and] as I apply it there it continues to dig deeper and deeper. What he was telling me was the way it digs is how it eats away cancer, so let the meat be eaten away okay. So… sometimes I bleed about half a bucket, I get deficit of blood, and it continues that way…Later on I saw that it was abnormal and not good.” “In addition, while some participants benefited from prayers as a source of comfort, others believed they could only be healed by prayers. Thus, they spent significant time with prayers alone until they recognized that the disease was still progressing.I used to go to prayers. I went, I prayed, they prayed for me. The condition was not improving. That is why I decided to come to the hospital.” “Societal stigmatization of cancer led some participants to fear revealing their symptoms to others, contributing to delay in seeking medical care. Others reported fear of physical deformity from surgery, that cancer was an incurable disease, or that going to the hospital was a death sentence.I told the professor, ‘If my breast was cut, I would die. If that is the case, then just leave me to die.” “In the environment that I live, I didn’t want anyone to know that I have the problem. In the end of the day, I think it is what made me delay to come to the hospital…There is no helping rather than laughing at one another. They mostly come and say I have seen so and so, she has this terrible disease that cannot be cured. So, people tell you it is better to have AIDS, you will be cured rather than this disease. There is when you get the fear.” “Relatives and friends had a substantial influence on how participants acted on their breast symptoms. They sometimes advised the participant to wait rather than seek prompt medical attention.I just used to show my close friends, the swelling and all that, they are the ones who advised me that we should observe it first.” “I told my husband, ‘I can feel as if there is a swelling starting here’. I told him, yes. Then he decided to wait a bit, we stayed for around four months.” “Relatives also relayed fears of the hospital to the participant, equating cancer diagnosis and treatment with death.I went home and told my relatives that if I delay it will develop into cancer. My sister, who has studied politics, said no, ‘you shouldn’t be operated to cut the breast because if it’s cut it will spread in the whole-body system’.” “The role of my few relatives is that they were giving me advice, but a few of them told me if I had my breast removed and I would die and they won’t be involved in it.” “Further, some relatives were the main advisors in encouraging participants to first seek traditional healers. Two participants reported consulting with their husbands who did not take their concerns about the symptoms seriously. In addition, participants reported struggling to balance their own welfare with the needs of their family, which led to delays in seeking health care. Participants had to attend to societal and familial obligations, such as organizing a relative’s burial ceremony or taking care of sick family members, prior to attending to their own medical care.In contrast to these many barriers, participants reported far fewer facilitators to timely breast cancer diagnosis. These included family and friends’ encouragement and prior breast cancer knowledge.While sometimes a barrier, in other cases relatives and friends were critical in facilitating and expediting the diagnostic process. Some relatives were the source of financial support for medical care. In other cases, friends and relatives advised that participants seek prompt medical attention and encouraged them throughout the whole process.The ones who pushed me are my brothers. To be honest, after I showed them the swelling and for everyday that the swelling was growing and hardening, my brothers advised me to go to the hospital, and they are the ones who challenged me, and I thank them for where we have reached.” “There was a lump that I was wondering about. I then called my daughter who is a nurse working in Korogwe; I asked her about the lump in my breast. I also told my other daughter who is also a nurse but working in Iringa, she advised to go to the hospital…The relatives are the ones helping me, my kids. They were the ones who were putting pressure on me.” “Two participants were knowledgeable about the signs and symptoms of breast cancer, prompting them to seek diagnostic evaluation. They had received information from television and radio programs. One participant received prior education as part of her maternal health services.I heard about the disease through the radio, RTD station, and I came to hear about it in the year 2009 after being pregnant when I was attending the reproductive health center. They informed us about the disease, so, I was aware with that. They taught us as part of maternal health…So after I noticed the lump, I went to the hospital". “I have heard it on the radio. Whenever I watch the TV I see them announcing that there is breast cancer. They explain explicitly that one can know that they have breast cancer by going to see a doctor so that they get investigated." “Nevertheless, knowledge of breast cancer alone was not sufficient to overcome the other barriers and even these patients experienced delays in diagnosis.This study explored the factors contributing to delayed diagnostic evaluation of symptomatic breast cancer among Tanzanian women. As in most sub-Saharan African countries, population-based mammographic screening programs have not yet been established in Tanzania. Therefore, diagnoses are almost exclusively dependent on the recognition of breast cancer signs and symptoms. It is well established that delay between onset of breast symptoms and the diagnosis of breast cancer is detrimental to survival . This quAt the individual-level, lack of knowledge and misconceptions about the signs and symptoms of breast cancer was a key contributor to delayed diagnosis. All participants admitted to self-detection of a new breast lump or swelling, but most were unaware that the symptom could be due to breast cancer, especially in the absence of associated pain. Some participants reported a misconception that cancer was a communicable disease; since they had no known close contact with a breast cancer patient, they erroneously believed they were unlikely to contract the disease. Most decided to ignore their symptom and did not seek medical attention immediately. This lack of breast cancer awareness has been similarly described in other countries in sub-Saharan Africa, including Rwanda, Kenya, Ethiopia, Ghana, Nigeria, and Malawi –27 as a Our study suggests that development of educational efforts to promote breast cancer awareness should extend beyond the patient level to the health provider level. Several participants reported that when they did seek medical attention for their symptoms, they faced barriers within their local healthcare system. For example, participants received false reassurance from their primary health care provider that their symptom was nothing worrisome. Others were sent home with analgesics or antibiotics. Participants reported difficulties in obtaining referrals from their local providers to higher-level facilities with cancer diagnostic capabilities. Our findings are in keeping with other studies conducted in sub-Saharan Africa which similarly demonstrated health system-related barriers with inappropriate appraisal and management of breast symptoms by local health providers , 26, 29.However, even after referrals were obtained, participants reported financial barriers to prompt diagnostic evaluation. Many described struggles to gather funds for recommended tests, further delaying their diagnosis. In addition to medical costs, participants reported challenges in obtaining money for travel and temporary accommodation near the referral hospitals. It should be noted that most of the Tanzanian community do not have health insurance, necessitating out-of-pocket payments for medical services. As a result, after being referred many had to return home to raise money. The contribution of financial constraints to delayed diagnosis of breast cancer and possibly other cancers is seen in several other low to middle-income countries especially in sub-Saharan Africa , 31. It Sociocultural barriers to timely breast cancer diagnosis included use of alternative treatments rather than medical evaluation. Some participants reported first seeking care with a traditional healer. In Tanzania, such services are often widely available and relatively affordable with promises of immediate relief. In addition, while many participants benefited from prayer and religion as a source of comfort, some believed that their breast symptoms could be healed by prayers alone, further delaying diagnostic medical evaluation. Studies in other sub-Saharan African countries have found that alternative therapies, such as the use of traditional healers, were a common contributor to delayed diagnosis of breast cancer , 27. In Similar to other studies from sub-Saharan Africa, a fatalistic view of cancer, fear of cancer diagnosis, and fear of public stigma were barriers to seeking evaluation and diagnosis , 34, 35.Lastly, we found that the advice and influence of family members and friends played a major impact in participants’ healthcare-seeking behaviors, serving both as facilitators and as barriers to timely cancer diagnosis. Family and friends were often the sole source of social and financial support. Given the impactful role of family and friends, breast cancer awareness and educational strategies should not simply target women at risk of developing breast cancer, but campaigns highlighting the importance of early breast cancer diagnosis should be disseminated to the Tanzanian population as a whole.Limitations of this research should be noted. First, this was a small exploratory study with a sample limited to those receiving care at a national referral hospital in Dar es Salaam, Tanzania. Many Tanzanian women with breast cancer may never reach this national referral hospital due to myriad barriers to breast cancer care; as the city of Dar es Salaam is not easily accessible by the majority rural population of Tanzania, our results may not be generalizable. Thus, this report may reflect some selection bias. In addition, participants were diagnosed months to years prior to being interviewed; therefore, data may be subject to some recall bias, and discussions of historic events may be affected by the current knowledge of their breast cancer diagnosis. For the purposes of this this qualitative study, the primary source of data was from the interviews. Quantitative review of the medical records was not conducted; details of clinical and surgical cancer stage, treatments, and outcomes were not collected. Although the results of this study may not be generalizable to all Tanzanian women, our results were similar to studies carried out in other sub-Saharan African countries and the key findings may be used to improve cancer diagnostic care more broadly.Our study was qualitative, as we aimed to deeply explore the experiences and journeys of Tanzanian women with breast cancer. To our knowledge, while similar studies have been conducted in other countries in sub-Saharan Africa, there is very little research on the causes of delayed diagnosis of breast cancer in Tanzania . The resIn summary, lack of basic knowledge and awareness of breast cancer, fear and stigma, financial barriers, and local healthcare system barriers were common factors which contributed to delayed diagnostic presentation of breast cancer. The influence of friends and family also played key roles as both facilitators and barriers.Our study highlights key areas of focus to guide future research, practice, and policies. We aim to use this information to inform and develop strategies to improve earlier diagnosis of symptomatic breast cancer in Tanzania. Specifically, increasing breast cancer awareness, reducing stigma, and educating individuals on the recognition of breast signs and symptoms, for example through community outreach and educational campaigns, may empower women and their primary healthcare providers to diagnose cancers early and improve survival. In addition, given the strong influence family and friends, these educational and outreach endeavors should target the Tanzanian population as a whole, not just those at risk of developing breast cancer.S1 File(ZIP)Click here for additional data file.


Aims: To analyze the incidence and mortality trends of breast cancer among women in China from 1990 to 2019 and explore the effects of age, period, and cohort on the incidence and mortality of breast cancer. Methods: We performed a Joinpoint regression model to describe trends in breast cancer incidence and mortality. We used an age–period–cohort analysis model to estimate the impact of age, period, and cohort on breast cancer incidence and mortality. We collected breast cancer incidence and mortality among women aged 20–89 in China (1990–2019) from the Global Health Data Exchange (GHDx) database. Results: The crude incidence and mortality of breast cancer from 1990 to 2019 in Chinese women showed an increasing trend, with an average annual increase percentage (AAPC) of 4.69% and 2.18%, respectively. The analysis on the age–period–cohort model revealed that the risk of incidence increased first and then decreased with age and peaked at 55–59 years old, whereas the risk of mortality increased by approximately 60.34 times from 20 to 89 years old. The risk of incidence and mortality increased by 2.64 and 1.49 times with the passage of time, respectively. The later the birth cohort is, the lower the risk of incidence and mortality will be. Conclusion: From 1990 to 2019, the incidence and mortality of breast cancer among Chinese women showed an increasing trend, and the prevention and control situation of breast cancer was still grim. Therefore, visual examination and palpation examination should be actively carried out in adult women with breast cancer, and the conventional population after 40 years of age, the high-risk population carrying hereditary breast cancer gene and the elderly population should be assisted with imaging examination along with palpation examination. When treating patients suffering from breast cancer, in order to reduce the death rate, a personalized treatment plan should be developed based on the characteristics of different patients. Being the most common cancer among women, breast cancer cases have exceeded the number of lung cancer cases worldwide making it the leading type of cancer, with about 2.3 million new cases according to the 2020 Global Burden of Cancer Report released by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO). In 2020, breast cancer caused about 685,000 deaths worldwide, and it dominantly led to the death of females with cancer . From 20http://ghdx.healthdata.org/gbd-results-tool (accessed on 27 March 2022). The data used in this study were the crude incidence and mortality of breast cancer in Chinese women from 1990 to 2019, and the incidence and mortality of the age group 20–89 years old .The data were collected from the Global Health Data Exchange (GHDx), a project organized by the Institute for Health Measurement and Evaluation at the University of Washington . The ChiThe Joinpoint regression model is used in cancer epidemiology to describe the incidence and mortality trends of disease and identify significant turning points by conducting the Monte Carlo test. The Joinpoint regression model can be expressed asy is the incidence or mortality of breast cancer, which is the dependent variable, and x refers to the independent variable and usually represents the year. The constant term in the model is denoted by Here, In this study, the annual percent change (APC) and average annual percent change (AAPC) were used to analyze the incidence and mortality changes of breast cancer during the observation period. APC > 0 means that the incidence or mortality of breast cancer increases with time in the current period; APC < 0 denotes that the incidence or mortality of breast cancer decreases with time in the current period; APC = 0 represents that it does not change with time. Similarly, AAPC > 0 indicates that the incidence or mortality of breast cancer increases over time over the whole period; AAPC < 0 indicates that the incidence or mortality of breast cancer decreases over the whole period; AAPC = APC indicates that the incidence or mortality of breast cancer has a monotonically increasing or decreasing trend. The Joinpoint Regression Program 4.9.0.1 was used for Joinpoint regression analysis.The age–period–cohort model is often used to describe the trend analysis of the incidence and mortality of chronic diseases, which can eliminate or control the interaction between age, cohort, and other factors to a certain extent . The ageHere, In this paper, the endogenous factor method was applied to solve the problem of model unrecognition. This method was proposed by Fu  and YangBased on the endogenous factor method, the ages from 20–24 to 85–89 were divided into 14 age groups with consecutive five years as an age interval. The period from 1990 to 2019 was divided into six periods with five-year intervals. The corresponding 1905–1999 birth cohort was divided into 19 birth cohorts at consecutive five-year intervals.Origin 2018 software was used to build a combined model of age, period, and cohort to fit the incidence and mortality of breast cancer. Stata15.0 software was used for age-age-cohort analysis, Akaike information criterion (AIC), and Bayesian information criterion (BIC) and variance were used to evaluate the degree of data-fitting diagnosis. The test level was 0.05.p < 0.05), followed by 1995 to 2011 when the APC was 5.34% (p < 0.05). The Joinpoint regression analysis on the mortality rate of breast cancer suggested that it experienced five nodes of change between 1990 and 2019. The period of the highest growth rate was same as the incidence rate, and the APC was 3.92% (p < 0.01) during 2016–2019. From 2004 to 2007, the mortality rate of breast cancer increased the least, and the APC was 1.07% (p > 0.05), but the change was not statistically significant.From 1990 to 2019, the incidence and mortality of breast cancer among Chinese women showed an increasing trend, with the crude incidence increasing from 14.14/100,000 in 1990 to 52.81/100,000 in 2019, and the crude mortality increasing from 7.22/100,000 in 1990 to 13.40/100,000 in 2019. The average annual growth rates were 4.69% and 2.18%, respectively. As shown in As can be seen from According to The results of age effect in According to the period effect in From 1905 to 1999, with the passage of birth cohort, the incidence and mortality risk of breast cancer shows a decreasing trend, as shown in From 1990 to 2019, the crude incidence and mortality of breast cancer among women aged 20–89 in China showed an increased trend year by year, and the growth rate of the incidence was higher than the mortality, which confirmed that the current situation of female breast cancer in China was not optimistic, and China should strengthen the prevention and control of breast cancer.From the perspective of age change trend, the incidence of breast cancer first increases and then decreases with the increase of age. Since 2009, the incidence rate of breast cancer in all age groups has increased, which may be related to the fact that more breast cancer cases have been detected since the implementation of the “Rural Women ‘Two Cancers’ Check Project Management Solutions” in 2009. The incidence peak appears in the 65–69 age group, which is about five years earlier than the high incidence rate of breast cancer in American women . Among yIn general, the incidence of breast cancer continues to rise with the passage of time. Since 1999, the incidence has increased significantly, but this change becomes significant only at ages over 50 years, which may be related to the fact that China entered the aging society in 1999, and the aging population increased the number of elderly breast cancer patients. The mortality shows a clear downward trend in the 45–49 age group, which may be attributed to China’s increased breast cancer screening efforts in recent years ,17. TherFrom the trend of birth cohort, the incidence, and mortality of young people in the birth cohort close to modern times are lower, whereas the morbidity and mortality of elderly people in the older birth cohort are higher, which is caused by the relationship between the birth cohort and period and age, so the age–period–cohort model is needed for further analysis.The age–period–cohort trend of the incidence and mortality of breast cancer in Chinese females cannot eliminate the interaction among the three factors. In order to explore the independent effects of age, period, and cohort, it is necessary to use the age–period–cohort model for further analysis. The analysis results of the age–period–cohort model proved that in the age effect, the risk of breast cancer increases first and then decreases with the increase of age and reaches the peak in the 55–64 age group, which is similar to the results of other studies ,21,22. WThere are some strengths and limitations in the present study. The strengths of this study are, first, the use of a large time span—nearly three decades of data—from the GBD database from 1990 to 2019. Secondly, the age range of the study population is 20 to 89-year-old Chinese women, which covers a wide range. Then, it used the age–period–cohort model to analyze the individual effects of age, period, and cohort, which makes up for the traditional descriptive analysis methods that cannot accurately reflect the impact of age, period, and cohort on incidence and mortality. The limitations of this study are first due to the limited nature of the data, which did not pay attention to the differences in incidence and mortality in different regions of China, as well as the differences in diagnosis and treatment caused by different levels of medical care. Secondly, it is difficult to completely avoid data inaccuracies due to data integrity and quality issues.In conclusion, the incidence and mortality of breast cancer in China show an upward trend, and the prevention and control situation remains grim. We should strengthen the prevention and control of breast cancer in China, and call for women to accept regular breast palpation and visual examinations as soon as they become adults. Most importantly, it is recommended that the conventional population (after reaching 40 years of age) the high-risk population carrying hereditary breast cancer genes, and the elderly population should be combined with imageological examinations. At the same time, we should popularize the knowledge of breast cancer and improve the awareness of all women with regard to breast cancer prevention. For the treatment of breast cancer patients, in order to prolong the life of breast cancer patients and improve the quality of life, it is necessary to formulate personalized treatment plans based on the type of breast cancer, the health status of patients, and their own needs. In short, the disease burden of females with breast cancer in China is a major problem that needs to be solved now and in the future.


BRCA1/2 testing criteria according to the guidelines. Transition probabilities were calculated based on real-world data of women tested for BRCA1/2 germline mutations in a cancer reference hospital from 2011 to 2020. We analyzed 275 BRCA mutated index cases and 356 BRCA mutation carriers that were first- or second-degree relatives of the patients. Costs were based on the Brazilian public health system reimbursement values. Health state utilities were retrieved from literature. The BRCA1/2 genetic test and preventive strategies result in more quality-adjusted life years (QALYs) and costs with an incremental cost-effectiveness ratio of R$ 11,900.31 /QALY. This result can represent a strong argument in favor of implementing genetic testing strategies for high-risk women even in countries with upper-middle income, considering not only the cancer prevention possibilities associated with the genetic testing but also its cost-effectiveness to the health system. These strategies are cost-effective, considering a willingness-to-pay threshold of R$ 25,000 /QALY, indicating that the government should consider offering them for women at high risk for HBOC. The results were robust in deterministic and probabilistic sensitivity analyses.Although BRCA1/2 genetic testing in developed countries is part of the reality for high-risk patients for hereditary breast and ovarian cancer (HBOC), the same is not true for upper-middle-income countries. For that reason, this study aimed to evaluate whether the BRCA1/2 genetic test and preventive strategies for women at high risk for HBOC are cost-effective compared to not performing these strategies in an upper-middle-income country. Adopting a payer perspective, a Markov model with a time horizon of 70 years was built to delineate the health states for a cohort of healthy women aged 30 years that fulfilled the  Breast cancer is the most common cancer worldwide and the leading cause of cancer death among women, with globally more than 2.6 million new cases and almost 700,000 deaths annually . DespiteBRCA1 and BRCA2 still account for most cases (BRCA1 mutation carriers and 69% (for breast cancer) and 17% (for ovarian cancer) for those with BRCA2 pathogenic alterations  in the last years, st cases . Pathogeerations –7.Women with personal and/or family history suggestive of HBOC should be referred for genetic counselling and genetic testing to investigate for the presence of pathogenic germline variants . BesidesBRCA1/2 genetic testing followed by preventive strategies for women at high risk for HBOC is cost-effective when compared to no genetic testing  in the context of the public health system of an upper middle-income country with continental dimensions as Brazil.Several studies on the cost-effectiveness analysis of genetic testing have been performed worldwide. Although previous economic modeling studies indicate that it is cost-effective to provide population-based genetic tests –19, the BRCA1/2 testing and preventive strategies for healthy women at high risk for HBOC are cost-effective compared to standard care (no testing and no preventive strategies). Using the TreeAge Pro, the model estimates the costs and benefits, and the latter is expressed as quality-adjusted life years (QALYs) and life years gained (LYG), highly used in cost-effectiveness studies. To reflect the long-term consequences of breast and ovarian cancer, the model had a 1-year cycle length and time horizon of 70 years (lifetime). The analysis was conducted from the perspective of the SUS as the payer. In line with recommendations from the Brazilian guideline for economic evaluations, costs and effects were discounted at 5%  clinical criteria for BRCA testing  recommended by the National Comprehensive Cancer Network (NCCN) guideline  intensified surveillance with MRI and bilateral mammography annually and breast specialist consultation, CA 125 exam, and transvaginal ultrasonography biannually; (ii) salpingo-oophorectomy; (iii) bilateral mastectomy; or (iv) both salpingo-oophorectomy and bilateral mastectomy (BRCA testing) were treated in consonance with the SUS standard care according to their age . The compared strategies consisted of carrying out the genetic counselling and uideline . Women istectomy –11. WomeThe Markov model structure comprises the states “well,” “non-metastatic breast cancer,” “metastatic breast cancer,” “ovarian cancer,” “post breast cancer,” “post ovarian cancer,” and “death” (absorbing state) Figure 2Women in the model started in the state well and could go to the states breast or ovarian cancer or die. From breast cancer, they could either stay there, go to post breast cancer, or develop metastatic breast cancer, or ovarian cancer. Women with contralateral breast cancer returned to the initial breast cancer state. The transition from ovarian to breast cancer was not included due to the low incidence of ovarian cancer and its high mortality rates .These states reflect possible clinical events for high-risk women for HBOC. The well state comprises women not diagnosed with cancer; the non-metastatic breast cancer state includes women in the first year after the diagnosis of first or contralateral breast cancer. The metastatic breast cancer state comprehends the first year of diagnosis of disseminated neoplastic cells in an organ distinct from the breast. Likewise, the ovarian cancer state includes women in the first year of diagnosis. Post-cancer states were modeled using tunnel states to reflect annual follow-up costs, utilities, and probabilities after cancer diagnosis until year 5. From the sixth year on, the patients stay in the post-cancer state unless other events occur. The ovarian cancer state was not separated between non-metastatic and metastatic due to its high risk of mortality which is caused by the difficulty to obtain an early detection of the disease .BRCA genetic test is not offered by hospitals operating in the Brazilian public health system, but the BCH can provide the test for its patients due to funds from donations obtained  dataset Table 1.obtained .The probabilities that could not be retrieved from the BCH dataset were taken preferably from sources that reflected the Brazilian population, e.g., the National Cancer Institute of Brazil (INCA), Brazilian Geography and Statistics Institute (IBGE), and the WHO. The specific references are provided in BRCA carriers from the state “well” to “cancer” only for those not submitted to prophylactic surgeries.In the BHC dataset, data were available for 2,307 women who performed BRCA1/2 genetic testing from 2011 to 2020. There were 1,544 index cases — among which there were 275 carriers and 1,269 non-carriers—and 763 first- or second-degree relatives . Using Kaplan–Meier in the SPSS software, the transition probabilities were calculated. We defined a different group eligible at baseline for each of the transition probabilities calculated to avoid selection bias regarding a previous cancer diagnosis. Briefly, we considered data from first- or second-degree relatives identified to be carriers to calculate the probability of opting for a prophylactic surgery and the respective risk of developing breast or ovarian cancer afterward. Then, we considered data from index cases to calculate transition probabilities for As BCH is a reference cancer center for women at high risk, women who tested negative were not followed up at BCH but referred back to the system for general population screening according to their ages, considering that women who tested negative have been shown to have the same risk as the general population –16. ThusBRCA non-carriers in Brazil are not available, we used the cumulative 10-year risk of secondary contralateral breast cancer for German non-carriers . The unit cost values for 2021 were obtained from the official SUS database, namely, the Table of Procedures, Medications and Ortheses, Prostheses, and Special Materials for the National Health System (DATASUS Tabnet). Resource use  was estimated based on recommendations from the NCCN guidelines and interviews with one oncologist and one gynecologist. The cost of breast cancer treatment was calculated as a weighted average that considered cancer molecular type and stage at BCH cohort, indicating a higher proportion of breast cancer diagnosis in the early stage for first- or second-degree relative women than index women  first- or second-degree relative women, that is, the BRCA-mutated women who had cancer after the test.Considering that the cost of treatment is potentially lower for breast cancer diagnosed at early stages, the annual mean cost was calculated for these two subgroups from the BCH dataset: (i) index women, that is, The cost of the genetic test refers to the price paid by the BCH Table 2 To validate the model, we consulted experts on the adequacy of input data and the conceptual appropriateness of the model. Technical accuracy was checked regarding data entry and potential programming errors . For cross-model validation, we assessed the extent to which other models for breast cancer prevention came to different conclusions . We perfBRCA testing strategy cost R$ 5,298  in the base-case scenario, resulting in an incremental cost of R$ 1,796 (U$ 830.71) compared with the non-testing strategy. Accordingly, women offered the genetic test had an incremental gain of 0.2 QALYs and 0.2 LYG. The incremental cost-effectiveness ratio (ICER) for the base-case analysis was R$ 11,900.31  per QALY and 10,988.67 (U$ 5082.64) per LYG.The genetic counseling and In the Brazilian scenario, an exact value of the cost-effectiveness threshold to be applied by the National Commission for the Incorporation of Technologies (CONITEC) in the SUS was not defined . HoweverIn the deterministic sensitivity analysis, the variables with the largest impact on the ICER were the discount rate, probability of moving from well to breast cancer after both risk-reducing surgeries, cost of the genetic test, probability from well to breast cancer after salpingo-oophorectomy, and breast cancer treatment costs. A discount rate of zero would reduce the ICER to R$ 3,336.10/QALY , and a discount rate of 10% would increase the ICER to R$ 31,617.71/QALY . In a scenario where the probability of moving from well to breast cancer after both risk-reducing surgeries is higher (0.08), the ICER increases to R$ 36,362.66/QALY . Moreover, in the scenario that only one first- or second-degree relative woman could be tested per index woman tested instead of two, the costs of a genetic test would increase to R$ 2,035.00 (U$941.26/QALY), increasing the ICER to R$ 17,862.54/QALY (U$ 8262.04/QALY), whereas, if the costs of a genetic test per woman decreased to R$ 685 (U$ 316.84) due to testing four relatives per index woman, the ICER would decrease to R$ 8,919.19/QALY (U$ 4125.43/QALY).The cost-effectiveness ratio was also sensitive to the probability of moving from well to ovarian cancer after salpingo-oophorectomy; if this probability was higher (0.03), the ICER would increase to R$ 16,766.88, while if it was smaller (0.004), the ICER would decrease to R$ 10,179.45. Regarding the breast cancer treatment cost for non-tested women, assuming a 40% higher cost of breast cancer treatment for the non-testing group, the ICER would decrease to R$ 10,630.77/QALY . However, if the breast cancer treatment for this group was 40% lower, the ICER would increase to R$ 17,813.11/QALY .The tornado diagram indicates that for almost all intervals considered in the analysis, the testing strategy is considered cost-effective when compared to the no testing strategy Figure 3The cost-effectiveness acceptability curve showed a probability of genetic testing being cost-effective of 68.03% at a willingness to pay (WTP) of R$ 25,000/QALY  Figure 5BRCA1/2 genetic tests, and preventive options in women at high risk for HBOC is a very cost-effective intervention compared to not carrying out these actions when considering a willingness to pay of R$ 25,000/QALY. The ICER for the base-case analysis was R$ 11,900.31 . The sensitivity analysis also revealed a superiority of the testing strategy. The tornado diagram points out that genetic testing is cost-effective for all scenarios. The probabilistic sensitivity analysis indicates a probability of genetic testing being cost-effective of 68.03%.While perceived by the upper-middle-income countries’ government as a potentially highly costly intervention, as our results show, carrying out the genetic counseling, BRCA, rates of uptake prophylactic procedures, breast or ovarian cancer development, etc.). It shows that genetic testing can be cost-effective even in upper-middle-income countries. The use of patients’ clinical data increases the representativeness of the results of our analysis for Brazilian women. This real-world evidence provides a more accurate representation of the target population for several reasons. First, the penetrance of BRCA is highly associated with the genetic profile of the population, and the Latin-American population is underrepresented in most international registries and databases. Second, rates of uptake prophylactic procedures vary widely worldwide since these are highly preference-sensitive decisions influenced by sociocultural factors. Therefore, our results add to the existing literature by demonstrating the cost-effectiveness of BRCA in a model that accurately reflects the epidemiology and the preferences of Latin-American women (from Brazil) at-risk for hereditary breast cancer.The main novelty of our results is that this is the first study for upper-middle-income countries on BRCA genetic tests whose probabilities were mainly extracted from trial-based analysis with Brazilian registries  had a similar structure. However, the data were extracted exclusively from the literature. For instance, the uptake rates taken from a UK cohort were 0.09 for prophylactic mastectomy and 0.22 for prophylactic salpingo-oophorectomy. In contrast, the uptake rates identified in our study were 0.03 and 0.12, respectively. These data demonstrate huge differences when considering real-world data from the Brazilian population. According to a recent systematic review by , the varRamos et al. (2019) evaluated the preventive strategies only for the relatives of patients diagnosed with ovarian cancer, while the present study analyzed preventive strategies for first- or second-degree relatives of patients diagnosed with breast or ovarian cancer. Finally, the study by  differs BRCA genetic test. Considering that breast or ovarian cancer risk among non-carrier women from positive families is similar to the general population , while the cost of testing a relative of the patient is R$ 235 (U$ 108). Thus, the average unit cost of testing a family member is calculated at R$ 1135 (U$ 525). However, if we consider that it is possible to test a higher number of family members for each index tested, the unit cost of testing a family member would be reduced, making the genetic testing strategy even more cost-effective, as its ICER would be reduced.The main strength of the present study was to conduct a trial-based analysis to obtain transition probabilities from the data of women tested from 2011 to 2020 in a Brazilian hospital. Another advantage was the cost data analysis. The unit cost values were obtained from the official Brazilian Health System database. Concerning breast cancer treatment, the costs were calculated separately for molecular types  and stages , 48 to rBRCA non-carriers had to be taken from the literature because those patients were not followed up at the BCH. In addition, because of the sample size of the BCH database, the transition probabilities calculated in the present study might not generalize to the entire Brazilian population. Another limitation of the model is the unknown risk of BRCA-negative women with a family history of cancer compared with cancer risks observed in the general population. It was considered that non-carriers of genetic mutations that came from positive families did not show an increased risk for HBOC  per QALY gained. The cost-effectiveness of the screen-and-treat intervention depends on a still undecided cost-effectiveness threshold for Brazil, but it would be cost-effective considering a willingness to pay of R$ 25,000  per QALY. These results might be reproducible in other upper middle-income countries.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Barretos Cancer Hospital’s research ethical committee . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Conceptualization, ML and EP. Methodology, ML, JC-G, AA, OM and EP. Software, ML and JC-G. Validation, ML, JC-G and OM. Formal analysis, ML. Investigation, ML and HG. Resources, HG and EP. Data curation, ML. Writing—original draft preparation, ML and RG. Writing—review and editing, EP, JO, JC-G, OM, RR, AC and EM. Visualization, ML. Supervision, EP. Project administration, EP. Funding acquisition, EP. All authors have read and agreed to the published version of the manuscript.This project was funded through grants from the National Oncology Care Support Program  from the Brazilian Ministry of Health. EIP and RMR are recipients of the National Council for Scientific and Technological Development (CNPq) productivity fellowships. The study sponsors had no involvement in the study design, collection, analyses or interpretation of data.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The reviewer MD declared a shared affiliation, with no collaboration, with the authors ML and JO to the handling editor at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Breast cancer is now the commonest cancer in most sub-Saharan African countries. Few studies of the epidemiology and genomics of breast cancer and its molecular subtypes in these countries have been done. The African Female Breast Cancer Epidemiology (AFBRECANE) study, a part of the Human Heredity and Health in Africa (H3Africa) initiative, is designed to study the genomics and epidemiology of breast cancer and its molecular subtypes in Nigerian women. We link recruitment of breast cancer cases at study sites with population-based cancer registries activities to enable ascertainment of the incidence of breast cancer and its molecular subtypes. We use centralized laboratory processing to characterize the histopathological and molecular diagnosis of breast cancer and its subtypes using multiple technologies. By combining genome-wide association study (GWAS) data from this study with that generated from 12,000 women participating in our prospective cohort study of cervical cancer, we conduct GWAS of breast cancer in an entirely indigenous African population. We test associations between dietary intakes and breast cancer and focus on vitamin D which we measure using dietary intakes, serum vitamin D, and Mendelian randomization. This paper describes the AFBRECANE project, its design, objectives and anticipated contributions to knowledge and understanding of breast cancer. While the incidence of breast cancer has stabilized in high-income countries (HIC), it is rising in low income countries (LIC) that hitherto had low incidence . The WHOIn contrast to developed countries, there has been few systematic studies of breast cancer in sub-Saharan Africa. Studying the epidemiology and genomics of breast in developing countries like Nigeria will enable identification of critical environmental and genetic risk factors and improve our knowledge of the causes of its rising incidence. The AFBRECANE study is funded by the Office of the Director of the US National Institutes of Health (NIH) and the National Human Genome Research Institute (NHGRI) under the Human Heredity and Health in Africa (H3Africa) initiative for five years starting in November 2018. The project is designed to study the genetic and environmental risk factors of breast cancer and its subtypes in an indigenous African population.The primary objectives of the AFBRECANE study are to determine the incidence and prevalence of total and molecular subtypes of breast cancer in Nigerian women and to characterize their secular trend in Nigeria. We achieve this through combination of case-control and cancer registration research methods through enrollment at our study sites and linkage with the Population Based Cancer Registries (PBCR) in the cities where participants are being enrolled in Nigeria. In this study, we link epidemiological risk factors’ data, cancer registry databases, clinical information and biorepository of tissues for breast cancer research in Nigeria. We engage multiple methods for determination of molecular subtypes of breast cancer in tissue biopsies and fine needle aspirates and evaluate determinants of discordance between the different methods.Another objective of the AFBRECANE project is to conduct GWAS of breast cancer and its molecular subtypes to look for mutations associated with breast cancer and its subtypes in indigenous African populations. In order to efficiently achieve this objective, the project takes advantage of the GWAS data from H3Africa funded African Collaborative Center for Microbiome and Genomics Research (ACCME) project which enrolled women who volunteered for cervical cancer screening and were free of cancer at baseline. The use of an enriched microarray chip designed by the H3Africa Consortium for this GWAS study promises to increase the likelihood of detecting new variants that are significantly associated with breast cancer in this African population. We will use Mendelian Randomization to test associations between SNPs associated with serum vitamin D and breast cancer in Nigerian women.The third objective of the AFBRECANE project is to evaluate associations between Nigerian diets and their food and nutrients composition, and breast cancer. Using our validated Food frequency questionnaire (FFQ), Food composition database (FCD), and Food picture book (FPB), we characterize the dietary intakes of our participants. Further, we specifically examine dietary and serum levels of vitamin of D, as well as use Mendelian Randomization (MR) of SNPs associated with serum levels of vitamin D, and risk of breast cancer in this population in Africa.In the AFBRECANE project, we establish clinical research sites in 3 cities in Nigeria and link these sites with the population-based cancer registries (PBCR) covering the population in these cities. This enables us to use cancer registration methods to ascertain the incidence of breast cancer and its molecular subtypes in this population. Further by enrolling population based controls, we evaluate the role of demographics, lifestyle, and diet in the epidemiology of incident breast cancer and its subtypes in Nigerian women –19.Several studies have reported that the growth in incidence of breast cancer in developed countries was largely due to increases in incidence of Luminal types A and B (hormone receptors rich) breast cancers, while the incidence of other subtypes including triple negative breast cancer (TNBC) remained stable , 20. In The growing adoption of western lifestyles including dietary patterns has been touted as one of the risk factors for the rising incidence of breast cancer in African populations , 23–26. Studies from developed high-income countries have suggested that there are strong associations between dietary intake of vitamin D or serum levels of vitamin D and breast cancer risk and outcomes –34. ThisIn addition to evaluating associations between vitamin D levels derived from nutrient levels in dietary intakes and serum vitamin D measurements, we also evaluate the association between vitamin D and breast cancer risk by Mendelian Randomization using a combination of SNPs as instrumental variables (IV). This overcomes the problems of reverse causation and confounders in assessing any causal relationships between vitamin D and breast cancer risk –51. 1,25Previous studies have described associations between some SNPs and breast cancer in African populations. Some of these SNPs have been reported in non-African ancestry populations while others appear to be specific to Africans . AlthougThe cases in this study are women aged 18 years and older with clinical and histological diagnosis of breast cancer. A total of 1000 cases will be enrolled over five years from clinical sites across Nigeria. Enrollment commenced in November 2018 at National Hospital Abuja and University of Abuja Teaching Hospital Gwagwalada in central Nigeria, University College Hospital Ibadan in Western Nigeria and University of Nigeria Teaching Hospital, Enugu in Eastern Nigeria. The sites were selected based on their case volume, representation of different geographical zones of Nigeria as well as availability of population-based cancer registries in those areas. For the GWAS component of this study, control participants are the ~12,000 women who are enrolled in the ACCME cohort study. These women had no history of any cancer at enrollment, were HIV negative by self-report and had given broad informed consent for future unspecified use genomic research. The profile of participants in the ACCME cohort has been previously described . To geneBreast cancer cases are followed up at regular clinic appointments after enrollment until end of study or loss to follow-up. Participants data are stored in REDCap database with paper forms for back-up. The contact details of participants and their next of kin are collected and used for following up. Patients are required to inform the next of kin of their participation in this study and obtain consent of the next of kin so they can be contacted if we cannot reach the participant.® open source software is used to check the data and analyze the registries data.Research associates administer the AFBRECANE study questionnaire earlier developed for breast cancer studies in the Nigerian population. Data collected include socio-demographic data, lifestyle data, dietary intakes data, medical history, obstetrics, and gynecology history of participants , 83. The® Tissue Fixative which ensures rapid penetration and fixation in 2 to 4 hours. The warm ischaemic time is recorded. The sample is inserted into PAXgene® Tissue Stabilizer to stabilize molecular contents and preserve morphology. A second sample are stored in -80°C. All samples were transported to the ACCME Laboratory at the Institute of Human Virology of Nigeria (IHVN), Abuja, Nigeria where two sets of slides are prepared.The breast cancer cases are staged using the American Joint Committee of Cancer’s classification of Tumor, Node and Metastasis (TNM). All the patients receive clinical examination of the breasts, chest x-rays, abdominal ultrasound, and bone scans. Breast biopsies are done using core biopsy needles, excisional or incisional biopsies as indicated. One breast tumor sample is inserted into PAXgeneESR1, PGR1, ERBB2, and MKi67 messenger RNAs (mRNAs), and one reference gene (CYFIP1) /College of American Pathologists (CAP). Scores of 0, 1, 2, 3 are assigned to the tumors based on the intensity of staining. Additional molecular subtyping of the breast tumors is also done using RT-PCR methods to measure four breast somatic biomarkers, (CYFIP1) . The res® in the ACCME Laboratory in Nigeria. Plasma samples are used for standard chemistry, trace metals, lipids, and biomarkers, and blood clots are used for analysis of fatty acids. Blood samples are collected from the study participants and separated into plasma, buffy coat, and blot clots which are stored -80°C. Germline DNA were extracted from the buffy coat using Qiagen Qiacube HT® tissue system for collection, handling, transport, and fixation of breast cancer samples reduces pre-analytic variation in tissue handling  More information on the data access protocol can be obtained at the H3Africa data archive @ https://www.h3abionet.org/resources/h3africa-archive. Specific inquiries and proposals for collaboration can be directed to the PI of the project. (cadebamowo@som.umaryland.edu).The project data release plan will be in accordance with the H3Africa data storage and release policy . Access 1. Oge Ikwueme2. Ayotunde Famooto3. Tolu Gbolahan4. Mary Ajayi5. Mary-Favour Edet6. Ayobami Ademola7. Yinka Owoade8. Faithful Nze9. Temitayo Oladimeji10. Robinson Ugwu11. Mr. Agbalu Ifeanyi Sebastian12. Temilola Yusuf13. Tobi Oyediran14. Adeola Akintola15. Temitope Olayinka16. Julius Adediji17. Chibuzor Nkwodimmah18. Bisola Famooto19. Banke Ipadeola1. Prof. Emmanuel Ezeome2. Prof. King-David Terna Yawe3. Dr. Badejo Olawale Ayodele4. Dr. Abike Fowotade5. Dr. Omobolaji. O. Ayandipo6. Dr. Gabriel Ogun7. Dr. Izuu Achuzi1. Dr. Festus Igbinoba2. Dr. Theresa Otu3. Prof. Emmanuel Ezeome1. Chinyere Chukwubuike2. Henry M. Kumai3. Ann OkoroaforThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by: 1. Institutional Review Board, University of Maryland School of Medicine, Baltimore; 2. National Health Research Ethics Committee of Nigeria, Federal Ministry of Health, Nigeria. The patients/participants provided their written informed consent to participate in this study.Conceptualization: CA, AFBRECANE Research group. Data curation: EE, K-DY, OA, OB, BA, AF, GO, CA, AFBRECANE Research group. Formal analysis: EE, SA, and CA. Funding acquisition: EE, K-DY, MA, OB, SA, and CA. Methodology: EE, K-DY, OA, OB, SA, BA, AF, GO, CA, AFBRECANE Research group. Project administration: EE, K-DY, MA, AF, and CA. Visualization: EE, K-DY, OA, OB, SA, BA, AF, GO, and CA. Writing–original draft: EE, SA, and CA. All authors contributed to the article and approved the submitted version.The project is supported by the African Female Breast Cancer Epidemiology  and the African Collaborative Center for Microbiome and Genomics Research (ACCME U54HG006947) grants from the National Institute of Health Office of the Director/National Human Genome Research Institute. Additional support was received from the Maryland Department of Health’s Cigarette Restitution Fund, the University of Maryland School of Medicine Greenebaum Comprehensive Cancer Center Support Grant , and the American Cancer Society Institutional Research Grant (IRG-18-160-16).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


AGER gene were dose-dependently correlated with sRAGE levels. Further, compared to the haplotype CT at the lowest quartile of AGEs, haplotypes TT and TA were prominently associated with breast cancer risk in the highest quartile of AGEs. This study emphasized the potential of the AGE-RAGE axis as a new biomarker of breast cancer in the future and aided in screening a high-risk population with breast cancer.The large-scale population-based evidence exploring genetically modified circulating levels of advanced glycation end-products (AGEs) and their receptor (RAGE) with risk and mortality of breast cancer is scarce. We aimed to evaluate the role of plasma AGEs, soluble RAGE (sRAGE), and AGEs/sRAGE-ratio level, as well as their interactions with a genetic predisposition in their metabolism-related genes on breast cancer. Higher levels of AGEs and AGEs/sRAGE-ratio were associated with an increased risk of breast cancer, but sRAGE levels were negatively associated with breast cancer risk. We also observed a positive association between AGEs and the bad prognosis of breast cancer. Although we did not observe a significant contribution of genetic variants to breast cancer risk, rs2070600 and rs1800624 in the AGER gene were dose-dependently correlated with sRAGE levels. Further, compared to the haplotype CT at the lowest quartile of AGEs, haplotypes TT and TA were prominently associated with breast cancer risk in the highest quartile of AGEs. This study depicted a significant association between circulating levels of AGEs-RAGE axis and breast cancer risk and mortality and revealed the potential of plasma AGEs, especially coupled with AGER polymorphism as biomarkers of breast cancer.The interaction of advanced glycation end-products (AGEs) with their receptor (RAGE) elicits oxidative stress and inflammation, which is involved in the development of breast cancer. However, large-scale population-based evidence exploring genetically modified circulating levels of AGEs-RAGE axis with risk and mortality of breast cancer is scarce. We recruited 1051 pairs of age-matched breast cancers and controls and measured plasma AGEs and sRAGE concentrations by enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression and Cox proportional hazard model were used to calculate the effects of plasma levels and genetic variants of the AGEs-RAGE axis and their combined effects on breast cancer risk and prognosis, respectively. Furthermore, linear regression was performed to assess the modifications in plasma AGEs/sRAGE levels by genetic predisposition. Higher levels of AGEs and AGEs/sRAGE-ratio were associated with an increased risk of breast cancer, but sRAGE levels were negatively associated with breast cancer risk, especially in women <60 years. We also observed a positive association between AGEs and the bad prognosis of breast cancer. Although we did not observe a significant contribution of genetic variants to breast cancer risk, rs2070600 and rs1800624 in the  Breast cancer is a serious threat to global women’s health. In 2020, there were around 2.26 million new cases and 680 thousand new deaths of breast cancer worldwide . Many stAGER gene encoding RAGE, have been found to be associated with multiple chronic diseases , and categorical variables were expressed as quantity and percentage. Quantitative variables were compared by Student’s P value of interaction in subgroup analysis was estimated by a multivariable logistic regression model. Based on Schoenfeld residual analysis, the proportional risk assumption was satisfied. The Kaplan--Meier method and multivariate Cox proportional hazards model were used to explore the relationship between the AGEs-RAGE axis and breast cancer prognosis, and results showed hazard ratios (HRs) and 95% CIs.Multivariate logistic regression analysis was applied to examine odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association of AGEs, sRAGE, AGEs/sRAGE-ratio with risks of breast cancer, and different molecular subtypes of breast cancer. The AGEs, sRAGE, and AGEs/sRAGE-ratio were analyzed both as a categorical variable in quartiles  and as a continuous variable, divided by its SD. The receiver operating curve (ROC), area under the curve (AUC), net reclassification improvements (NRI), and integrated discrimination improvement (IDI) were used to assess the ability of AGEs-RAGE axis and traditional risk factors to distinguish subjects with or without breast cancer. The nonlinear associations of the AGEs-RAGE axis with the risk of breast cancer were presented by using the restricted cubic spline (RCS) model. Subgroup analyses were performed according to body mass index (BMI), menopausal status, and age group, and the Finally, the distribution of observed and anticipated genotype frequencies was compared using a Chi-squared test to investigate whether the genotype was in Hardy-Weinberg equilibrium. The distribution of AGEs and sRAGE by SNPs genotypes was observed in case-control, then we performed linear regression to explore the influence of SNPs on AGEs or sRAGE levels. To evaluate the joint effects of the SNPs associated with AGEs or sRAGE levels, haplotypes were constructed using Shapeit2. We used multivariable logistic regression and Cox proportional hazard model to assess the impact of the genotypes and interaction of haplotypes with AGEs on breast cancer risk and prognosis.http://www.r-project.org, accessed on 1 June 2022, version 4.0.2). A level of <0.05 for two-sided p values was considered statistically significant.All analyses were performed using SAS version 9.4  and R software , which increased with higher concentrations of AGEs and AGEs/RAGE-ratios, with the risk reaching plateaus at 7.1 ng/mL of AGEs. On the contrary, higher sRAGE was linearly associated with a substantially decreased risk of breast cancer (Pnonlinear = 0.114).We used RCS to flexibly model and visualize the relation of AGEs and sRAGE with breast cancer B–D and oWe further compared the ability of the AGEs-RAGE axis to distinguish patients and controls. AGEs, sRAGE, and AGEs/sRAGE-ratio were used as predictors with an AUC of 0.672, 0.607, and 0.697, respectively . In addip = 0.070). After stratifying by age, we could observe that the effects of AGEs, sRAGE, and AGEs/sRAGE-ratio in women younger than 60 were significantly greater than those older than 60, and there was a significant interaction between sRAGE and age group (p = 0.019).Subgroup analyses were conducted according to BMI, menopausal status, and age group . The effp = 0.028). Compared with the first quartile, estradiol (E2) and luteinizing hormone (LH) concentrations increased in all the higher quartiles of AGEs (p = 0.025) and sRAGE (p = 0.001), respectively. The subsequent correlation analysis demonstrated that follicle-stimulating hormone (FSH) was negatively correlated with AGEs, while E2 and LH were positively correlated with AGEs and sRAGE, respectively (The distributions of AGEs and sRAGE quartiles in tumor node metastasis (TNM) stage, subtypes of breast cancer, and breast densities were not significantly diverse . Howeverectively .p = 0.027; p values > 0.05, Compared with the Q1 of AGEs, the Q3 and Q4 increased all-cause mortality of breast cancer  and control group . Weak linkage disequilibrium between these two AGER SNPs was observed , and we subsequently conducted haplotype analysis to better understand their roles. All the AGER haplotypes were not associated with breast cancer risk, except that haplotype CA was associated with a reduced risk of all-cause mortality when haplotype CT was used as the reference  at Q1 of AGEs, haplotypes CT, CA, TT, and TA at Q3 and Q4 of AGEs were significantly associated with increased breast cancer risk gradually, particularly haplotype TA and TT at Q4 of AGEs  ,10,11. TRAGE, a multi-ligand cell surface protein receptor belonging to the immunoglobulin superfamily, can recognize and bind to AGEs, contributing to the activation of key signaling pathways ,12,27. TWe did not observe a connection between AGEs-RAGE axis-related SNPs and breast cancer risk, consistent with a previous genotyping study of RAGE gene polymorphisms in the Han Chinese population in Northeast China , except There are several strengths in the present study. Firstly, this was the first and largest study to comprehensively evaluate the potential role of the AGEs-RAGE axis in breast cancer. Secondly, we investigated the interaction between AGEs-RAGE axis receptor-related SNPs and AGEs levels in a Chinese population in the development of breast cancer. However, several limitations of this study merited special consideration. Our study had the inherent limitations of a case-control study, such as recall bias and selection bias. Second, the primary population studied in this study was citizens of Tianjin (a Northern City in China), which may not be representative of the entire Chinese population, and a validation cohort was lacking. Finally, the study may be underpowered to demonstrate the effect of genetic variation in AGEs-RAGE axis receptor-related genes in the development of breast cancer due to the relatively smaller sample size for genetic analysis.In conclusion, our findings provided the first comprehensive depiction of a significant association between plasma levels of the AGEs-RAGE axis and breast cancer risk in a Chinese population, especially in women aged <60 years which requires special attention. Higher levels of AGEs had a significantly positive effect on breast cancer risk in the population carrying haplotypes TA and TT (SNPs rs2070600 and rs1800624). Therefore, this study emphasized the potential of the AGE-RAGE axis as a new biomarker of breast cancer in the future and aided in screening a high-risk population with breast cancer.


This study aimed to investigate the influencing factors of breast cancer recurrence by comparing the risk factors and lifestyle patterns related to breast cancer in Korean women with and without recurrence.This cross-sectional survey comprised 241 Korean women diagnosed with breast cancer who had received follow-up treatment. Participants were recruited from a university hospital in Seoul and an online social media platform for breast cancer patients. Data were collected either via online or a paper survey, using a structured questionnaire that included general and disease-related characteristics and lifestyle behaviors. Data were analyzed using descriptive statistics, univariate analysis, and logistic regression.p=.010), fewer green/yellow vegetables , drinking behavior , and a lower level of recovery from fatigue after sleep .Recurrence of breast cancer was influenced by four factors; childbirth experience, consumption of green/yellow vegetables, drinking behavior, and recovery from fatigue after sleep.Prevalence of recurrent breast cancer was associated with no childbirth experience (OR=2.29, Aside from having experienced childbirth, this study identified several modifiable factors that influence breast cancer recurrence. Increasing green/yellow vegetable intake, alleviating fatigue, and reducing alcohol intake are important. Intervention strategies in clinical research and practice can be applied to address risk factors and reduce the prevalence of recurrent breast cancer. According to the National Cancer Registry in South Korea (hereafter Korea), the life expectancy of the general population in Korea is approximately 83 years, with an estimated 34.2% lifetime incidence of cancer in the female population . Breast The 5-year relative survival of patients with breast cancer in Korea increased from 79.2% between 1993 and 1995 to 93.3% between 2014 and 2018 [Determining causative factors of breast cancer remains unclear, but a variety of factors, such as personal characteristics and lifestyle patterns, have been reported in previous studies. These risk factors include family history, estrogen exposure, old age, absence of childbirth and breastfeeding experience, radiation exposure, alcohol consumption, a high-fat diet, obesity, and exposure to endocrine disruptors ,6.The factors related to breast cancer recurrence, however, are far less understood than the risk factors for early breast cancer. It is known that lifestyle affects not only the incidence but also the likelihood of breast cancer recurrence . The ideIn Korea, while studies have investigated the risk factors and lifestyle related to early breast cancer incidence, studies regarding the influencing factors of breast cancer recurrence are lacking. In addition to treatment-related factors, identifying lifestyle factors correlated with recurrent breast cancer is crucial to designing nursing interventions for patients. For long-term survivors of cancer, despite the importance of a healthy daily lifestyle to prevent recurrence or metastasis, they tend to seek advice from a wide array of sources of varying quality . It is eEthics statement: This study was approved by the Institutional Review Board of The Catholic University of Korea (KC20QASI0878). Obtaining written informed consent was exempted because the survey was completely anonymous and considering the online survey design.https://www.strobe-statement.org/).This cross-sectional survey employed a descriptive correlational design to investigate the influencing factors of breast cancer recurrence by comparing the risk factors and lifestyle patterns related to breast cancer in women with and without recurrence. This report followed the STROBE  reporting guidelines  of .80, significance level of .05, and an effect size of .15. Because there are sparse reports on the influence of lifestyle factors on recurrence of breast cancer, a conventional low level was set for the effect size . A minimThe variables in this study were measured using a structured questionnaire that was modified and revised by the investigator based on the influencing factors of breast cancer reported in previous studies . Due to Questions on influencing factors related to general characteristics consisted of nine questions in total, including three questions on estrogen exposure  and six questions on age, family history, comorbid diseases before the diagnosis of breast cancer, education level, household income, and occupation. To derive these nine variables included in this study, a literature search was conducted using keywords such as ‘breast cancer risk factor,’ ‘breast cancer lifestyle,’ ‘breast cancer recurrence,’ ‘breast neoplasm risk factor,’ ‘breast neoplasm lifestyle,’ and ‘breast neoplasm recurrence.’ General characteristics that were reported as significantly associated with breast cancer recurrence in at least one previous study were included as the variables of this study.2)  [Data on influencing factors related to lifestyle were obtained through 37 questions in relation to four conceptual domains: eating habits (21 items), physical activity (five items), stress management (three items), and other factors (eight items) which include overweight, alcohol consumption, smoking, hair dyeing, hours of brassiere wearing, plastic surgery on breast, the duration of having taken menopausal hormone therapy, and the duration of having taken oral contraceptive pill. The questions concerning eating habits, physical activity, and stress management were rated on a 5-point Likert scale . The questions on overeating, unbalanced eating, and eating instant foods were reverse coded . Higher scores  indicated more engagement in healthy lifestyles in the domain of eating habits, physical activity, and stress management. Obesity was measured in terms of body mass index (BMI), obtained by dividing weight (kg) by the square of height  . ParticiThe data were collected between December 15, 2020 and February 19, 2021. Recruitment advertisement was done by posting a link to a breast cancer support community using a Google questionnaire developed by the researchers so that potential participants could visit the link to voluntarily participate in the anonymized online survey. Patients with breast cancer admitted to or visiting the hospital were also invited to the study, after the consent of the nursing department at The Catholic University of Korea Seoul St. Mary’s Hospital regarding data collection. Individuals who were contacted in-person and verbally consented to participate were provided a paper questionnaire, which took 10 to 15 minutes. Participants were asked to recall their general lifestyles after initial diagnosis of breast cancer.The collected data were analyzed using IBM SPSS for Windows ver. 25.0 . The personal characteristics of the participants are presented in terms of frequency, percentage, mean, and standard deviation. Variations in risk factors and lifestyle were examined using a chi-square test between the recurrent and nonrecurrent groups. In terms of breast cancer recurrence factors, variables showing a significant difference in the univariate analysis were used as independent variables in the logistic regression analysis. The questionnaires were designed to be anonymous, and the data are managed in compliance with the Personal Information Protection Act (Korea) .The mean age of the participants was 49.45 years, of whom the majority were married (78.0%) and were college or university graduates (63.5%). Less than one-third were currently working (28.2%) and the mean monthly income was 4.308 million Korean won , which is slightly greater than the mean average household income for 2020 . Stage 2p=.012). The percentage of participants without childbirth experience was higher in the recurrent group (39.5%) than in the nonrecurrent group (21.3%) (p=.002), and the percentage of participants without breastfeeding experience was higher in the recurrent group (53.5%) than in the nonrecurrent group (37.8%) (p=.014)  groups, and the results showed significant differences in terms of a history of benign breast cancer, childbirth experience, and breastfeeding experience. The percentage of participants with a history of benign breast cancer was higher in the recurrent group (25.4%) than in the nonrecurrent group (12.6%) ((p=.014) .p=.001), skipped breakfast more often (p=.008), and tended to overeat (p=.041). The recurrent group also had an imbalanced diet (p=.007), ate fewer green and yellow vegetables (p=.003), and consumed instant foods to a higher degree (p=.046)  .p=.005). The recurrent group was also found to take insufficient rest when recovering from fatigue (p=.003) and reported experiencing an incomplete recovery after sleep (p<.001). In terms of alcohol consumption and smoking, the rate of those who were engaged in these behaviors was higher in the recurrent group (p=.001). In addition, the recurrent group reported a longer time wearing a brassiere all day (p=.017). Concerning stress management, no significant differences were observed between the two groups , eating green and yellow vegetables , alcohol consumption , and degree of recovery from fatigue after sleep . Specifically, the risk of breast cancer recurrence increased by 2.29 times in participants without childbirth experience and decreased by 0.71 times with the consumption of green and yellow vegetables. Recurrence decreased by 0.24 times in participants who did not consume alcohol, and by 0.51 times in participants who reported complete recovery from fatigue after sleep  in the questionnaire, which may have generated recall biases of the participants. Although the face validity of the questionnaire was obtained through expert panel review, caution is required as other types of validity were not possible. Second, cause-effect relationships could not be determined because the study used a cross-sectional descriptive design. Therefore, in the future, a longitudinal study with a larger sample size should be conducted to facilitate generalization of the results. Additionally, clinical variables such as cancer subtype information and the period after being diagnosed with cancer were not included because the data were collected based on self-reports from the patients, and exact information regarding clinical status was not available. Examining homogeneity in treatment status of breast cancer will be necessary to increase validity of the study findings in future studies. Thus, assessment of duration of maintaining lifestyle factors and clinical information through review of medical records will help to clarify factors influencing breast cancer recurrence. Because our sample size was relatively small, further research with a larger dataset will be beneficial. Overall, the influencing factors identified in this study for breast cancer recurrence should be considered as relevant intervention variables in follow-up studies to promote evidence-based practice for the prevention of breast cancer.In conclusion, this study identified not having experienced childbirth, lack of eating green and yellow vegetables, alcohol consumption, and poor recovery from fatigue after sleep as factors influencing breast cancer recurrence. Noting that several are modifiable factors, healthcare professionals can use these findings to assess the lifestyle patterns of patients with breast cancer and implement appropriately targeted intervention plans to decrease the risk of breast cancer recurrence.