Narrative Review Medicine ®

Breast cancer
A review of risk factors and diagnosis
Emmanuel Ifeanyi Obeagu, PhDa,* , Getrude Uzoma Obeagu, BN Scb

Abstract
Breast cancer remains a complex and prevalent health concern affecting millions of individuals worldwide. This review paper
presents a comprehensive analysis of the multifaceted landscape of breast cancer, elucidating the diverse spectrum of risk factors
contributing to its occurrence and exploring advancements in diagnostic methodologies. Through an extensive examination of
current literature, various risk factors have been identified, encompassing genetic predispositions such as BRCA mutations,
hormonal influences, lifestyle factors, and reproductive patterns. Age, family history, and environmental factors further contribute
to the intricate tapestry of breast cancer etiology. Moreover, this review delineates the pivotal role of diagnostic tools in the early
detection and management of breast cancer. Mammography, the cornerstone of breast cancer screening, is augmented by
emerging technologies like magnetic resonance imaging and molecular testing, enabling improved sensitivity and specificity in
diagnosing breast malignancies. Despite these advancements, challenges persist in ensuring widespread accessibility to screening
programs, particularly in resource-limited settings. In conclusion, this review underscores the importance of understanding diverse
risk factors in the development of breast cancer and emphasizes the critical role of evolving diagnostic modalities in enhancing
early detection. The synthesis of current knowledge in this review aims to contribute to a deeper comprehension of breast cancer’s
multifactorial nature and inform future directions in research, screening strategies, and preventive interventions.
Abbreviations: bCSCs = breast cancer stem cells, BRCA1 = breast cancer gene 1, BRCA2 = breast cancer gene 2, CSCs =
cancer stem cells, FNA = fine needle aspiration, HER2 = human epidermal growth factor receptor 2, HRT = hormone replacement
therapy, WHI = Women’s Health Initiative.
Keywords: breast cancer, cancers, diagnosis, mortality, prevention, risk factors

1. Introduction glands to the nipple. Ductal carcinoma is the name given to

this subtype of breast cancer. The cells of the lobules, which
One of the frequent and numerous malignant tumors that affect are the collections of milk-producing glands, can also give
women is breast cancer. Breast cancer develops and occurs as a rise to cancer.[6,7] Lobular carcinoma is the name of this type
result of several internal and external factors.[1–3] Poor lifestyle of cancer. Both ductal and lobular carcinomas can be in situ,
choices, environmental factors, and social-psychological factors which means the cancer is still present in the area where it first
are all linked to its occurrence. It has been demonstrated that appeared and has not spread to adjacent tissues. They may
5% to 10% of breast cancers can be attributed to genetic muta- also be invasive, which indicates that they have spread into the
tions and family history, and 20% to 30% of breast cancers can tissues around them.[8] Breast cancer can also manifest itself in
be attributed to factors that may be modifiable.[4] Breast cells are less common forms. These include triple-negative breast can-
where breast cancer first develops. A collection of cancer cells cer, breast Paget disease, and inflammatory breast cancer. Non-
known as a cancerous tumor is capable of spreading into and Hodgkin lymphoma and soft tissue sarcoma are uncommon
destroying nearby tissue. As well as spreading throughout the forms of breast cancer.[9] Despite having a low incidence of
body, it can. Breast cells occasionally undergo changes that pre- breast cancer, studies show that it has been steadily rising in
vent them from growing or behaving normally. Non-cancerous China. By 2022, the number of Chinese women who will have
breast conditions atypical hyperplasia and cysts may result from the disease will surpass 100 per 100,000, and there will be 2.5
these changes. Additionally, they may result in benign tumors million women with the disease overall, aged 35 to 49. Thus,
like intraductal papillomas.[5] it is crucial to research breast cancer risk factors to lower the
However, breast cancer can occasionally result from changes disease’s incidence.[10] Breast cancer is the most prevalent can-
to breast cells. Breast cancer typically begins in the cells that cer in women worldwide and the main reason why women die
line the ducts, which are the tubes that carry milk from the from cancer. About 630,000 women lost their lives to breast

The authors have no funding and conflicts of interest to disclose. Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
The datasets generated during and/or analyzed during the current study are not This is an open access article distributed under the Creative Commons
publicly available, but are available from the corresponding author on reasonable Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and
request. reproduction in any medium, provided the original work is properly cited.
a
Department of Medical Laboratory Science, Kampala International University, How to cite this article: Obeagu EI, Obeagu GU. Breast cancer: A review of risk
Kampala, Uganda, bSchool of Nursing Science, Kampala International University, factors and diagnosis. Medicine 2024;103:3(e36905).
Kampala, Uganda. Received: 29 July 2023 / Received in final form: 15 December 2023 / Accepted:
* Correspondence: Emmanuel Ifeanyi Obeagu, Department of Medical 18 December 2023
Laboratory Science, Kampala International University, Kampala, Uganda (email: http://dx.doi.org/10.1097/MD.0000000000036905
[email protected]).

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cancer in 2018, and there were approximately 2.09 million Early diagnosis increases the likelihood of survival. Poor
newly diagnosed cases. While there are regional variations in prognosis and distant metastasis are caused by the tumor’s pro-
breast cancer incidence, it is rising. Due to China’s large pop- pensity to spread lymphatically and hemologically. This clarifies
ulation and high incidence of breast cancer, which ranks first and highlights the significance of programs for breast cancer
globally and has increased over the past few years (17.6% and screening.[15] Anything that raises the possibility of developing
15.6%, respectively), even though the incidence of breast can- cancer is a risk factor. It might be a habit, substance, or illness.
cer (36.1/105) and mortality (8.8/105) are both relatively low Many risk factors combine to cause the majority of cancers.
worldwide. The burden of the disease is rising alongside the Women are more likely than men to develop breast cancer.
incidence of breast cancer globally, which has grown to be a Women are more likely to develop breast cancer when estro-
significant issue for global public health.[11] Breast cancer is a gen and progesterone are exposed to their breast cells. Breast
multifactorial disease with major genetic, environmental, and cancer is more prevalent in high-income, developed nations like
behavioral/lifestyle components. The objective of the current Canada, the United States, and some European nations. These
review was to investigate the epidemiology and associated risk hormones, particularly estrogen, are linked to the disease and
factors of breast cancer globally to comprehend its prevalence promote its growth. As you get older, your risk of developing
and aid in early detection. The main risk factors for breast breast cancer rises. Most breast cancer cases in women are diag-
cancer are genetic factors, specifically family history; diet, and nosed between the ages of 50 and 69 years.[14]
obesity, as the quality of life in our country improves, women
are getting more and more obese, and their diet tends to be
more and more high-fat; smoking and drinking; the other 2. Risk factors for developing breast cancer among
is ionizing radiation; still have, specifically menstruation, women
bear, and whether lactation, these factors also can affect the
occurrence of breast cancer. To lessen the impact exogenous 2.1. Personal history of breast cancer
hormones, have on the body, we should try to avoid using cos- An increased risk of breast cancer recurrence exists in women
metics that contain estrogen in our daily lives. Around these who have previously experienced it. The second breast cancer
appeals, there has been a lot of debate. As a result, it is essential may appear in the same breast as the first one or in a different
to thoroughly examine the risk factors for breast cancer using breast. Although the majority of women who have ductal carci-
meta-methods to direct clinical prevention and treatment.[12] noma in situ or lobular carcinoma in situ breast cancers do not
We conducted a meta-analysis of breast cancer risk factors in recur, these women are at an increased risk of doing so.[16]
Chinese women in the current study by gathering pertinent
literature from 2001 to 2021, even though Chinese scholars
have already done so.[13] Our goal was to provide fundamen- 2.2. Breast and other types of cancer in the family history
tal information for the prevention of breast cancer in Chinese
The presence of breast cancer in one or more close blood rela-
women. Something that raises your chance of getting cancer is
tives indicates that the disease runs in the family. More breast
a risk factor. A habit, substance, or illness could be the culprit.
cancer cases than one might anticipate randomly occur in some
Numerous risk factors contribute to the majority of cancers.
families. It can be difficult to determine whether a family’s his-
However, breast cancer can occasionally develop in women
tory of cancer is the result of coincidence, a common lifestyle,
who don’t have any of the risk factors listed below. Women
genes passed down from parents to children, or a combination
are more likely than men to develop breast cancer. Women are
of these factors.[17]
more likely to develop breast cancer when estrogen and pro-
gesterone are exposed to their breast cells.
Some breast cancers are aided in their growth by these hor-
2.3. Mutations in the BRCA gene
mones, particularly estrogen, which has been linked to breast
cancer. Canada, the United States, and a few European nations An altered gene is referred to as a genetic mutation. Certain
are examples of high-income, developed nations where breast types of cancer may be more likely to develop as a result of
cancer is more prevalent. Age raises the likelihood of getting some gene changes. A parent can pass on inherited gene muta-
breast cancer. Women between the ages of 50 and 69 are the tions to their offspring. Only a small percentage of breast
most common demographic for breast cancer.[14] The most fre- cancers (roughly 5%–10%) are brought on by inherited gene
quently diagnosed cancer in women and a major global health mutations. Normal human physiology includes both BRCA1
concern is breast cancer. Researchers have found several risk and BRCA2, which are breast cancer genes. As a result of what
factors that can raise a woman’s likelihood of getting breast can- seems to be their involvement in regulating the growth of can-
cer, even though the disease’s precise cause is still unknown. For cer cells, these genes are known as tumor suppressors. BRCA1
early detection, prevention, and efficient management of breast or BRCA2 gene mutations may cause them to lose their ability
cancer,[14] it is essential to comprehend these risk factors. With to regulate the development of cancer. Rarely occur these muta-
more than 1 in 10 new cancer diagnoses each year, breast cancer tions. Roughly 1 in 500 people experience them. A mutated
is the most common cancer in women. In the entire world, it is BRCA gene can be inherited by both men and women from
the second most typical cause of cancer-related death in females. either their mother or father. Children of those who carry the
Milk-producing glands are located in front of the chest wall on gene mutation may also inherit it. A child has a 50% chance of
the anatomy of the breast. They rest on the pectoralis major inheriting the gene mutation if 1 of the 2 copies of the BRCA
muscle, and the breast is supported by ligaments that join it gene has the mutation in 1 or both parents. A child also has a
to the chest wall. The breast is made up of 15 to 20 lobes that 50% chance of not inheriting the gene mutation, according to
are arranged in a circle. The size and shape of the breasts are this.[18] According to studies, women who inherit BRCA1 or
determined by the fat that covers the lobes. Each lobe is made BRCA2 gene mutations have an 85% lifetime risk of devel-
up of lobules that contain the glands that produce milk when oping breast cancer. Additionally, compared to other women,
hormones are stimulated. Breast cancer always progresses sub- those who carry these inherited mutations are at an increased
tly. The majority of patients learn they have their illness while risk of developing breast cancer earlier in life. Breast cancer
getting their regular screenings. Others may exhibit nipple dis- in both breasts is more likely to strike women who have the
charge, a breast shape or size change, or an unintentionally dis- BRCA gene mutation. They are more likely to get cancer in
covered breast lump. Mastalgia is not unusual, though. Breast the other breast if they have cancer in 1 breast. Ovarian can-
cancer diagnosis requires a physical examination, imaging, par- cer can strike a woman at any age if she carries a BRCA gene
ticularly mammography, and tissue biopsy.[14] mutation.[19]
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2.4. Large breasts 2.9. Estrogen

Compared to fatty tissue, dense breasts have more milk ducts, Breast cancer risk is linked to estrogens, both endogenous and
glands, and connective tissue. Breast density is a genetic trait. exogenous. In premenopausal women, the ovary typically pro-
Compared to women with little or no dense breast tissue, duces endogenous estrogen, and ovarian removal can lower
women with dense breast tissue have a higher risk of devel- the risk of breast cancer. HRT and oral contraceptives are the
oping breast cancer. Breast density can only be detected by a main exogenous estrogen sources. Since the 1960s, oral con-
mammogram, but dense breasts also make the image more traceptives have been extensively used, and their formulations
difficult to interpret. On a mammogram, dense tissue appears have been improved to minimize side effects. The odd ratio is
white, like tumors, while fatty tissue appears dark, concealing still higher than 1.5 for Iranian and African American female
a tumor.[20] populations, though. Oral contraceptives do not, however,
raise the risk of breast cancer in women who stop using them
for more than 10 years. For menopausal or postmenopausal
2.5. The late menopause women, HRT entails the administration of exogenous estrogen
The body’s level of hormones, primarily estrogen and proges- or other hormones. The use of HRT can raise the risk of breast
terone, begins to decline as the ovaries stop producing them, cancer, according to several studies. According to the Million
resulting in menopause. A woman’s menstrual cycle is stopped Women Study in the UK, there is a 1.66 relative risk between
as a result of this. Your cells are exposed to estrogen and other those who currently use HRT and those who have never used
hormones for a longer period if you enter menopause later in it. A cohort study of 22,929 Asian women found that after
life (after age 55). This raises the possibility of breast cancer. using HRT for 4 and 8 years, respectively, hazard ratios (HRs)
Likewise, breast tissue is exposed to estrogen and other hor- of 1.48 and 1.95 were found. After 2 years of stopping HRT,
mones for a shorter period when menopause occurs earlier it has been demonstrated that the risk of breast cancer signifi-
in life. A lower risk of breast cancer is associated with early cantly declines. With a 3.6 HR for a new breast tumor, the
menopause.[21] recurrence rate is also high among breast cancer survivors who
take HRT. Since the negative effects of HRT were revealed in
2003 based on the WHI randomized controlled trial, there has
2.6. Whether there are late or no pregnancies been a 7% decrease in the incidence rate of breast cancer in
America.[25]
Breast cells’ exposure to circulating estrogen is halted during
pregnancy. It also reduces the overall number of menstrual
cycles a woman experiences throughout her lifetime. A woman’s 3. Breast cancer in women: Diagnosed through
risk of breast cancer is marginally higher than it is for a woman appended technologies
who has at least one full-term pregnancy before the age of 30.
Reduced risk of breast cancer is associated with early pregnancy. Breast tumors typically start as benign tumors or even meta-
A woman is more protected from breast cancer the more chil- static carcinomas due to ductal hyperproliferation, which is
dren she has. Breast cancer risk is increased if a woman never then constantly stimulated by various carcinogenic factors.
conceives.[22] Breast cancer is initiated and progresses differently depending
on the microenvironment of the tumor, such as stromal influ-
ences or macrophages. When only the stroma of the rat mam-
2.7. Hormonal replacement treatment mary gland was exposed to carcinogens—not the extracellular
matrix or the epithelium—neoplasms could be induced. A muta-
According to the Women’s Health Initiative (WHI) study, estro- genic inflammatory microenvironment that macrophages can
gen alone increased breast cancer risk by about 1% per year create can encourage angiogenesis and help cancer cells avoid
and combined hormone replacement therapy (HRT) increased immune rejection. Different DNA methylation patterns between
risk by about 8% per year. The study also discovered that, in the typical and tumor-associated microenvironments have been
comparison to a placebo, the risk increased even with rela- observed, suggesting that epigenetic changes in the tumor micro-
tively brief use of combined HRT. After stopping HRT for a environment can encourage carcinogenesis. Cancer stem cells
few years, the higher risk seems to be gone. The WHI study also (CSCs), a new subclass of malignant cells within tumors, have
revealed that, among Canadian women aged 50 to 69, there was recently been identified and linked to tumor initiation, escape,
a notable decline in the number of new cases of breast cancer and recurrence. This small population of cells, which may orig-
between 2002 and 2004. The use of combined HRT decreased inate from stem cells or progenitor cells in healthy tissues, can
at the same time as this drop. Other nations around the world, regenerate itself and is resistant to traditional treatments like
such as the United States, Australia, Germany, the Netherlands, chemotherapy and radiotherapy. Ai Hajj was the first to iden-
Switzerland, and Norway, have also noticed this trend. The risks tify breast cancer stem cells (bCSCs), and immunocompromised
associated with the long-term use of combined HRT are now mice could develop new tumors from as few as 100 bCSCs. As
thought to outweigh the advantages.[23] opposed to basal stem cells, luminal epithelial progenitors are
more likely to be the source of bCSCs. The self-renewal, prolif-
eration, and invasion of bCSCs are mediated by signaling path-
2.8. Being overweight ways that include Wnt, Notch, Hedgehog, p53, PI3K, and HIF.
In post-menopausal women, obesity increases the risk of devel- More research is nevertheless required to comprehend bCSCs
oping breast cancer. According to studies, women with a body and create fresh methods for their complete eradication.[19]
mass index of 31.1 or higher who have never used HRT are 2.5 The CSC theory and the stochastic theory are 2 specu-
times more likely to develop breast cancer than those with a lative theories for how breast cancer starts and spreads.
body mass index of 22.6 or lower. In particular, estrogens from According to the theory about CSCs, all subtypes of tumors
the ovaries play a significant role in breast cancer. Many breast are descended from the same stem cells or transit-amplifying
cancer risk factors are thought to be caused by the cumula- cells. A variety of tumor phenotypes are caused by acquired
tive estrogen dose that the breast tissue absorbs over time. The genetic and epigenetic mutations in stem cells or progenitor
majority of the body’s estrogen is produced by the ovaries, but cells. According to the stochastic theory, a single type of cell is
after menopause, fat tissue only produces a small amount of the source of all tumor subtypes. Any breast cell can gradually
estrogen. A higher estrogen level can result from having more develop random mutations, and when enough mutations have
fat tissue, which raises the risk of breast cancer.[24] accumulated, the breast cell can transform into a tumor cell.
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Even though both theories have a lot of data to back them are performed in a hospital, and once they are complete, you can
up, neither can fully explain how human breast cancer first leave for home.[29]
developed.[26]

5.4. The core biopsy

4. Biology-based breast cancer prevention Removes tissue from the body using a unique hollow needle.
To enhance the quality of life for breast cancer patients, bio- It is employed by doctors to obtain a sample from a breast
logical prevention, primarily known as monoclonal antibodies region that is thought to be suspicious. During the procedure,
for the disease, has recently been developed. These monoclo- they might take several samples from the area. To remove more
nal antibodies have human epidermal growth factor receptor tissue through the hollow needle, doctors occasionally use a spe-
2 (HER2) as one of their primary targets. The HER2 protein is cial vacuum. Vacuum-assisted core biopsy is the name of this
overexpressed or the HER2 gene is amplified in about 20% to method.[17]
30% of all breast cancer cases. The first HER2-targeted med-
ication to receive FDA approval is trastuzumab (Herceptin), a
recombinant humanized monoclonal antibody. It can directly 5.5. A lymph node biopsy
interact with the C-terminal region of domain IV in the extra- A lymph node biopsy is a surgical procedure that involves the
cellular region of HER2. Trastuzumab’s anti-tumor mechanism removal of lymph nodes so they can be examined under a micro-
has not yet been fully understood. Trastuzumab may inhibit scope to determine if they contain cancer. Breast cancer cells can
the growth and proliferation of cancer cells through several separate from the tumor and move through the lymphatic sys-
possible mechanisms, including activating the immune sys- tem. Lymph nodes beneath the arm are where they might spread
tem against cancer cells through an effect known as antibody- first. To help determine the stage of breast cancer, doctors count
dependent cell-mediated cytotoxicity, inhibiting the MAPK the number of lymph nodes that contain the disease.[30]
and PI3K/Akt pathways, and enlisting ubiquitin to inter-
nalize and degrade HER2. With an objective response rate
of 26%, trastuzumab was initially used to treat metastatic 5.6. Fine needle aspiration
breast cancer. Trastuzumab interacts favorably with other
anti-tumor medications, including nimotuzumab, carboplatin, Removes a small amount of tissue from a lump using a syringe
4-hydroxycyclophosphamide, docetaxel, and vinorelbine, and a very thin needle. It helps doctors determine whether a
according to in vitro studies. According to the HERA and TRAIN lump is a cyst or a solid tumor. Whether a cancer is non-
trials, chemotherapy given in combination with adjuvant trastu- invasive or invasive cannot be determined by fine needle aspira-
zumab for a year can prolong disease-free survival in HER2+ tion (FNA).[31] During the procedure, a healthcare professional
breast cancer patients (HR = 0.76). Trastuzumab plus docetaxel inserts a thin needle into the breast lump, guided by palpation or
was shown to be more effective than docetaxel alone in treat- imaging techniques such as ultrasound. A syringe attached to the
ing HER2-positive metastatic breast cancer, with an objective needle is used to suction out cells or fluid from the lump. These
response rate of 50% versus 32%, in a randomized phase II trial cells or fluid samples are then examined under a microscope
carried out by Marty. Patients receiving trastuzumab, however, by a pathologist to determine if they are cancerous (malignant)
also experienced adverse effects like congestive heart failure and or noncancerous (benign). FNA is a minimally invasive proce-
a decline in their left ventricular ejection fraction.[4] dure that can provide valuable information about the nature
of the breast lump. It helps in the diagnosis of breast cancer by
analyzing the characteristics of the cells, aiding in determining
5. Breast cancer in women is diagnosed the presence of cancerous cells, and guiding further diagnostic
or treatment procedures. However, depending on the situation,
5.1. Mammography additional tests like a core needle biopsy or surgical biopsy may
Diagnostic mammography is an x-ray that creates an image of be recommended for a more comprehensive evaluation.
the breast using low radiation doses. It is used to follow up on
unexpected findings from a clinical breast exam or a screening
mammogram. It is also possible to use mammography during a 6. Preventative measures and ongoing research
biopsy to identify an abnormal area.[27] efforts
Certainly, preventive measures and ongoing research efforts are
crucial components in the fight against breast cancer.
5.2. Ultrasound
An ultrasound creates images of various body parts using
high-frequency sound waves. It is used to determine whether a 7. Preventative measures
lump in the breast is a solid tumor or a cyst. Additionally, ultra- Encouraging women to undergo regular mammograms and
sound can be used by medical professionals to direct them to the screenings based on age and risk factors can aid in early detec-
biopsy site. An ultrasound may be performed on women with tion, leading to better treatment outcomes.[32] Promoting a
advanced breast cancer to determine whether liver metastasis healthy lifestyle that includes maintaining a balanced diet, reg-
has occurred.[28] ular exercise, limiting alcohol consumption, avoiding smoking,
and maintaining a healthy weight can reduce the risk of devel-
oping breast cancer. Encouraging breastfeeding, which has been
5.3. Biopsy shown to have protective effects against breast cancer, can be
Breast cancer can only be accurately identified through a biopsy. promoted as a preventive measure.[33] Providing comprehensive
The purpose of a biopsy is to remove tissues or cells from the and accessible education on breast cancer risks, symptoms, and
patient’s body for laboratory testing. The pathologist’s report the importance of early detection can empower individuals to
will determine whether or not cancer cells were discovered in the take proactive measures and seek timely medical attention. For
sample. The type of biopsy performed will depend on whether individuals with a family history or known genetic mutations
the lump is palpable, meaning you can feel it, or non-palpable, (like BRCA1 or BRCA2), genetic counseling and testing can
meaning you can’t. To locate the area to be tested, the doctor help in assessing risks and making informed decisions about
may use ultrasound or mammography. The majority of biopsies preventive measures.[34] Understanding the risks associated
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Conceptualization: Emmanuel Ifeanyi Obeagu, Getrude Uzoma [23] Mills ZB, Faull RLM, Kwakowsky A. Is hormone replacement therapy
Obeagu. a risk factor or a therapeutic option for Alzheimer’s disease? Int J Mol
Methodology: Emmanuel Ifeanyi Obeagu. Sci. 2023;24:3205.
Resources: Emmanuel Ifeanyi Obeagu, Getrude Uzoma Obeagu. [24] Kunyahamu MS, Daud A, Jusoh N. Obesity among health-care work-
Supervision: Emmanuel Ifeanyi Obeagu, Getrude Uzoma ers: which occupations are at higher risk of being obese? Int J Environ
Obeagu. Res Public Health. 2021;18:4381.
[25] Belachew EB, Sewasew DT. Molecular mechanisms of endocrine resistance
Visualization: Emmanuel Ifeanyi Obeagu, Getrude Uzoma
in estrogen-positive breast cancer. Front Endocrinol. 2021;12:689705.
Obeagu. [26] Kim M, Jung MS. Effects of chemotherapy-induced peripheral neurop-
Writing – original draft: Emmanuel Ifeanyi Obeagu, Getrude athy in women with breast cancer: a structural equation approach with
Uzoma Obeagu. the theory of unpleasant symptoms. Cancer Nurs. 2021;44:145–53.
Writing – review & editing: Emmanuel Ifeanyi Obeagu, Getrude [27] Chang CC, Ho TC, Lien CY, et al. The effects of prior mammography
Uzoma Obeagu. screening on the performance of breast cancer detection in Taiwan.
Validation: Getrude Uzoma Obeagu. Healthcare (Basel). 2022;10:1037.

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