research paper topics on breast cancer

Cochrane Breast Cancer

Top 10 breast cancer topics needing a cochrane systematic review.

Deciding which research topics to focus on in medicine and health depends on many factors. These factors can include the currency of a topic, feedback from people providing or receiving care, and the priorities of funders.

In late 2019, the Cochrane Breast Cancer Group (part of Cochrane’s Cancer Network) conducted a formal priority-setting exercise to help decide which review topics were most needed in the Cochrane Library. The Group did this by circulating a survey listing 25 new or existing review topics to a diverse group of individuals who are part of the international breast cancer community. The survey asked individuals to rank their top 10 topics from the list. Read details about the aims and methods used for this priority-setting exercise, which adhered to the standards outlined in Cochrane’s priority setting guidance note .

What were the top 10 review topics?

Read about the ranking of the 25 new or existing review topics .

What is next?

Support to author teams For the top 10 topics, the Cochrane Breast Cancer Group will prioritise these topics during the editorial and peer-review process.

For all breast cancer review topics registered with Cochrane, the Cochrane Breast Cancer Group continues to work on these topics with author teams as these remain important topics. There will be no noticeable change in the support provided to author teams.

Future topics The Cochrane Breast Cancer Group is open to receiving new topic ideas. If you have suggestions for new topics that are not currently covered in the Cochrane Library, please send your idea to [email protected] .

Repeating this priority-setting exercise The priority-setting exercise may be repeated every 3 years, depending on resources.

Who responded to the survey?

The survey was circulated to over 800 individuals. Of the 199 people who responded, 90 people (45%) provided complete responses. The respondents were doctors (59%), researchers (18%) and people who had received treatment or currently receiving treatment for breast cancer (14%). Most respondents were from the UK, followed by the USA, Argentina, and India.

How did we calculate the ranking for each review topic?

The average ranking was calculated for each topic. This method is commonly used to determine ranking scores from surveys. This approach considers the number of counts for each ranking on a topic, the weighting of each rank (where a ranking of 1 gets the most weight) and the total number of counts. 

[Cover image: foliage of the Yew tree. Taxanes, a class of chemotherapy drugs, were originally derived from the Yew tree]

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117 Breast Cancer Essay Topic Ideas & Examples

Inside This Article

Breast cancer is a prevalent and life-threatening disease that affects millions of individuals worldwide. It is important to raise awareness about breast cancer, its causes, prevention methods, and treatment options. Writing an essay on breast cancer can help educate others, spread awareness, and provide support to those affected by the disease. To help you get started, here are 117 breast cancer essay topic ideas and examples:

• The history of breast cancer research.
• Understanding breast cancer: Causes, risk factors, and prevention.
• The impact of genetics on breast cancer development.
• Exploring the different types and stages of breast cancer.
• The role of hormonal imbalances in breast cancer.
• Environmental factors and their link to breast cancer.
• The importance of regular breast self-examinations.
• The significance of early detection in breast cancer survival rates.
• The impact of breast cancer on mental health.
• The emotional journey of breast cancer survivors.
• The role of support groups in the breast cancer community.
• Breast cancer in men: Understanding the challenges and misconceptions.
• The importance of mammograms in breast cancer screening.
• The role of lifestyle choices in breast cancer prevention.
• Exploring the various treatment options for breast cancer.
• The impact of chemotherapy on breast cancer patients.
• Radiation therapy: Benefits and side effects.
• Surgical interventions for breast cancer: Mastectomy vs. lumpectomy.
• Breast reconstruction surgery: A personal choice after breast cancer.
• The role of targeted therapies in breast cancer treatment.
• The impact of hormone therapy on breast cancer patients.
• The role of immunotherapy in advanced breast cancer cases.
• The psychological effects of breast cancer on patients' relationships.
• Coping strategies for dealing with the emotional toll of breast cancer.
• The role of nutrition in supporting breast cancer treatment.
• The importance of exercise during and after breast cancer treatment.
• Alternative and complementary therapies for breast cancer patients.
• The financial burden of breast cancer treatment.
• Breast cancer advocacy: The fight for better research and resources.
• The role of technology in advancing breast cancer detection methods.
• Breast cancer awareness campaigns: Their impact on public perception.
• Breast cancer in developing countries: Challenges and solutions.
• The impact of breast cancer on fertility and reproductive choices.
• The role of genetic testing in breast cancer risk assessment.
• The relationship between obesity and breast cancer.
• The impact of race and ethnicity on breast cancer outcomes.
• The importance of early education about breast health.
• Breast cancer in young women: Unique challenges and considerations.
• The role of social media in raising breast cancer awareness.
• Breast cancer and pregnancy: Navigating treatment decisions.
• The impact of breast cancer on sexual health and intimacy.
• The role of survivorship programs in supporting breast cancer patients.
• The impact of breast cancer on workplace dynamics and discrimination.
• Breast cancer and the LGBTQ+ community: Unique experiences and challenges.
• The importance of clinical trials in advancing breast cancer research.
• Breast cancer and the role of epigenetics.
• The impact of stress and emotional trauma on breast cancer outcomes.
• The role of advocacy organizations in supporting breast cancer patients.
• Breast cancer and the role of spirituality in coping.
• The impact of hormone replacement therapy on breast cancer risk.
• The role of patient navigation programs in improving breast cancer outcomes.
• Breast cancer and the impact on body image and self-esteem.
• The significance of breast cancer education in schools and colleges.
• The role of art therapy in supporting breast cancer patients.
• Breast cancer recurrence: Challenges and treatment options.
• The impact of breast cancer on caregivers and their mental health.
• The role of exercise in reducing the risk of breast cancer recurrence.
• Exploring the relationship between breast cancer and autoimmune diseases.
• Breast cancer and the impact on fertility preservation options.
• The role of palliative care in supporting advanced breast cancer patients.
• The impact of breast cancer on survivorship and quality of life.
• The role of community-based organizations in supporting breast cancer patients.
• Breast cancer and the impact on body image in the media.
• The importance of peer support in the breast cancer community.
• Breast cancer and the role of spirituality in healing and recovery.
• The impact of breast cancer on families and children.
• The role of mindfulness-based interventions in supporting breast cancer patients.
• Breast cancer in the elderly population: Challenges and considerations.
• The importance of clinical breast exams in early detection.
• Breast cancer and the impact on sexual orientation and gender identity.
• The role of survivorship care plans in supporting breast cancer survivors.
• Breast cancer and the impact on fertility preservation options for transgender individuals.
• The significance of dietary supplements in breast cancer prevention.
• The impact of breast cancer on body image and self-acceptance.
• Breast cancer and the role of spirituality in coping with treatment side effects.
• The importance of breast cancer education in underserved communities.
• Breast cancer and the impact on mental health in marginalized populations.
• The role of music therapy in supporting breast cancer patients.
• Breast cancer and the impact on access to healthcare in rural areas.
• The significance of breastfeeding in reducing the risk of breast cancer.
• Breast cancer and the role of integrative medicine in treatment.
• The impact of breast cancer on sexual identity and gender dysphoria.
• The role of survivorship clinics in addressing long-term effects of breast cancer treatment.
• Breast cancer and the impact on body image in different cultures.
• The importance of mentorship programs for young breast cancer survivors.
• Breast cancer and the role of spiritual practices in coping with treatment side effects.
• The impact of breast cancer on mental health in refugee populations.
• The significance of art therapy in supporting breast cancer patients during treatment.
• Breast cancer and the impact on healthcare disparities in minority communities.
• The role of laughter therapy in improving the well-being of breast cancer patients.
• Breast cancer and the importance of culturally sensitive healthcare practices.
• The impact of breast cancer on mental health in adolescent survivors.
• The significance of dance therapy in improving physical and emotional well-being of breast cancer patients.
• Breast cancer and the role of mobile health applications in self-management.
• The impact of breast cancer on mental health in immigrant populations.
• The importance of peer mentoring programs for breast cancer survivors.
• Breast cancer and the role of mindfulness meditation in managing treatment side effects.
• The impact of breast cancer on mental health in the LGBTQ+ community.
• The significance of pet therapy in providing emotional support to breast cancer patients.
• Breast cancer and the role of community health workers in improving access to care.
• The impact of breast cancer on mental health in rural populations.
• The importance of gardening therapy in promoting well-being among breast cancer survivors.
• Breast cancer and the impact on mental health in older adults.
• The role of equine therapy in supporting emotional well-being of breast cancer patients.
• The significance of telehealth in improving access to healthcare for breast cancer patients.
• Breast cancer and the impact on mental health in low-income populations.
• The importance of aromatherapy in managing treatment-related symptoms for breast cancer patients.
• The impact of breast cancer on mental health in individuals with disabilities.
• The role of horticultural therapy in promoting emotional healing among breast cancer survivors.
• Breast cancer and the significance of patient navigators in improving health outcomes.
• The impact of breast cancer on mental health in incarcerated populations.
• The importance of acupuncture in managing treatment side effects for breast cancer patients.
• Breast cancer and the impact on mental health in military veterans.
• The role of aquatic therapy in improving physical and emotional well-being of breast cancer patients.
• The significance of technology-based interventions in supporting breast cancer survivors.
• Breast cancer and the impact on mental health in individuals with substance use disorders.
• The importance of laughter yoga in promoting emotional well-being among breast cancer patients.

These essay topic ideas provide a diverse range of perspectives on breast cancer, allowing you to choose a topic that resonates with you. Remember to conduct thorough research, use credible sources, and share compelling stories to make your essay impactful and informative. Together, we can continue to raise awareness and support those affected by breast cancer.

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118 Breast Cancer Essay Topic Ideas & Examples

🏆 best breast cancer topic ideas & essay examples, 💡 most interesting breast cancer topics to write about, 📌 simple & easy breast cancer essay titles, 👍 good essay topics on breast cancer.

• Health Psychology: Going Through a Breast Cancer Diagnosis He is unaware that she has been diagnosed with depression and that she is going for breast screening Stress from work is also a contributing factor to her condition.
• Breast Cancer as a Genetic Red Flag It is important to note that the genetic red flags in Figure 1 depicted above include heart disease, hypertension, and breast cancer.
• Hormone Receptor-Positive Breast Cancer Pathophysiology The contemporary understanding of the etiopathogenesis of breast cancer addresses the origin of invasive cancer through a substantive number of molecular alterations at the cellular level.
• Breast Cancer Symptoms and Causes The mammogram is the first indication of breast cancer, even though other indications such as the presence of the lymph nodes in the armpits are also the early indications of breast cancer.
• Breast Cancer Screening Studies Evaluation The data collection and analysis processes used in this study’s methodology included a literature search to find papers that satisfied the inclusion criteria and a systematic approach to analyzing the findings for the common themes […]
• Breast Cancer: Prevalence and Mortality Rates The estimated number of new cancer cases in North America shows the high probability of having the disease Canada and the US.
• Breast Cancer and Its Population Burden The other objectives that are central to this paper are highlighted below: To determine which group is at a high risk of breast cancer To elucidate the impact of breast cancer on elderly women and […]
• Mindfulness Practice During Adjuvant Chemotherapy for Breast Cancer She discusses the significance of the study to the nursing field and how nurses can use the findings to help their patients cope with stress.
• Breast Cancer: The Effective Care Domain Information about how the patient is seen, how often the patient is seen, and whether she will return for mammograms can be collected and analyzed to verify the successful intervention to extend consistency with mammograms.
• Garden Pesticide and Breast Cancer Therefore, taking into account the basic formula, the 1000 person-years case, the number of culture-positive cases of 500, and culture-negative of 10000, the incidence rate will be 20 new cases.
• Breast Cancer Surveillance Consortium Analysis Simultaneously, the resource is beneficial because it aims to “improve the delivery and quality of breast cancer screening and related outcomes in the United States”.
• Drinking Green Tea: Breast Cancer Patients Therefore, drinking green tea regularly is just a necessity- it will contribute to good health and physical vigor throughout the day and prevent severe diseases.
• Breast Cancer Prevention: Ethical and Scientific Issues Such information can potentially impact the patient and decide in favor of sharing the information about the current condition and risks correlating with the family history.
• Breast Cancer: Epidemiology, Risks, and Prevention In that way, the authors discuss the topics of breast cancer and obesity and the existing methods of prevention while addressing the ethnic disparities persistent in the issue.
• Breast Cancer Development in Black Women With consideration of the mentioned variables and target population, the research question can be formulated: what is the effect of nutrition and lifestyle maintained on breast cancer development in black women?
• Breast Cancer in Miami Florida The situation with the diagnosis of breast cancer is directly related to the availability of medicine in the state and the general awareness of the non-population.
• Breast Cancer: Genetics and Malignancy In the presence of such conditions, the formation of atypical cells is possible in the mammary gland. In the described case, this aspect is the most significant since it includes various details of the patient’s […]
• Genes Cause Breast Cancer Evidence suggests the role of BRCA1 in DNA repair is more expansive than that of BRCA2 and involves many pathways. Therefore, it is suggested that BRCT ambit containing proteins are involved in DNA repair and […]
• Breast Cancer. Service Management The trial specifically looks at the effect on breast-cancer mortality of inviting women to screening from age 40 years compared with invitation from age 50 years as in the current NHS breast-screening programme.
• Fibrocystic Breast Condition or Breast Cancer? The presence of the fibrocystic breast condition means that the tissue of the breast is fibrous, and cysts are filled with the liquid or fluid. The main characteristic feature of this cancer is that it […]
• Coping With Stress in Breast Cancer Patients Therefore, it is important for research experts to ensure and guarantee adherence to methodologies and guidelines that define scientific inquiry. However, various discrepancies manifest with regard to the initiation and propagation of research studies.
• Breast Self-Examination and Breast Cancer Mortality Though it is harsh to dismiss self-exams entirely due to studies that indicate little in deaths of women who performed self-exams and those who did not, the self-exams should not be relied on exclusively as […]
• Breast Self-Exams Curbing Breast Cancer Mortality The results of the study were consistent with the findings of other studies of the same nature on the effectiveness of breast self-examination in detecting and curbing breast cancer.
• Taxol Effectiveness in Inhibiting Breast Cancer Cells The following were the objectives of this experiment: To determine the effectiveness of Taxol in inhibiting breast cancer cells and ovarian cancer cells using culture method.
• Control Breast Cancer: Nursing Phenomenon, Ontology and Epistemology of Health Management Then, the evidence received is presented in an expert way leading to implementation of the decision on the management of the disease.
• Breast Cancer: Effects of Breast Health Education The design of the research focused on research variables like skills, performance, self-efficacy, and knowledge as the researchers aimed at examining the effectiveness of these variables among young women who underwent training in breast cancer […]
• Community Nursing Role in Breast Cancer Prevention However, early detection still remains important in the prevention and treatment of breast cancer. The community has thus undertaken activities aimed at funding the awareness, treatment and research in order to reduce the number of […]
• Self-Examination and Knowledge of Breast Cancer Among Female Students Shin, Park & Mijung found that a quarter of the participants practiced breast self-examination and a half had knowledge regarding breast cancer.
• “Tracking Breast Cancer Cells on the Move” by Gomis The article serves the purpose of examining the role of NOG, a gene that is essential in bone development and its role in breast cancer.
• Breast Cancer Survivorship: Are African American Women Considered? The finding of the analysis is that the issue of cancer survivorship is exclusive, developing, and at the same time it depends on what individuals perceive to be cancer diagnosis as well as personal experiences […]
• Gaining Ground on Breast Cancer: Advances in Treatment The article by Esteva and Hortobagyi discusses breast cancer from the aspect of increased survival rates, the novel treatments that have necessitated this and the promise in even more enhanced management of breast cancer.
• Effects of Hypoxia, Surrounding Fibroblasts, and p16 Expression on Breast Cancer The study was conducted to determine whether migration and invasion of breast cancer cells were stimulated by hypoxia, as well as determining whether the expression of p16 ectopically had the potential to modulate the cell […]
• Breast Cancer: Preventing, Diagnosing, Addressing the Issue In contrast to the MRI, which presupposes that the image of the tissue should be retrieved with the help of magnetic fields, the mammography tool involves the use of x-rays.
• Dietary Fat Intake and Development of Breast Cancer This study aimed to determine the relationship between dietary fat intake and the development of breast cancer in women. The outcome of the study strongly suggests that there is a close relationship between a high […]
• The Detection and Diagnosis of Breast Cancer The severity of cancer depends on the movement of the cancerous cells in the body and the division and growth or cancerous cells.
• Breast Cancer: WMI Research and the Current Approaches Although the conclusions provided by the WHI in the study conducted to research the effects of estrogen and progesterone cessation on the chance of developing a breast cancer do not comply with the results of […]
• Breast Cancer Susceptibility Gene (BRCA2) The mechanisms underlying the genetic predisposition to a particular disease are manifold and this concept is the challenging one to the investigators since the advent of Molecular Biology and database resources.
• Prediction of Breast Cancer Prognosis It has been proposed that the fundamental pathways are alike and that the expression of gene sets, instead of that of individual genes, may give more information in predicting and understanding the basic biological processes.
• Breast Cancer Survivors: Effects of a Psychoeducational Intervention While the conceptual framework is justified in analysis of the quality of life, there is the likelihood of influence of the context with quality of life adopting different meanings to patients in different areas and […]
• Providers’ Role in Quality Assurance in Breast Cancer Screening In order to ensure the quality assurance of mammography, the providers involved in the procedure need to be aware of the roles they ought to play.
• Clinical Laboratory Science of Breast Cancer The word cancer is itself so much dreaded by people that the very occurrence of the disease takes half of the life away from the patient and the relatives.
• Induced and Spontaneous Abortion and Breast Cancer Incidence Among Young Women There is also no question as to whether those who had breast cancer was only as a result of abortion the cohort study does not define the total number of women in population.
• New Screening Guidelines for Breast Cancer On the whole, the Task Force reports that a 15% reduction in breast cancer mortality that can be ascribed to the use of mammograms seems decidedly low compared to the risks and harm which tend […]
• Breast Cancer in Afro- and Euro-Americans It is seen that in the age group of more than 50 years, EA was more at risk of contracting cancer, as compared to AA.
• Breast Cancer Assessment in London In light of these developments, it is therefore important that an evaluation of breast cancer amongst women in London be carried out, in order to explore strategies and policy formulations that could be implemented, with […]
• Breast Cancer: At-Risk Population, Barriers, and Improvement Thus, the principal purpose of Part Two is to explain why older women face a higher risk of getting breast cancer, what barriers lead to this adverse state of affairs, and how to improve the […]
• Breast Cancer: Moral and Medical Aspects In addition to the question of the surgery, there is an ethical problem associated with the genetic characteristics of the disease.
• Breast Cancer and AIDS: Significant Issues in the United States in the Late 20th Century Thus, the given paper is going to explain why these activists challenged regulatory and scientific authorities and what they demanded. That is why the enthusiasts challenged their practices and made specific demands to improve the […]
• Breast Cancer Risk Factors: Genetic and Nutritional Influences However, the problems of genetics contribute to the identification of this disease, since the essence of the problem requires constant monitoring of the state of the mammary glands to detect cancer at an early stage.
• Breast Cancer Genetics & Chromosomal Analysis In this paper, the chromosomal analysis of breast cancer will be assessed, and the causes of the disorder will be detailed.
• Breast Cancer: The Case of Anne H. For this reason, even females with a high level of health literacy and awareness of breast cancer, such as Anne H, might still belong to the group risk and discover the issue at its late […]
• Genetic Predisposition to Breast Cancer: Genetic Testing Their choice to have their first baby later in life and hormonal treatment for symptoms of menopause further increase the risk of breast cancer in women.
• Breast Cancer: Causes and Treatment According to Iversen et al this situation is comparable to the finding of abnormal cells on the surface of the cervix, curable by excision or vaporization of the tissue.
• Breast Cancer: Women’s Health Initiative & Practices The new standard of care shows evidence that a low-fat diet, deemed insignificant by the WHI study, is beneficial to women for preventing or improving their risks of breast cancer.
• Breast Cancer: Health Psychology Plan The goal of the plan is to identify the psychological issues and health priorities of the subject and propose a strategy for addressing them.
• Best Practices in Breast Cancer Care Based on this, the final stage of therapy should include comprehensive support for patients with breast cancer as one of the main health care practices within the framework of current treatment guidelines.
• Complementary and Alternative Medicine for Women With Breast Cancer The treatment of breast CA has developed over the past 20 years, and many treatment centers offer a variety of modalities and holistic treatment options in addition to medical management.
• Screening for Breast Cancer The main goal of this paper is to describe the specific set of clinical circumstances under which the application of screening is the most beneficial for women aged 40 to 74 years.
• Annual Breast Cancer Awareness Campaign It may also need more time to be implemented as the development of the advertisement, and all visuals will take time.
• Breast Cancer Patients’ Functions and Suitable Jobs The key symptom of breast cancer is the occurrence of a protuberance in the breast. A screening mammography, scrutiny of the patient’s family history and a breast examination help in the diagnosis of breast cancer.
• Jordanian Breast Cancer Survival Rates in 1997-2002 This objective came from the realization that the best way to test the efficacy of breast cancer treatment and to uncover intervening factors influencing the efficacy of these treatments was to investigate the rates of […]
• Breast Cancer Screening Among Non-Adherent Women This is one of the aspects that can be identified. This is one of the short-comings that can be singled out, and this particular model may not be fully appropriate in this context.
• Breast Cancer: Treatment and Rehabilitation Options Depending on the site of occurrence, breast cancer can form ductal carcinomas and lobular carcinomas if they occur in the ducts and lobules of the breast, respectively. Breast cancer and treatment methods have significant effects […]
• Women Healthcare: Breast Cancer Reducing the levels of myoferlin alters the breast cancer cells’ mechanical properties, as it is evident from the fact that the shape and ability of breast cancer cells to spread is low with reduced production […]
• Breast Cancer Public Relations Campaign Audiences It is clear that the breast cancer campaign will target at women in their 30-40s as this is one of the most vulnerable categories of women as they often pay little attention to the […]
• Health Information Seeking and Breast Cancer Diagnosis Emotional support is also concerned with the kind of information given to patients and how the information is conveyed. It is equally significant to underscore the role of information in handling breast cancer patients immediately […]
• Breast Cancer: Disease Prevention The first indicator of breast cancer is the presence of a lump that feels like a swollen matter that is not tender like the rest of the breast tissues.
• Breast Cancer Definition and Treatment In the case where “the cells which appear like breast cancer are still confined to the ducts or lobules of the breast, it is called pre-invasive breast cancer”.”The most widespread pre-invasive type of breast cancer […]
• Breast Cancer Incidence and Ethnicity This paper explores the different rates of breast cancer incidence as far as the different ethnic groups in the US are concerned as well as the most probable way of reducing the rates of incidence […]
• Treatment Options for Breast Cancer This type of breast cancer manifests itself in the tubes/ducts which form the channel for transporting milk from the breast to the nipple.”Lobular carcinoma: this type of cancer usually begins in the milk producing regions […]
• Risk Factors, Staging, and Treatment of Breast Cancer This is so because huge amounts of resources have been used in the research and the development of the breast cancer drugs that in effect help the body to combat the cancer by providing additional […]
• Case Management for Breast Cancer Patients In this respect, preventive measures should be taken in order to decrease the mortality rates all over the world in terms of cancer illness and breast cancer in particular.
• The Second Leading Cause of Death Is the Breast Cancer
• The Benefits and Effects of Exercise on Post-treatment Breast Cancer Patients
• Women’s Experiences Undergoing Reconstructive Surgery After Mastectomy Due to Breast Cancer
• Advanced Technology of the Treatment of Breast Cancer
• The Role of Perivascular Macrophages in Breast Cancer Metastasis
• Using Genetic Testing for Breast Cancer
• The Psychological Aspect of Coping With Breast Cancer
• An Analysis of an Alternative Prevention in Breast Cancer for Young Women in America
• The Complicated Biology of Breast Cancer
• The Impact of Tamoxifen Adjuvant Therapy on Breast Cancer
• The Prevalence of Breast Cancer Among Black Women
• The Embodiment Theory, Holistic Approach and Breast Cancer in the South African Context
• The Long-Term Evolution of Quality of Life for Breast Cancer Treated Patients
• The Signs and Early Prevention of Breast Cancer
• The Effect of Fast Food in Developing Breast Cancer Among Saudi Populations
• The Effect of Breastfeeding on Ovarian and Breast Cancer
• The Best Method of Medicine for the Treatment of Breast Cancer: CAM or Drugs
• The Causes of Breast Cancer – Genetically or Environmentally Influenced
• The Symptoms, Causes and Treatment of Breast Cancer, a Malignant Disease
• The Risks, Characteristics and Symptoms of Breast Cancer, a Malignant Disease
• The Most Common Cancer in the UK: Breast Cancer
• Types of Preventive Services for a Higher Risk of Breast Cancer
• The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women
• The Impact of Culture and Location on Breast Cancer Around the World
• Understanding Breast Cancer, Its Triggers and Treatment Options
• The Risk, Development, Diagnosis, and Treatment of Breast Cancer in Women
• The Pathophysiology of Breast Cancer
• The Effects of DNA Methylation on Breast Cancer
• The Treatment and Management Options for Breast Cancer Patients
• Alternative Forms of Medicine for Breast Cancer Rates
• The Impact of Nutrition on Breast Cancer and Cervical Cancer
• The Economic Evaluation of Screening for Breast Cancer: A Tentative Methodology
• Etymology of Breast Cancer: Types, Risk Factors, Early Detection Methods, and Demographics
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• The Various Views and Approaches in the Treatment and Management of Breast Cancer
• The Growing Health Problem of Breast Cancer in the United States
• The Importance of Considering Breast Cancer Prevention Aside From Treatment
• The Different Ways That Can Reduce the Risk of Having Breast Cancer
• The Use of Radiation for Detection and Treatment of Breast Cancer
• The Condition of Breast Cancer and Its Relevant Treatment
• The Relationship Between a High-Dairy Diet and Breast Cancer in Women
• Treatment of Solid Tumors Including Metastatic Breast Cancer
• Which Is More Effective in Reducing Arm Lymphoedema for Breast Cancer Patients
• The Use of Telomerase in Diagnosis, Prognosis, and Treatment of Cancer: With a Special Look at Breast Cancer
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IvyPanda. (2024, November 18). 118 Breast Cancer Essay Topic Ideas & Examples. https://ivypanda.com/essays/topic/breast-cancer-essay-topics/

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Breast Cancer Research Table Topics

Established and probable risk factors, mammography, ductal carcinoma in situ (dcis), early and locally advanced breast cancer, inflammatory breast cancer (non-metastatic), metastatic breast cancer.

Updated 11/20/24

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Cilengitide sensitivity is predicted by overall integrin expression in breast cancer

Treatment options for triple-negative breast cancer (TNBC) are limited and patients face a poor prognosis. Here, we sought to identify drugs that target TNBC vulnerabilities and understand the biology underlyi...

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Protective effects of miR-24-2-5p in early stages of breast cancer bone metastasis

Bone is the most frequent site of metastasis for breast cancer (BC). Metastatic BC cells interact with bone cells, including osteoclasts and osteoblasts, creating a cancer niche where they seed and proliferate...

ERBB2 / HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers

The HOXB13/IL17RB gene expression biomarker has been shown to predict response to adjuvant and extended endocrine therapy in patients with early-stage ER+ HER2- breast tumors. HOXB13 gene expression is the primar...

A hybrid epithelial-mesenchymal transition program enables basal epithelial cells to bypass stress-induced stasis and contributes to a metaplastic breast cancer progenitor state

Human mammary epithelial cell (HMEC) cultures encounter a stress-associated barrier termed stasis, during which most cells adopt a senescence-like phenotype. From these cultures, rare variants emerge from the ...

Oncogene activated human breast luminal progenitors contribute basally located myoepithelial cells

Basal-like breast cancer originates in luminal progenitors, frequently with an altered PI3K pathway, and focally in close association with genetically altered myoepithelial cells at the site of tumor initiatio...

Stromal tumor-infiltrating lymphocytes and pathologic response to neoadjuvant chemotherapy with the addition of platinum and pembrolizumab in TNBC: a single-center real-world study

Immunochemotherapy with pembrolizumab has been integrated into clinical practice as part of the standard-of-care for non-metastatic triple-negative breast cancer (TNBC) with high risk. We conducted a real-worl...

Intraoperative radiotherapy versus whole breast radiotherapy in early-stage breast cancer: a retrospective outcome analysis based on ASTRO guidelines on PBI

Intraoperative radiotherapy (IORT) is a convenient treatment techniques for patients with early-stage breast cancer. We aimed to compare the outcome of IORT to that of whole-breast external beam radiotherapy (...

Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer

The tumor immune microenvironment, particularly tumor-infiltrating lymphocytes (TILs), plays a critical role in disease progression and treatment response in triple-negative breast cancers (TNBCs). This study ...

Alcohol cessation and breast cancer risk stratified by hormone receptor status

Because alcohol consumption is an established cause of female breast cancer, understanding whether cessation affects risk is of public health importance. In a recent meta-analysis, compared with continuing con...

Multimodal genome-wide survey of progressing and non-progressing breast ductal carcinoma in-situ

Ductal carcinoma in-situ (DCIS) is a pre-invasive form of invasive breast cancer (IBC). Due to improved breast cancer screening, it now accounts for ~ 25% of all breast cancers. While the treatment success rat...

Image analysis-based identification of high risk ER-positive, HER2-negative breast cancers

Breast cancer subtypes Luminal A and Luminal B are classified by the expression of PAM50 genes and may benefit from different treatment strategies. Machine learning models based on H&E images may contain featu...

Social vulnerability is associated with advanced breast cancer presentation and all-cause mortality: a retrospective cohort study

Disparities in breast cancer mortality persist despite improvements in screening and therapeutic options. Understanding the impact of social determinants of health on disparate breast cancer outcomes is challe...

NF-κB associated markers of prognosis in early and metastatic triple negative breast cancer

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. While PD-1 based immunotherapies overall have led to improved treatment outcomes for this disease, a diverse response to fr...

Gremlin-2 is a novel tumor suppressor that negatively regulates ID1 in breast cancer

Breast cancer is one of the most common cancers in women and is closely associated with obesity. Gremlin-2 (GREM2), an antagonist for bone morphogenetic proteins (BMPs), has been considered an inhibitor of adi...

Correction: Quantification of intratumoral heterogeneity using habitat-based MRI radiomics to identify HER2-positive, -low and -zero breast cancers: a multicenter study

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Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review

Sergiusz łukasiewicz, marcin czeczelewski, alicja forma, robert sitarz, andrzej stanisławek.

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Correspondence: [email protected]

Received 2021 Jul 6; Accepted 2021 Aug 23; Collection date 2021 Sep.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/ ).

Simple Summary

Breast cancer is the most common cancer among women. It is estimated that 2.3 million new cases of BC are diagnosed globally each year. Based on mRNA gene expression levels, BC can be divided into molecular subtypes that provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. This review addresses the overview on the BC epidemiology, risk factors, classification with an emphasis on molecular types, prognostic biomarkers, as well as possible treatment modalities.

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences.

Keywords: breast cancer, epidemiology, risk factors, classification, diagnosis, prognosis, marker, treatment

1. Introduction

Being characterized by six major hallmarks, carcinogenesis might occur in every cell, tissue, and organ, leading to the pathological alternations that result in a vast number of cancers. The major mechanisms that enable its progression include evasion of apoptosis, limitless capacity to divide, enhanced angiogenesis, resistance to anti-growth signals and induction of own growth signals, as well as the capacity to metastasize [ 1 ]. Carcinogenesis is a multifactorial process that is primarily stimulated by both—genetic predispositions and environmental causes. The number of cancer-related deaths is disturbingly increasing every year ranking them as one of the major causes of death worldwide. Even though a significant number of cancers do not always need to result in death, they significantly lower the quality of life and require larger costs in general.

Breast cancer is currently one of the most prevalently diagnosed cancers and the 5th cause of cancer-related deaths with an estimated number of 2.3 million new cases worldwide according to the GLOBOCAN 2020 data [ 2 ]. Deaths due to breast cancer are more prevalently reported (an incidence rate approximately 88% higher) in transitioning countries (Melanesia, Western Africa, Micronesia/Polynesia, and the Caribbean) compared to the transitioned ones (Australia/New Zealand, Western Europe, Northern America, and Northern Europe). Several procedures such as preventive behaviors in general as well as screening programs are crucial regarding a possible minimization of breast cancer incidence rate and the implementation of early treatment. Currently, it is the Breast Health Global Initiative (BHGI) that is responsible for the preparation of proper guidelines and the approaches to provide the most sufficient breast cancer control worldwide [ 3 ]. In this review article, we have focused on the female breast cancer specifically since as abovementioned, it currently constitutes the most prevalent cancer amongst females.

2. Breast Cancer Epidemiology

According to the WHO, malignant neoplasms are the greatest worldwide burden for women, estimated at 107.8 million Disability-Adjusted Life Years (DALYs), of which 19.6 million DALYs are due to breast cancer. [ 4 ]. Breast cancer is the most frequently diagnosed cancer in women worldwide with 2.26 million [95% UI, 2.24–2.79 million] new cases in 2020 [ 5 ]. In the United States, breast cancer alone is expected to account for 29% of all new cancers in women [ 6 ]. The 2018 GLOBOCAN data shows that age-standardized incidence rates (ASIR) of breast cancer are strongly and positively associated with the Human Development Index (HDI) [ 7 ]. According to 2020 data, the ASIR was the highest in very high HDI countries (75.6 per 100,000) while it was more than 200% lower in medium and low HDI countries (27.8 per 100,000 and 36.1 per 100,000 respectively) [ 5 ].

Besides being the most common, breast cancer is also the leading cause of cancer death in women worldwide. Globally, breast cancer was responsible for 684,996 deaths [95% UI, 675,493–694,633] at an age-adjusted rate of 13.6/100,000 [ 5 ]. Although incidence rates were the highest in developed regions, the countries in Asia and Africa shared 63% of total deaths in 2020 [ 5 ]. Most women who develop breast cancer in a high-income country will survive; the opposite is true for women in most low-income and many middle-income countries [ 8 ].

In 2020 breast cancer mortality-to-incidence ratio (MIR) as a representative indicator of 5-year survival rates [ 9 ] was 0.30 globally [ 5 ]. Taking into consideration the clinical extent of breast cancer, in locations with developed health care (Hong-Kong, Singapore, Turkey) the 5-year survival was 89.6% for localized and 75.4% for regional cancer. In less developed countries (Costa Rica, India, Philippines, Saudi Arabia, Thailand) the survival rates were 76.3% and 47.4% for localized and regional breast cancer respectively [ 10 ].

Breast cancer incidence and death rates have increased over the last three decades. Between 1990 and 2016 breast cancer incidence has more than doubled in 60/102 countries (e.g., Afghanistan, Philippines, Brazil, Argentina), whereas deaths have doubled in 43/102 countries (e.g., Yemen, Paraguay, Libya, Saudi Arabia) [ 11 ]. Current projections indicate that by 2030 the worldwide number of new cases diagnosed reach 2.7 million annually, while the number of deaths 0.87 million [ 12 ]. In low- and medium-income countries, the breast cancer incidence is expected to increase further due to the westernization of lifestyles (e.g., delayed pregnancies, reduced breastfeeding, low age at menarche, lack of physical activity, and poor diet), better cancer registration, and cancer detection [ 13 ].

3. Risk Factors of Breast Cancer

The number of risk factors of breast cancer is significant and includes both modifiable factors and non-modifiable factors ( Table 1 ).

Modifiable and non-modifiable risk factors of breast cancer.

3.1. Non-Modifiable Factors

3.1.1. female sex.

Female sex constitutes one of the major factors associated with an increased risk of breast cancer primarily because of the enhanced hormonal stimulation. Unlike men who present insignificant estrogen levels, women have breast cells which are very vulnerable to hormones (estrogen and progesterone in particular) as well as any disruptions in their balance. Circulating estrogens and androgens are positively associated with an increased risk of breast cancer [ 14 ]. The alternations within the physiological levels of the endogenous levels of sex hormones result in a higher risk of breast cancer in the case of premenopausal and postmenopausal women; these observations were also supported by the Endogenous Hormones and Breast Cancer Collaborative Group [ 15 , 16 , 17 ].

Less than 1% of all breast cancers occur in men. However, breast cancer in men is a rare disease that’s at the time of diagnosis tends to be more advanced than in women. The average age of men at the diagnosis is about 67. The important factors increase a man’s risk of breast cancer are: older age, BRCA2/BRCA1 mutations, increased estrogen levels, Klinefelter syndrome, family history of breast cancer, and radiation exposure [ 18 ].

3.1.2. Older Age

Currently, about 80% of patients with breast cancer are individuals aged >50 while at the same time more than 40% are those more than 65 years old [ 19 , 20 , 21 ]. The risk of developing breast cancer increases as follows—the 1.5% risk at age 40, 3% at age 50, and more than 4% at age 70 [ 22 ]. Interestingly, a relationship between a particular molecular subtype of cancer and a patient’s age was observed –aggressive resistant triple-negative breast cancer subtype is most commonly diagnosed in groups under 40 age, while in patients >70, it is luminal A subtype [ 21 ]. Generally, the occurrence of cancer in older age is not only limited to breast cancer; the accumulation of a vast number of cellular alternations and exposition to potential carcinogens results in an increase of carcinogenesis with time.

3.1.3. Family History

A family history of breast cancer constitutes a major factor significantly associated with an increased risk of breast cancer. Approximately 13–19% of patients diagnosed with breast cancer report a first-degree relative affected by the same condition [ 23 ]. Besides, the risk of breast cancer significantly increases with an increasing number of first-degree relatives affected; the risk might be even higher when the affected relatives are under 50 years old [ 24 , 25 , 26 ]. The incidence rate of breast cancer is significantly higher in all of the patients with a family history despite the age. This association is driven by epigenetic changes as well as environmental factors acting as potential triggers [ 27 ]. A family history of ovarian cancer—especially those characterized by BRCA1 and BRCA2 mutations—might also induce a greater risk of breast cancer [ 28 ].

3.1.4. Genetic Mutations

Several genetic mutations were reported to be highly associated with an increased risk of breast cancer. Two major genes characterized by a high penetrance are BRCA1 (located on chromosome 17) and BRCA2 (located on chromosome 13). They are primarily linked to the increased risk of breast carcinogenesis [ 29 ]. The mutations within the above-mentioned genes are mainly inherited in an autosomal dominant manner, however, sporadic mutations are also commonly reported. Other highly penetrant breast cancer genes include TP53 , CDH1 , PTEN , and STK11 [ 30 , 31 , 32 , 33 , 34 ]. Except for the increased risk of breast cancer, carriers of such mutations are more susceptible to ovarian cancer as well. A significant number of DNA repair genes that can interact with BRCA genes including ATM , PALB2 , BRIP1 , or CHEK2 , were reported to be involved in the induction of breast carcinogenesis; those are however characterized by a lower penetrance (moderate degree) compared to BRCA1 or BRCA2 ( Table 2 ) [ 29 , 35 , 36 , 37 , 38 ]. According to quite recent Polish research, mutations within the XRCC2 gene could also be potentially associated with an increased risk of breast cancer [ 39 ].

Major genes associated with an increased risk of breast cancer occurrence.

3.1.5. Race/Ethnicity

Disparities regarding race and ethnicity remain widely observed among individuals affected by breast cancer; the mechanisms associated with this phenomenon are not yet understood. Generally, the breast cancer incidence rate remains the highest among white non-Hispanic women [ 51 , 52 ]. Contrarily, the mortality rate due to this malignancy is significantly higher among black women; this group is also characterized by the lowest survival rates [ 53 ].

3.1.6. Reproductive History

Numerous studies confirmed a strict relationship between exposure to endogenous hormones—estrogen and progesterone in particular—and excessive risk of breast cancer in females. Therefore, the occurrence of specific events such as pregnancy, breastfeeding, first menstruation, and menopause along with their duration and the concomitant hormonal imbalance, are crucial in terms of a potential induction of the carcinogenic events in the breast microenvironment. The first full-term pregnancy at an early age (especially in the early twenties) along with a subsequently increasing number of births are associated with a reduced risk of breast cancer [ 54 , 55 ]. Besides, the pregnancy itself provides protective effects against potential cancer. However, protection was observed at approximately the 34th pregnancy week and was not confirmed for the pregnancies lasting for 33 weeks or less [ 56 ]. Women with a history of preeclampsia during pregnancy or children born to a preeclamptic pregnancy are at lower risk of developing breast cancer [ 57 ]. No association between the increased breast cancer risk and abortion was stated so far [ 58 ].

The dysregulated hormone levels during preeclampsia including increased progesterone and reduced estrogen levels along with insulin, cortisol, insulin-like growth factor-1, androgens, human chorionic gonadotropin, corticotropin-releasing factor, and IGF-1 binding protein deviating from the physiological ranges, show a protective effect preventing from breast carcinogenesis. The longer duration of the breastfeeding period also reduces the risk of both the ER/PR-positive and -negative cancers [ 59 ]. Early age at menarche is another risk factor of breast cancer; it is possibly also associated with a tumor grade and lymph node involvement [ 60 ]. Besides, the earlier age of the first menstruation could result in an overall poorer prognosis. Contrarily, early menopause despite whether natural or surgical, lowers the breast cancer risk [ 61 ].

3.1.7. Density of Breast Tissue

The density of breast tissue remains inconsistent throughout the lifetime; however, several categories including low-density, high-density, and fatty breasts have been established in clinical practice. Greater density of breasts is observed in females of younger age and lower BMI, who are pregnant or during the breastfeeding period, as well as during the intake of hormonal replacement therapy [ 62 ]. Generally, the greater breast tissue density correlates with the greater breast cancer risk; this trend is observed both in premenopausal and postmenopausal females [ 63 ]. It was proposed that screening of breast tissue density could be a promising, non-invasive, and quick method enabling rational surveillance of females at increased risk of cancer [ 64 ].

3.1.8. History of Breast Cancer and Benign Breast Diseases

Personal history of breast cancer is associated with a greater risk of a renewed cancerous lesions within the breasts [ 65 ]. Besides, a history of any other non-cancerous alternations in breasts such as atypical hyperplasia, carcinoma in situ, or many other proliferative or non-proliferative lesions, also increases the risk significantly [ 66 , 67 , 68 ]. The histologic classification of benign lesions and a family history of breast cancer are two factors that are strongly associated with breast cancer risk [ 66 ].

3.1.9. Previous Radiation Therapy

The risk of secondary malignancies after radiotherapy treatment remains an individual matter that depends on the patient’s characteristics, even though it is a quite frequent phenomenon that arises much clinical concern. Cancer induced by radiation therapy is strictly associated with an individual’s age; patients who receive radiation therapy before the age of 30, are at a greater risk of breast cancer [ 69 ]. The selection of proper radiotherapy technique is crucial in terms of secondary cancer risk—for instance, tangential field IMRT (2F-IMRT) is associated with a significantly lower risk compared to multiple-field IMRT (6F-IMRT) or double partial arcs (VMAT) [ 70 ]. Besides, the family history of breast cancer in patients who receive radiotherapy additionally enhances the risk of cancer occurrence [ 71 ]. However, Bartelink et al. showed that additional radiation (16 Gy) to the tumor bed combined with standard radiotherapy might decrease the risk of local recurrence [ 72 ].

3.2. Modifiable Factors

3.2.1. chosen drugs.

Data from some research indicates that the intake of diethylstilbestrol during pregnancy might be associated with a greater risk of breast cancer in children; this, however, remains inconsistent between studies and requires further evaluation [ 73 , 74 ]. The intake of diethylstilbestrol during pregnancy is associated with an increased risk of breast cancer not only in mothers but also in the offspring [ 75 ]. This relationship is observed despite the expression of neither estrogen nor progesterone receptors and might be associated with every breast cancer histological type. The risk increases with age; women at age of ≥40 years are nearly 1.9 times more susceptible compared to women under 40. Moreover, breast cancer risk increases with greater diethylstilbestrol doses [ 76 ]. Numerous researches indicate that females who use hormonal replacement therapy (HRT) especially longer than 5 or 7 years are also at increased risk of breast cancer [ 77 , 78 ]. Several studies indicated that the intake of chosen antidepressants, mainly paroxetine, tricyclic antidepressants, and selective serotonin reuptake inhibitors might be associated with a greater risk of breast cancer [ 79 , 80 ]. Lawlor et al. showed that similar risk might be achieved due to the prolonged intake of antibiotics; Friedman et al. observed that breast risk is mostly elevated while using tetracyclines [ 81 , 82 ]. Attempts were made to investigate a potential relationship between hypertensive medications, non-steroidal anti-inflammatory drugs, as well as statins, and an elevated risk of breast cancer, however, this data remains highly inconsistent [ 83 , 84 , 85 ].

3.2.2. Physical Activity

Even though the mechanism remains yet undeciphered, regular physical activity is considered to be a protective factor of breast cancer incidence [ 86 , 87 ]. Chen et al. observed that amongst females with a family history of breast cancer, physical activity was associated with a reduced risk of cancer but limited only to the postmenopausal period [ 88 ]. However, physical activity is beneficial not only in females with a family history of breast cancer but also in those without such a history. Contrarily to the above-mentioned study, Thune et al. pointed out more pronounced effects in premenopausal females [ 89 ]. There are several hypotheses aiming to explain the protective role of physical activity in terms of breast cancer incidence; physical activity might prevent cancer by reducing the exposure to the endogenous sex hormones, altering immune system responses or insulin-like growth factor-1 levels [ 88 , 90 , 91 ].

3.2.3. Body Mass Index

According to epidemiological evidence, obesity is associated with a greater probability of breast cancer. This association is mostly intensified in obese post-menopausal females who tend to develop estrogen-receptor-positive breast cancer. Yet, independently to menopausal status, obese women achieve poorer clinical outcomes [ 92 ]. Wang et al. showed that females above 50 years old with greater Body Mass Index (BMI) are at a greater risk of cancer compared to those with low BMI [ 93 ]. Besides, the researchers observed that greater BMI is associated with more aggressive biological features of tumor including a higher percentage of lymph node metastasis and greater size. Obesity might be a reason for greater mortality rates and a higher probability of cancer relapse, especially in premenopausal women [ 94 ]. Increased body fat might enhance the inflammatory state and affects the levels of circulating hormones facilitating pro-carcinogenic events [ 95 ]. Thus, poorer clinical outcomes are primarily observed in females with BMI ≥ 25 kg/m 2 [ 96 ]. Interestingly, postmenopausal women tend to present poorer clinical outcomes despite proper BMI values but namely due to excessive fat volume [ 97 ]. Greater breast cancer risk with regards to BMI also correlates with the concomitant family history of breast cancer [ 98 ].

3.2.4. Alcohol Intake

Numerous evidences confirm that excessive alcohol consumption is a factor that might enhance the risk of malignancies within the gastrointestinal tract; however, it was proved that it is also linked to the risk of breast cancer. Namely, it is not alcohol type but rather the content of alcoholic beverages that mostly affect the risk of cancer. The explanation for this association is the increased levels of estrogens induced by the alcohol intake and thus hormonal imbalance affecting the risk of carcinogenesis within the female organs [ 99 , 100 ]. Besides, alcohol intake often results in excessive fat gain with higher BMI levels, which additionally increases the risk. Other hypotheses include direct and indirect carcinogenic effects of alcohol metabolites and alcohol-related impaired nutrient intake [ 101 ]. Alcohol consumption was observed to increase the risk of estrogen-positive breast cancers in particular [ 102 ]. Consumed before the first pregnancy, it significantly contributes to the induction of morphological alterations of breast tissue, predisposing it to further carcinogenic events [ 103 ].

3.2.5. Smoking

Carcinogens found in tobacco are transported to the breast tissue increasing the plausibility of mutations within oncogenes and suppressor genes ( p53 in particular). Thus, not only active but also passive smoking significantly contributes to the induction of pro-carcinogenic events [ 104 ]. Besides, longer smoking history, as well as smoking before the first full-term pregnancy, are additional risk factors that are additionally pronounced in females with a family history of breast cancer [ 105 , 106 , 107 , 108 ].

3.2.6. Insufficient Vitamin Supplementation

Vitamins exert anticancer properties, which might potentially benefit in the prevention of several malignancies including breast cancer, however, the mechanism is not yet fully understood. Attempts are continually made to analyze the effects of vitamin intake (vitamin C, vitamin E, B-group vitamins, folic acid, multivitamin) on the risk of breast cancer, nevertheless, the data remains inconsistent and not sufficient to compare the results and draw credible data [ 108 ]. In terms of breast cancer, most studies are currently focused on vitamin D supplementation confirming its potentially protective effects [ 109 , 110 , 111 ]. High serum 25-hydroxyvitamin D levels are associated with a lower incidence rate of breast cancer in premenopausal and postmenopausal women [ 110 , 112 ]. Intensified expression of vitamin D receptors was shown to be associated with lower mortality rates due to breast cancer [ 113 ]. Even so, further evaluation is required since data remains inconsistent in this matter [ 108 , 114 ].

3.2.7. Exposure to Artificial Light

Artificial light at night (ALAN) has been recently linked to increased breast cancer risk. The probable causation might be a disrupted melatonin rhythm and subsequent epigenetic alterations [ 115 ]. According to the studies conducted so far, increased exposure to ALAN is associated with a significantly greater risk of breast cancer compared to individuals with lowered ALAN exposure [ 116 ]. Nonetheless, data regarding the excessive usage of LED electronic devices and increased risk of breast cancer is insufficient and requires further evaluation as some results are contradictory [ 116 ].

3.2.8. Intake of Processed Food/Diet

According to the World Health Organization (WHO), highly processed meat was classified as a Group 1 carcinogen that might increase the risk of not only gastrointestinal malignancies but also breast cancer. Similar observations were made in terms of an excessive intake of saturated fats [ 117 ]. Ultra-processed food is rich in sodium, fat, and sugar which subsequently predisposes to obesity recognized as another factor of breast cancer risk [ 118 ]. It was observed that a 10% increase of ultra-processed food in the diet is associated with an 11% greater risk of breast cancer [ 118 ]. Contrarily, a diet high in vegetables, fruits, legumes, whole grains, and lean protein is associated with a lowered risk of breast cancer [ 119 ]. Generally, a diet that includes food containing high amounts of n-3 PUFA, vitamin D, fiber, folate, and phytoestrogen might be beneficial as a prevention of breast cancer [ 120 ]. Besides, lower intake of n-6 PUFA and saturated fat is recommended. Several in vitro and in vivo studies also suggest that specific compounds found in green tea might present anti-cancer effects which has also been studied regarding breast cancer [ 121 ]. Similar properties were observed in case of turmeric-derived curcuminoids as well as sulforaphane (SFN) [ 122 , 123 ].

3.2.9. Exposure to Chemical

Chronic exposure to chemicals can promote breast carcinogenesis by affecting the tumor microenvironment subsequently inducing epigenetic alterations along with the induction of pro-carcinogenic events [ 124 ]. Females chronically exposed to chemicals present significantly greater plausibility of breast cancer which is further positively associated with the duration of the exposure [ 125 ]. The number of chemicals proposed to induce breast carcinogenesis is significant; so far, dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyl (PCB) are mostly investigated in terms of breast cancer since early exposure to those chemicals disrupts the development of mammary glands [ 126 , 127 ]. A potential relationship was also observed in the case of increased exposure to polycyclic aromatic hydrocarbons (PAH), synthetic fibers, organic solvents, oil mist, and insecticides [ 128 ].

3.2.10. Other Drugs

Other drugs that might constitute potential risk factors for breast cancer include antibiotics, antidepressants, statins, antihypertensive medications (e.g., calcium channel blockers, angiotensin II-converting enzyme inhibitors), as well as NSAIDs (including aspirin, ibuprofen) [ 129 , 130 , 131 , 132 , 133 ].

4. Breast Cancer Classification

4.1. histological classification.

Invasive breast cancers (IBC) comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. The World Health Organization (WHO) distinguish at least 18 different histological breast cancer types [ 134 ].

Invasive breast cancer of no special type (NST), formerly known as invasive ductal carcinoma is the most frequent subgroup (40–80%) [ 135 ]. This type is diagnosed by default as a tumor that fails to be classified into one of the histological special types [ 134 ]. About 25% of invasive breast cancers present distinctive growth patterns and cytological features, hence, they are recognized as specific subtypes (e.g., invasive lobular carcinoma, tubular, mucinous A, mucinous B, neuroendocrine) [ 136 ].

Molecular classification independently from histological subtypes, invasive breast cancer can be divided into molecular subtypes based on mRNA gene expression levels. In 2000, Perou et al. on a sample of 38 breast cancers identified 4 molecular subtypes from microarray gene expression data: Luminal, HER2-enriched, Basal-like, and Normal Breast-like [ 137 ]. Further studies allowed to divide the Luminal group into two subgroups (Luminal A and B) [ 138 , 139 ]. The normal breast-like subtype has subsequently been omitted, as it is thought to represent sample contamination by normal mammary glands. In the Cancer Genome Atlas Project (TCGA) over 300 primary tumors were thoroughly profiled (at DNA, RNA, and protein levels) and combined in biological homogenous groups of tumors. The consensus clustering confirmed the distinction of four main breast cancer intrinsic subtypes based on mRNA gene expression levels only (Luminal A, Luminal B, HER2-enriched, and basal-like) [ 140 ]. Additionally, the 5th intrinsic subtype—claudin-low breast cancer was discovered in 2007 in an integrated analysis of human and murine mammary tumors [ 141 ].

In 2009, Parker et al. developed a 50-gene signature for subtype assignment, known as PAM50, that could reliably classify particular breast cancer into the main intrinsic subtypes with 93% accuracy [ 142 ]. PAM50 is now clinically implemented worldwide using the NanoString nCounter ® , which is the basis for the Prosigna ® test. The Prosigna ® combines the PAM50 assay as well as clinical information to assess the risk of distant relapse estimation in postmenopausal women with hormone receptor-positive, node-negative, or node-positive early-stage breast cancer patients, and is a daily-used tool assessing the indication of adjuvant chemotherapy [ 143 , 144 , 145 ].

4.2. Luminal Breast Cancer

Luminal breast cancers are ER-positive tumors that comprise almost 70% of all cases of breast cancers in Western populations [ 146 ]. Most commonly Luminal-like cancers present as IBC of no special subtype, but they may infrequently differentiate into invasive lobular, tubular, invasive cribriform, mucinous, and invasive micropapillary carcinomas [ 147 , 148 ]. Two main biological processes: proliferation-related pathways and luminal-regulated pathways distinguish Luminal-like tumors into Luminal A and B subtypes with different clinical outcomes.

Luminal A tumors are characterized by presence of estrogen-receptor (ER) and/or progesterone-receptor (PR) and absence of HER2. In this subtype the ER transcription factors activate genes, the expression of which is characteristic for luminal epithelium lining the mammary ducts [ 149 , 150 ]. It also presents a low expression of genes related to cell proliferation [ 151 ]. Clinically they are low-grade, slow-growing, and tend to have the best prognosis.

In contrast to subtype A, Luminal B tumors are higher grade and has worse prognosis. They are ER positive and may be PR negative and/or HER2 positive. Additionally, it has high expression of proliferation-related genes (e.g., MKI67 and AURKA) [ 152 , 153 , 154 ]. This subtype has lower expression of genes or proteins typical for luminal epithelium such as the PR [ 150 , 155 ] and FOXA1 [ 146 , 156 ], but not the ER [ 157 ]. ER is similarly expressed in both A and B subtypes and is used to distinguish luminal from non-luminal disease.

4.3. HER2-Enriched Breast Cancer

The HER2-enriched group makes up 10–15% of breast cancers. It is characterized by the high expression of the HER2 with the absence of ER and PR. This subtype mainly expresses proliferation—related genes and proteins (e.g., ERBB2/HER2 and GRB7), rather than luminal and basal gene and protein clusters [ 154 , 156 , 157 ]. Additionally, in the HER2-enriched subtype there is evidence of mutagenesis mediated by APOBEC3B. APOBEC3B is a subclass of APOBEC cytidine deaminases, which induce cytosine mutation biases and is a source of mutation clusters [ 158 , 159 , 160 ].

HER2-enriched cancers grow faster than luminal cancers and used to have the worst prognosis of subtypes before the introduction of HER2-targeted therapies. Importantly, the HER2-enriched subtype is not synonymous with clinically HER2-positive breast cancer because many ER-positive/HER2-positive tumors qualify for the luminal B group. Moreover, about 30% of HER2-enriched tumors are classified as clinically HER2-negative based on immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) methods [ 161 ].

4.4. Basal-Like/Triple-Negative Breast Cancer

The Triple-Negative Breast Cancer (TNBC) is a heterogeneous collection of breast cancers characterized as ER-negative, PR-negative, and HER2-negative. They constitute about 20% of all breast cancers. TNBC is more common among women younger than 40 years of age and African-American women [ 161 ]. The majority (approximately 80%) of breast cancers arising in BRCA1 germline mutation are TNBC, while 11–16% of all TNBC harbor BRCA1 or BRCA2 germline mutations. TNBC tends to be biologically aggressive and is often associated with a worse prognosis [ 162 ]. The most common histology seen in TNBC is infiltrating ductal carcinoma, but it may also present as medullary-like cancers with a prominent lymphocytic infiltrate; metaplastic cancers, which may show squamous or spindle cell differentiation; and rare special type cancers like adenoid cystic carcinoma (AdCC) [ 163 , 164 , 165 ].

The terms basal-like and TNBC have been used interchangeably; however, not all TNBC are of the basal type. On gene expression profiling, TNBCs can be subdivided into six subtypes: basal-like (BL1 and BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR), as well as an unspecified group (UNS) [ 166 , 167 ]. However, the clinical relevance of the subtyping still unclear, and more research is needed to clarify its impact on TNBC treatment decisions [ 168 ].

4.5. Claudin-Low Breast Cancer

Claudin-low (CL) breast cancers are poor prognosis tumors being mostly ER-negative, PR-negative, and HER2-negative. CL tumors account for 7–14% of all invasive breast cancers [ 147 ]. No differences in survival rates were observed between claudin-low tumors and other poor-prognosis subtypes (Luminal B, HER2-enriched, and Basal-like). CL subtype is characterized by the low expression of genes involved in cell-cell adhesion, including claudins 3, 4, and 7, occludin, and E-cadherin. Besides, these tumors show high expression of epithelial-mesenchymal transition (EMT) genes and stem cell-like gene expression patterns [ 169 , 170 ]. Moreover, CL tumors have marked immune and stromal cell infiltration [ 171 ]. Due to their less differentiated state and a preventive effect of the EMT-related transcription factor, ZEB1 CL tumors are often genomically stable [ 172 , 173 ].

4.6. Surrogate Markers Classification

In clinical practice, the key question is the discrimination between patients who will or will not benefit from particular therapies. By using molecular assays, more patients can be spared adjuvant chemotherapy, but these tests are associated with significant costs. Therefore, surrogate subgroups based on pathological morphology and widely available immunohistochemical (IHC) markers are used as a tool for risk stratification and guidance of adjuvant therapy [ 174 ]. A combination of the routine pathological markers ER, PR, and HER2 is used to classify tumors into intrinsic subtypes [ 175 ]. Semiquantitative evaluation of Ki-67 and PR is helpful for further typing of the Luminal subtype [ 176 , 177 ]. Moreover, evaluation of cytokeratin 5/6 and epidermal growth factor receptor is utilized to identify the Basal-like breast cancer among the TNBC [ 178 ].

In St. Gallen’s 2013 guidelines the IHC-based surrogate subtype classification was recommended for clinical decision making [ 179 ]. However, these IHC-based markers are only a surrogate and cannot establish the intrinsic subtype of any given cancer, with discordance rates between IHC-based markers and gene-based assays as high as 30% [ 180 ].

4.7. American Joint Committee on Cancer Classification

The baseline tool to estimate the likely prognosis of patients with breast cancer is the AJCC staging system that includes grading, immunohistochemistry biomarkers, and anatomical advancement of the disease. Since its inception in 1977, the American Joint Committee on Cancer (AJCC) has published an internationally accepted staging system based on anatomic findings: tumor size (T), nodal status (N), and metastases (M). However, gene expression profiling has identified several molecular subtypes of breast cancer [ 181 ]. The eighth edition of the AJCC staging manual (2018), outlines a new prognostic staging system for breast cancer that, in addition to anatomical features, acknowledges biological factors [ 182 ]. These factors—ER, PR, HER2, grade, and multigene assays—are recommended in practice to define prognosis [ 183 , 184 ].

The most widely used histologic grading system of breast cancer is the Elston-Ellis modification [ 185 ] of Scarff-Bloom-Richardson grading system [ 186 ], also known as the Nottingham grading system. The grade of a tumor is determined by assessing morphologic features: (a) formation of tubules, (b) mitotic count, (c) variability, and the size and shape of cellular nuclei. A score between 1 (most favorable) and 3 (least favorable) is assigned for each feature. Grade 1 corresponds to combined scores between 3 and 5, grade 2 corresponds to a combined score of 6 or 7, and grade 3 corresponds to a combined score of 8 or 9.

In addition to grading and biomarkers, the commercially available multigene assays provide additional prognostic information suitable for incorporation in the AJCC 8th edition. The 21-gene assay Oncotype DX ® assessed by reverse transcription-polymerase chain reaction (RT-PCR) was the only assay sufficiently evaluated and included in the staging system. This assay is valuable in the staging of patients with hormone receptor-positive, HER2-negative, node-negative tumors that are <5 cm. Patients with results of the assay (Recurrence Score) less than 11 had excellent disease-free survival at 6.9 years of 98.6% with endocrine therapy alone [ 187 ]. Hence, adjuvant systemic chemotherapy can be safely omitted in patients with a low-risk multigene assay [ 188 ].

The AJCC staging manual includes a pathological and a clinical-stage group. The clinical prognostic stage group should be utilized in all patients on initial evaluation before any systemic therapy. Clinical staging uses the TNM anatomical information, grading, and expression of these three biomarkers. When patients undergo surgical resection of their primary tumor, the post-resection anatomic information coupled with the pretreatment biomarker findings results in the final Pathologic Prognostic Stage Group.

The recent update of breast cancer staging by the biologic markers improved the outcome prediction in comparison to prior staging based only on anatomical features of the disease. The validation studies involving the reassessment of the Surveillance, Epidemiology, and End Results (SEER) database ( n = 209,304, 2010–2014) and the University of Texas MD Anderson Cancer Center database ( n = 3327, years of treatment 2007–2013) according to 8th edition AJCC manual proved the more accurate prognostic information [ 189 , 190 ].

5. Prognostic Biomarkers

5.1. estrogen receptor.

Estrogen receptor (ER) is an important diagnostic determinant since approximately 70–75% of invasive breast carcinomas are characterized by significantly enhanced ER expression [ 191 , 192 ]. Current practice requires the measurement of ER expression on both—primary invasive tumors and recurrent lesions. This procedure is mandatory to provide the selection of those patients who will most benefit from the implementation of the endocrine therapy mainly selective estrogen receptor modulators, pure estrogen receptor downregulators, or third-generation aromatase inhibitors [ 193 ]. Even though the diagnosis of altered expression of ER is particularly relevant in terms of the proper therapy selection, ER expression might also constitute a predictive factor—patients with high ER expression usually present significantly better clinical outcomes [ 194 ]. A relationship was observed between ER expression and the family history of breast cancer which further facilitates the utility of ER expression as a diagnostic biomarker of breast cancer especially in cases of familial risk [ 195 ]. Besides, Konan et al. reported that ERα-36 expression could constitute one of the potential targets of PR-positive cancers and a prognostic marker at the same time [ 196 ].

5.2. Progesterone Receptor

PR is highly expressed (>50%) in patients with ER-positive while quite rarely in those with ER-negative breast cancer [ 197 ]. PR expression is regulated by ER therefore, physiological values of PR inform about the functional ER pathway [ 197 ]. However, both ER and PR are abundantly expressed in breast cancer cells and both are considered as diagnostic and prognostic biomarkers of breast cancer (especially ER-positive ones) [ 198 ]. Greater PR expression is positively associated with the overall survival, time to recurrence, and time to either treatment failure or progression while lowered PR levels are usually related to a more aggressive course of the disease as well as poorer recurrence and prognosis [ 199 ]. Thus, favorable management of breast cancer patients highly depends on the assessment of PR expression. Nevertheless, the predictive value of PR expression still remains controversial [ 200 ].

5.3. Human Epidermal Growth Factor Receptor 2

The expression of human epidermal growth factor receptor 2 (HER2) accounts for approximately 15–25% of breast cancers and its status is primarily relevant in the choice of proper management with breast cancer patients; HER2 overexpression is one of the earliest events during breast carcinogenesis [ 201 ]. Besides, HER2 increases the detection rate of metastatic or recurrent breast cancers from 50% to even more than 80% [ 202 ]. Serum HER2 levels are considered to be a promising real-time marker of tumor presence or recurrence [ 203 ]. HER2 amplification leads to further overactivation of the pro-oncogenic signaling pathways leading to uncontrolled growth of cancer cells which corresponds with poorer clinical outcomes in the case of HER2-positive cancers [ 204 ]. Overexpression of HER2 also correlates with a significantly shorter disease-free period [ 205 ] as well as histologic type, pathologic state of cancer, and a number of axillary nodes with metastatic cancerous cells [ 205 ].

5.4. Antigen Ki-67

The Ki-67 protein is a cellular marker of proliferation and the Ki-67 proliferation index is an excellent marker to provide information about the proliferation of cancerous cells particularly in the case of breast cancer. The proliferative activities determined by Ki-67 reflect the aggressiveness of cancer along with the response to treatment and recurrence time [ 206 ]. Thus, Ki-67 is crucial in terms of the choice of the proper treatment therapy and the potential follow-ups due to recurrence. Though, due to several limitations of the analytical validity of Ki-67 immunohistochemistry, Ki-67 expression levels should be considered benevolently in terms of definite treatment decisions. Ki-67 might be considered as a potential prognostic factor as well; according to a meta-analysis of 68 studies involving 12,155 patients, the overexpression of Ki-67 is associated with poorer clinical outcomes of patients [ 207 ]. High expression of Ki-67 also reflects poorer survival rates of breast cancer patients [ 208 ]. There are speculations whether Ki-67 could be considered as a potential predictive marker, however, such data is still limited and contradictory.

Mib1 (antibody against Ki-67) proliferation index remains a reliable diagnostic biomarker of breast cancer, similarly to Ki-67. A decrease in both Mib1 and Ki-67 expression levels is associated with a good response of breast cancer patients to preoperative treatment [ 209 ]. Mib1 levels are significantly greater in patients with concomitant p53 mutations [ 210 ]. Mib1 assessment might be especially useful in cases of biopsy specimens small in size, inappropriate for neither mitotic index nor S-phase fraction evaluation [ 211 ].

5.6. E-Cadherin

E-cadherin is a critical protein in the epithelial-mesenchymal transition (EMT); loss of its expression leads to the gradual transformation into mesenchymal phenotype which is further associated with increased risk of metastasis. The utility of E-cadherin as a breast biomarker is yet questionable, however, some research indicated that its expression is potentially associated with several breast cancer characteristics such as tumor size, TNM stage, or lymph node status [ 212 ]. Low or even total loss of E-cadherin expression might be potentially useful in the determination of histologic subtype of breast cancer [ 213 , 214 ]. E-cadherin levels do not seem to be promising in terms of patients’ survival rates assessment, however, there are some reports indicating that higher levels of E-cadherin were associated with shorter survival rates in patients with invasive breast carcinoma [ 213 , 215 ]. Lowered E-cadherin expression is positively associated with lymph node metastasis [ 216 ].

5.7. Circulating Circular RNA

Circulating circular RNAs (circRNAs) belong to the group of non-coding RNA and were quite recently shown to be crucial in terms of several hallmarks of breast carcinogenesis including apoptosis, enhanced proliferation, or increased metastatic potential [ 217 ]. One of the most comprehensively described circRNAs, mostly specific to breast cancer include circFBXW7—which was proposed as a potential diagnostic biomarker as well as therapeutic tool for patients with triple-negative breast cancer (TNBC), as well as hsa_circ_0072309 which is abundantly expressed in breast cancer patients and usually associated with poorer survival rates [ 218 ]. Has_circ_0001785 is considered to be promising as a diagnostic biomarker of breast cancer [ 219 ]. The number of circRNAs dysregulated during breast carcinogenesis is significant; their expression might be either upregulated (e.g., has_circ_103110, circDENND4C) or downregulated (e.g., has_circ_006054, circ-Foxo3) [ 220 ]. Besides, specific circRNAs have been reported in different types of breast cancer such as TNBC, HER2-positive, and ER-positive [ 221 ]. Recently it was showed that an interaction between circRNAs and micro-RNA—namely in the form of Cx43/has_circ_0077755/miR-182 post-transcriptional axis, might predict breast cancer initiation as well as further prognosis. Cx43 is transmembrane protein responsible for epithelial homeostasis that mediates junction intercellular communication and its loss dysregulates post-transcriptional axes in breast cancer initiation [ 222 ].

Loss-of-function mutations in the TP53 (P53) gene have been found in numerous cancer types including osteosarcomas, leukemia, brain tumors, adrenocortical carcinomas, and breast cancers [ 223 , 224 ]. P53 protein is essential for normal cellular homeostasis and genome maintenance by mediating cellular stress responses including cell cycle arrest, apoptosis, DNA repair, and cellular senescence [ 225 ]. The silencing mutation of the P53 gene is evident at an early stage of cancer progression. In breast cancer, the prevalence of TP53 mutations is present in approximately 80% of patients with the TNBC and 10% of patients with Luminal A disease [ 226 ].

There have been many studies showing the prognostic role of p53 loss-of-function mutation in breast cancer [ 227 , 228 ]. However, the missense mutations may alters p53 properties causing not only a loss of wild-type function, but also acquisition novel activities-gain of function [ 229 ]. The IHC status of p53 has been proposed as a specific prognostic factor in TNBC, and a feature that divides TNBC into 2 distinct subgroups: a p53-negative normal breast-like TN subgroup, and a p53-positive basal-like subgroup with worse overall survival [ 230 , 231 , 232 ]. However, there is not enough evidence to utilize p53 gene mutational status or immunohistochemically measured protein for determining standardized prognosis in patients with breast cancer [ 233 ].

5.9. MicroRNA

MicroRNAs (miRNA) are a major class of endogenous non-coding RNA molecules (19–25 nucleotides) that have regulatory roles in multiple pathways [ 234 ]. Some miRNAs are related to the development, progression, and response of the tumor to therapy [ 235 ]. Several studies have investigated abnormally expressed miRNAs as biomarkers in breast cancer tissue samples. According to meta-analysis by Adhami et al. two miRNAs (miRNA-21 and miRNA-210) were upregulated consistently and six miRNAs (miRNA-145, miRNA-139-5p, miRNA-195, miRNA-99a, miRNA-497, and miRNA-205) were downregulated consistently in at least three studies [ 236 ].

The miRNA-21 overexpression was observed in TNBC tissues and was associated with enhanced invasion and proliferation of TNBC cells as well as downregulation of the PTEN expression [ 237 ]. Similarly, the high expression of miRNA-210 is related to tumor proliferation, invasion, and poor survival rates in breast cancer patients [ 238 , 239 ].

The miRNA-145 is an anti-cancer agent having the property of inhibiting migration and proliferation of breast cancer cells via regulating the TGF-β1 expression [ 240 ]. However, the miRNA-145 is downregulated in both plasma and tumors of breast cancer patients [ 241 ]. Similarly, miRNA-139-5p and miRNA-195 have tumor suppressor activity in various cancers [ 242 , 243 ].

Nevertheless, further clinical researches focusing on these miRNAs are needed to utilize them as reproducible, disease-specific markers that have a high level of specificity and sensitivity.

5.10. Tumor-Associated Macrophages

Macrophages are known for their immunomodulatory effects and they can be divided according to their phenotypes into M1- or M2-like states [ 244 , 245 ]. M1 macrophages secrete IL-12 and tumor necrosis factor with antimicrobial and antitumor effects. M2 macrophages produce cytokines, including IL-10, IL-1 receptor antagonist type II, and IL-1 decoy receptor. Therefore, macrophages with M1-like phenotype have been linked to good disease course while M2-like phenotype has been associated with adverse outcome, potentially through immunosuppression and the promotion of angiogenesis and tumor cell proliferation and invasion [ 246 , 247 ]. In literature, tumor-associated macrophages (TAMs) are associated with M2 macrophages which promote tumor growth and metastasis.

For breast cancer, studies have shown that the density of TAMs is related to hormone receptor status, stage, histologic grade, lymph node metastasis, and vascular invasion [ 248 , 249 , 250 , 251 ]. According to meta-analysis conducted by Zhao et al. high density of TAMs was related to overall survival disease-free survival [ 252 ].

Conversely, M1 polarized macrophages are linked to favorable prognoses in various cancers [ 253 , 254 , 255 ]. In breast cancer, the high density of M1-like macrophages predicted improved survival in patients with HER2+ phenotype and may be a potential prognostic marker [ 256 ].

However, further studies are needed to clarify the influence of macrophages on breast cancer biology as well as investigate the role of their intratumoral distribution and surface marker selection.

5.11. Inflammation-Based Models

The host inflammatory and immune responses in the tumor and its microenvironment are critical components in cancer development and progression [ 257 ]. The tumor-induced systemic inflammatory response leads to alterations of peripheral blood white blood cells [ 258 ]. Therefore, the relationship between peripheral blood inflammatory cells may serve as an accessible and early method of predicting patient prognosis. Recent studies have reported the predictive role of the inflammatory cell ratios: neutrophil-to-lymphocyte ratio, the lymphocyte-to-monocyte ratio, and the platelet-to-lymphocyte ratio for prognosis in different cancers [ 258 , 259 , 260 , 261 ].

5.11.1. The Neutrophil-to-Lymphocyte Ratio (NLR)

In an extensive study on 27,031 cancer patients, Proctor et al. analyzed the prognostic value of NLR and found a significant relationship between NLR and survival in various cancers including breast cancer [ 262 ]. There are pieces of evidence of the role of lymphocytes in breast cancer immunosurveillance [ 263 , 264 ]. Opposingly neutrophils suppress the cytolytic activity of lymphocytes, leading to enhanced angiogenesis and tumor growth and progression [ 265 ].

Azab et al. first reported that NLR before chemotherapy was an independent factor for long-term mortality and related it to age and tumor size in breast cancer [ 266 ]. In a recent meta-analysis by Guo et al., performed on 17,079 individuals, the high NLR level was associated with both poor overall survival as well as disease-free survival for breast cancer patients. Moreover, it was reported that association between NLR and overall survival was stronger in TNBC patients than in HER2-positive ones [ 267 ].

5.11.2. Lymphocyte-to-Monocyte Ratio

The association of the lymphocyte-to-monocyte ratio (LMR) with patients’ prognosis has been reported for several cancers [ 268 , 269 ]. As lymphocytes have an antitumor activity by inducing cytotoxic cell death and inhibiting tumor proliferation [ 270 ], the monocytes are involved in tumorigenesis, including differentiation into TAMs [ 246 , 247 , 271 ]. In the tumor microenvironment, cytokines, and free radicals that are secreted by monocytes and macrophages are associated with angiogenesis, tumor cell invasion, and metastasis [ 271 ].

A meta-analysis investigating the prognostic effect of LMR showed that low LMR levels are associated with shorter overall survival outcomes in Asian populations, TNBC patients, and patients with non-metastatic and mixed stages [ 272 ]. Moreover, high LMR levels are associated with favorable disease-free survival of breast cancer patients under neoadjuvant chemotherapy [ 273 ].

5.11.3. Platelet-to-Lymphocyte Ratio (PLR)

A high platelet count has been associated with poor prognosis in several types of cancers [ 274 , 275 , 276 ]. Platelets contain both pro-inflammatory molecules and cytokines (P-selectin, CD40L, and interleukin (IL)-1, IL-3, and IL-6) and many anti-inflammatory cytokines. Tumor angiogenesis and growth may be stimulated by the secretion of platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor-beta, and platelet factor 4 [ 277 , 278 , 279 ].

A meta-analysis study investigated the prognostic importance of PLR by analyzing 5542 breast cancer patients. High PLR level was associated with poor prognosis (overall survival and disease-free survival), yet, its prognostic value was not determined for molecular subtypes of breast cancer. Nevertheless, an association was found between PLR and clinicopathological features of the tumor, including stage, lymph node metastasis, and distant metastasis [ 280 ]. In the aforementioned meta-analysis, there was a difference in the incidence of high levels of PLR between HER2 statuses [ 280 ], while other studies found a difference between hormone ER or PR statuses [ 281 , 282 ].

6. Treatment Strategies

6.1. surgery.

There are two major types of surgical procedures enabling the removal of breast cancerous tissues and those include (1) breast-conserving surgery (BCS) and (2) mastectomy. BCS—also called partial/segmental mastectomy, lumpectomy, wide local excision, or quadrantectomy—enables the removal of the cancerous tissue with simultaneous preservation of intact breast tissue often combined with plastic surgery technics called oncoplasty. Mastectomy is a complete removal of the breast and is often associated with immediately breast reconstruction. The removal of affected lymph nodes involves sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND). Even though BCS seems to be highly more beneficial for patients, those who were treated with this technique often show a tendency for a further need for a complete mastectomy [ 283 ]. However, usage of BCS is mostly related to significantly better cosmetic outcomes, lowered psychological burden of a patient, as well as reduced number of postoperative complications [ 284 ]. Guidelines of the European Society for Medical Oncology (ESMO) for patients with early breast cancer make the choice of therapy dependent to tumor size, feasibility of surgery, clinical phenotype, and patient’s willingness to preserve the breast [ 285 ].

6.2. Chemotherapy

Chemotherapy is a systemic treatment of BC and might be either neoadjuvant or adjuvant. Choosing the most appropriate one is individualized according to the characteristics of the breast tumor; chemotherapy might also be used in the secondary breast cancer. Neoadjuvant chemotherapy is used for locally advanced BC, inflammatory breast cancers, for downstaging large tumors to allow BCS or in small tumors with worse prognostics molecular subtypes (HER2 or TNBC) which can help to identify prognostics and predictive factors of response and can be provided intravenously or orally. Currently, treatment includes a simultaneous application of schemes 2–3 of the following drugs—carboplatin, cyclophosphamide, 5-fluorouracil/capecitabine, taxanes (paclitaxel, docetaxel), and anthracyclines (doxorubicin, epirubicin). The choice of the proper drug is of major importance since different molecular breast cancer subtypes respond differently to preoperative chemotherapy [ 286 ]. Preoperative chemotherapy is comparably effective to postoperative chemotherapy [ 287 ].

Even though chemotherapy is considered to be effective, its usage very often leads to several side effects including hair loss, nausea/vomiting, diarrhea, mouth sores, fatigue, increased susceptibility to infections, bone marrow supression, combined with leucopenia, anaemia, easier bruising or bleeding; other less frequent side effects include cardiomyopathy, neuropathy, hand-foot syndrome, impaired mental functions. In younger women, disruptions of the menstrual cycle and fertility issues might also appear. Special form of chemotherapy is electrochemotherapy which can be used in patients with breast cancer that has spread to the skin, however, it is still quite uncommon and not available in most clinics.

6.3. Radiation Therapy

Radiotherapy is local treatment of BC, typically provided after surgery and/or chemotherapy. It is performed to ensure that all of the cancerous cells remain destroyed, minimizing the possibility of breast cancer recurrence. Further, radiation therapy is favorable in the case of metastatic or unresectable breast cancer [ 288 ]. Choice of the type of radiation therapy depends on previous type of surgery or specific clinical situation; most common techniques include breast radiotherapy (always applied after BC), chest-wall radiotherapy (usually after mastectomy), and ‘breast boost’ (a boost of high-dose radiotherapy to the place of tumor bed as a complement of breast radiotherapy after BCS). Regarding breast radiotherapy specifically, several types are distinguished including

intraoperative radiation therapy (IORT)

3D-conformal radiotherapy (3D-CRT)

intensity-modulated radiotherapy (IMRT)

brachytherapy—which refers to internal radiation in contrast to other above-mentioned techniques.

Irritation and darkening of the skin exposed to radiation, fatigue, and lymphoedema are one of the most common side effects of radiation therapy applied in breast cancer patients. Nonetheless, radiation therapy is significantly associated with the improvement of the overall survival rates of patients and lowered risk of recurrence [ 289 ].

6.4. Endocrinal (Hormonal) Therapy

Endocrinal therapy might be used either as a neoadjuvant or adjuvant therapy in patients with Luminal–molecular subtype of BC; it is effective in cases of breast cancer recurrence or metastasis. Since the expression of ERs, a very frequent phenomenon in breast cancer patients, its blockage via hormonal therapy is commonly used as one of the potential treatment modalities. Endocrinal therapy aims to lower the estrogen levels or prevents breast cancer cells to be stimulated by estrogen. Drugs that block ERs include selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene) and selective estrogen receptor degraders (SERDs) (fulvestrant) while treatments that aim to lower the estrogen levels include aromatase inhibitors (AIs) (letrozole, anastrazole, exemestane) [ 290 , 291 ]. In the case of pre-menopausal women, ovarian suppression induced by oophorectomy, luteinizing hormone-releasing hormone analogs, or several chemotherapy drugs, are also effective in lowering estrogen levels [ 292 ]. However, approximately 50% of hormonoreceptor-positive breast cancer become progressively resistant to hormonal therapy during such treatment [ 293 ]. Endocrinal therapy combined with chemotherapy is associated with the reduction of mortality rates amongst breast cancer patients [ 294 ].

6.5. Biological Therapy

Biological therapy (targeted therapy) can be provided at every stage of breast therapy– before surgery as neoadjuvant therapy or after surgery as adjuvant therapy. Biological therapy is quite common in HER2-positive breast cancer patients; major drugs include trastuzumab, pertuzumab, trastuzumab deruxtecan, lapatinib, and neratinib [ 295 , 296 , 297 , 298 , 299 ]. Further, the efficacy of angiogenesis inhibitors such as a recombinant humanized monoclonal anti-VEGF antibody (rhuMAb VEGF) or bevacizumab are continuously investigated [ 300 ].

In the case of Luminal, HER2-negative breast cancer, pre-menopausal women more often receive everolimus -TOR inhibitor with exemestane while postmenopausal women often receive CDK 4–6 inhibitor palbociclib or ribociclib simultaneously, combined with hormonal therapy [ 301 , 302 , 303 ]. Two penultimate drugs along with abemaciclib and everolimus can also be used in HER2-negative and estrogen-positive breast cancer [ 304 , 305 ]. Atezolizumab is approved in triple-negative breast cancer, while denosumab is approved in case of metastasis to the bones [ 306 , 307 , 308 ].

7. Conclusions

In this review, we aimed to summarize and update the current knowledge about breast cancer with an emphasis on its current epidemiology, risk factors, classification, prognostic biomarkers, and available treatment strategies. Since both the morbidity and mortality rates of breast cancer have significantly increased over the past decades, it is an urgent need to provide the most effective prevention taking into account that modifiable risk factors might be crucial in providing the reduction of breast cancer incidents. So far, mammography and sonography is the most common screening test enabling quite an early detection of breast cancer. The continuous search for prognostic biomarkers and targets for the potential biological therapies has significantly contributed to the improvement of management and clinical outcomes of breast cancer patients.

Author Contributions

Conceptualization, A.F., R.S. and A.S.; critical review of literature, S.Ł., M.C., A.F., J.B., R.S., A.S.; writing—original draft preparation, M.C., A.F.; writing—review and editing, S.Ł., M.C., A.F., J.B., R.S., A.S.; supervision, R.S. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Breast Cancer Research Results and Study Updates

See Advances in Breast Cancer Research for an overview of recent findings and progress, plus ongoing projects supported by NCI.

Some women who receive a false-positive result on a mammogram may not come back for routine breast cancer screening in the future, a new study finds. Better doctor–patient communication about the screening process is needed, several researchers said.

A new study may provide important new insights into breast cancer metastasis. Blood vessels within tumors release a molecule that draws sensory nerves closer to the tumors, the study shows. This close proximity turns on genes in the cancer cells that drive metastasis.

Drs. Ruth Pfeiffer and Peter Kraft of NCI’s Division of Cancer Epidemiology and Genetics discuss how breast cancer risk assessment tools are created and how people can use them to understand and manage their risk.

Some people with no evidence of cancer in nearby lymph nodes after presurgical chemotherapy can skip radiation to that area without increasing the risk of the cancer returning, a clinical trial found. But some experts caution that more details are needed.

For women in their 70s and older, the risk of overdiagnosis with routine screening mammography is substantial, a new study suggests. The findings highlight the need for conversations between older women and their health care providers about the potential benefits and harms of continuing screening mammography.

Many young women who are diagnosed with early-stage breast cancer want to become pregnant in the future. New research suggests that these women may be able to pause their hormone therapy for up to 2 years as they try to get pregnant without raising the risk of a recurrence in the short term.

For younger women with advanced breast cancer, the combination of ribociclib (Kisqali) and hormone therapy was much better at shrinking metastatic tumors than standard chemotherapy treatments, results from an NCI-funded clinical trial show.

In a large clinical trial, a condensed course of radiation therapy was as effective and safe as a longer standard course for those with higher-risk early-stage breast cancer who had a lumpectomy. This shorter radiation course makes treatment less of a burden for patients.

Adding the immunotherapy drug pembrolizumab (Keytruda) to chemotherapy can help some patients with advanced triple-negative breast cancer live longer. In the KEYNOTE-355 trial, overall survival improved among patients whose tumors had high levels of the PD-L1 protein.

People with metastatic breast cancer whose tumors had low levels of HER2 protein lived longer after treatment with trastuzumab deruxtecan (Enhertu) than those treated with standard chemotherapy, results of the DESTINY-Breast04 clinical trial show.

NCI researchers have shown that an experimental form of immunotherapy that uses an individual’s own tumor-fighting immune cells could potentially be used to treat people with metastatic breast cancer who have exhausted all other treatment options.

Most breast cancer risk tools were developed with data mainly from White women and don’t work as well for Black women. A new tool that estimates risk for Black women may help identify those who might benefit from earlier screening, enabling earlier diagnosis and treatment.

In people with metastatic HER2-positive breast cancer, the targeted drug trastuzumab deruxtecan (Enhertu) markedly lengthened progression-free survival compared with trastuzumab emtansine (Kadcycla), new study results show.

In a large clinical trial, women with HR-positive, HER2-negative metastatic breast cancer treated with ribociclib (Kisqali) and letrozole (Femara) as their initial treatment lived approximately 1 year longer than women treated with letrozole only.

Women with early-stage breast cancer who had one or both breasts surgically removed (a unilateral or bilateral mastectomy) had lower scores on a quality-of-life survey than women who had breast-conserving surgery, a new study has found.

For women undergoing chemotherapy for breast cancer, meeting the national physical activity guidelines may help alleviate cognitive issues, a new study suggests. The benefits may be even greater for patients who were physically active before treatment.

Sacituzumab govitecan (Trodelvy) now has regular FDA approval for people with locally advanced or metastatic triple-negative breast cancer (TNBC). The update follows last year’s accelerated approval of the drug for people with TNBC.

For some people with ER-positive breast cancer, a new imaging test may help guide decisions about receiving hormone therapy, according to a new study. The test can show whether estrogen receptors in tumors are active and responsive to estrogen.

The test, which helps guide treatment decisions, was not as good at predicting the risk of death from breast cancer for Black patients as for White patients, a new study has found. The findings highlight the need for greater racial diversity in research studies.

The drug abemaciclib (Verzenio) may be a new treatment option for people with the most common type of breast cancer, with new study findings suggesting that it can reduce the risk of the cancer returning.

Fertility preservation for young women with breast cancer doesn’t increase their risk of dying in the ensuing decades, a new study affirmed. Experts said the findings support routinely offering fertility preservation to patients who want it.

Some postmenopausal women with HR-positive, HER2-negative breast cancer may not benefit from chemotherapy and can safely forgo the treatment, according to clinical trial results presented at the San Antonio Breast Cancer Symposium.

A heart-related event, like a heart attack, may make breast cancer grow faster, a new study suggests. In mice, heart attacks accelerated breast tumor growth and human studies linked cardiac events with breast cancer recurrence, researchers reported.

FDA has approved sacituzumab govitecan (Trodelvy) for the treatment of triple-negative breast cancer that has spread to other parts of the body. Under the approval, patients must have already undergone at least two prior treatment regimens.

Women with high-risk breast cancer who engaged in regular exercise before their cancer diagnosis and after treatment were less likely to have their cancer return or to die compared with women who were inactive, a recent study found.

Researchers have developed a “microscaled” approach to analyze the proteins and genetic changes (proteogenomics) of a tumor that uses tissue from a core needle biopsy. The analyses can provide important information that may help guide treatment.

Tucatinib improved survival for women in the HER2CLIMB trial, including some whose cancer had spread to the brain. Trastuzumab deruxtecan improved survival and shrank many tumors in the DESTINY-Breast01 trial, which led to its accelerated approval.

A TAILORx analysis shows women with early-stage breast cancer and high recurrence scores on the Oncotype DX who received chemotherapy with hormone therapy had better long-term outcomes than what would be expected from hormone therapy alone.

Men with breast cancer may be more likely to die of the disease than women, particularly during the first 5 years after diagnosis, a new study suggests. The higher likelihood of death was linked in part to undertreatment and later diagnosis.

In a survey of nearly 600 breast cancer survivors, researchers found that the cost of care factored into the decisions the women made about what type of surgery to get. Many women also reported never discussing costs with their physicians.

FDA has expanded the approved use of the drug ado-trastuzumab emtansine (Kadcyla), also called T-DM1, to include adjuvant treatment in some women with early-stage HER2-positive breast cancer.

Many women diagnosed with ovarian and breast cancer are not undergoing tests for inherited genetic mutations that can provide important information to help guide decisions about treatment and longer-term cancer screening, a new study has found.

FDA has approved atezolizumab (Tecentriq) in combination with chemotherapy for the treatment of some women with advanced triple-negative breast cancer. This is the first FDA-approved regimen for breast cancer to include immunotherapy.

The build-up of connective tissue around some types of cancer can act as a barrier to immunotherapy. A new study uses a bone marrow transplant drug, plerixafor, to break down this barrier and improve the efficacy of immune checkpoint inhibitors in animal models of breast cancer.

A new study in mice shows that disrupting the relationship between breast cancer cells that spread to bone and normal cells surrounding them makes the cancer cells sensitive to treatment.

In women with early-stage breast cancer, two clinical trials have shown that both whole- and partial-breast radiation therapy are effective at preventing the cancer from returning after breast-conserving surgery.

Researchers are testing a topical-gel form of the drug tamoxifen to see if it can help prevent breast cancer as effectively as the oral form of the drug but with fewer side effects.

Findings from a clinical study and a mouse study may shed light on genetic risk factors for developing cancer-related cognitive problems in older breast cancer survivors. The results suggest a gene associated with Alzheimer’s disease may play a role.

Arsenic trioxide and retinoic acid work together to target the master regulator protein Pin1, a new study shows. In cancer cell lines and mice, the drug combination slowed the growth of triple-negative breast cancer tumors.

FDA has expanded the approved uses of ribociclib (Kisqali) for women with advanced breast cancer, including new uses in pre- and postmenopausal women. It’s the first approval under a new FDA program to speed the review of cancer drugs.

Using a liquid biopsy to test for tumor cells circulating in blood, researchers found that, in women with breast cancer, the presence of these cells could identify women at risk of their cancer returning years later.

Findings from the TAILORx clinical trial show chemotherapy does not benefit most women with early breast cancer. The new data, released at the 2018 ASCO annual meeting, will help inform treatment decisions for many women with early-stage breast cancer.

Do cancer study participants want to receive their genetic test results? A recent study involving women with a history of breast cancer tested an approach for returning genetic research results and evaluated the impact those results had on the women.

Researchers compared the risk of death for women with breast cancer who had low skeletal muscle mass, or sarcopenia, at the time of their cancer diagnosis and women who had adequate muscle mass.

Some people who have been treated for breast cancer or lymphoma have a higher risk of developing congestive heart failure than people who haven’t had cancer, results from a new study show.

FDA has approved the CDK4/6 inhibitor abemaciclib (Verzenio) as a first-line treatment in some women with advanced or metastatic breast cancer. Under the approval, the drug must be used in combination with an aromatase inhibitor.

A new study in mice raises the possibility that using microscopic, oxygen-carrying bubbles may improve the effectiveness of radiation therapy in the treatment of breast cancer.

The drug olaparib (Lynparza®) is the first treatment approved by the Food and Drug Administration for patients with metastatic breast cancer who have inherited mutations in the BRCA1 or BRCA2 genes.

Joint pain caused by aromatase inhibitors in postmenopausal women with breast cancer can cause some women to stop taking the drugs. Reducing their symptoms may translate into better adherence to therapy.