Breast cancer is a heterogeneous group of malignant tumors arising from the terminal duct-lobular unit of the breast. It includes biologically distinct diseases defined by histology, estrogen receptor (ER), progesterone receptor (PR), HER2/ERBB2 status, grade, and stage. These features determine prognosis and guide systemic and local treatment.^[1]

Breast cancer is the most common non-skin cancer in women and remains a major cause of cancer mortality worldwide. Clinical care progresses from risk-based screening and diagnostic imaging to tissue diagnosis, biomarker testing, staging, subtype-directed multimodal treatment, and survivorship care.^[2]

• Histology: Most invasive tumors are invasive carcinoma of no special type (NST, formerly invasive ductal carcinoma). Invasive lobular carcinoma is a distinct entity with different growth patterns and patterns of recurrence.^[3]
• Receptor-based clinical subtype: Hormone receptor (HR) status refers primarily to ER and PR. Tumors are categorized clinically as HR-positive/HER2-negative, HR-positive/HER2-positive, HR-negative/HER2-positive, or triple-negative breast cancer (TNBC).
• Intrinsic molecular subtype: PAM50-based classification includes luminal A, luminal B, HER2-enriched, basal-like, and normal-like subtypes. Molecular and immunohistochemical classifications are related but not completely concordant.^[4]
• Genomic classification: Validated genomic assays, including the 21-gene recurrence score, can provide prognostic information and help determine the value of adjuvant chemotherapy in selected HR-positive/HER2-negative cancers.^[5]

Clinical subtype	Overview of treatment logic
HR-positive/HER2-negative	Endocrine therapy is the systemic-treatment backbone. Genomic assays may refine chemotherapy decisions, and adjuvant CDK4/6 inhibitor therapy may be added in selected high-risk early-stage disease.
HR-positive/HER2-positive	Endocrine therapy is combined with HER2-directed treatment, usually within a trastuzumab-based regimen and with treatment intensity determined by stage and risk.
HR-negative/HER2-positive	HER2-directed therapy, commonly trastuzumab-based, is integrated with chemotherapy according to stage, tumor burden, and treatment response.
Triple-negative breast cancer	For stage II–III disease, neoadjuvant chemotherapy plus pembrolizumab followed by adjuvant pembrolizumab is an established treatment paradigm. Residual disease and germline findings may influence additional therapy.[6]

HER2-low and HER2-ultralow describe treatment-relevant levels of HER2 expression rather than separate traditional receptor subtypes. These categories may affect eligibility for antibody-drug conjugates in selected advanced or metastatic settings.^[7][8]

• For average-risk women, the USPSTF recommends biennial screening mammography from age 40 through 74 years (Grade B).^[9]
• Screening recommendations differ among organizations. The ACR/SBI and NCCN generally recommend annual mammography beginning at age 40, while the ACS and ACP use different age and interval frameworks.^[10][11][12]
• Women with an estimated lifetime breast cancer risk of at least 20%, including many BRCA1/2 carriers, generally require annual mammography plus annual contrast-enhanced breast MRI according to high-risk screening frameworks.^[10]

• A suspicious breast lesion requires diagnostic evaluation with appropriate breast imaging and tissue diagnosis. Core needle biopsy is the definitive diagnostic test for most suspicious lesions.
• Every invasive breast cancer should be characterized by ER, PR, and HER2 status because these biomarkers directly affect systemic treatment selection.^[13]
• The AJCC 8th edition retains anatomic TNM staging but incorporates grade and ER, PR, and HER2 status into prognostic staging. Thus, anatomic stage and tumor biology are interpreted together.^[14]
• A normal mammogram does not exclude cancer, particularly in dense breasts or with invasive lobular carcinoma. A clinically suspicious palpable lesion requires appropriate diagnostic assessment even when screening imaging is unrevealing.

Treatment is multidisciplinary and depends on stage, receptor status, histology, patient factors, and response to neoadjuvant therapy.

• Local therapy: In appropriately selected early-stage disease, breast-conserving surgery followed by radiation provides outcomes comparable to mastectomy. Sentinel lymph node biopsy has replaced routine axillary dissection for many clinically node-negative patients, with further axillary de-escalation in selected settings.^[15][16]
• HR-positive/HER2-negative disease: Endocrine therapy is generally given for 5–10 years. Genomic assays can help identify patients who may safely avoid or require adjuvant chemotherapy in appropriate clinical settings.^[17][18]
• HER2-positive disease: Trastuzumab-based therapy, with or without pertuzumab and other HER2-directed agents, is selected according to stage and risk. Post-neoadjuvant treatment may be escalated when residual invasive disease is present.
• TNBC: Neoadjuvant chemoimmunotherapy is central for many stage II–III tumors. Treatment after surgery is influenced by pathologic response, residual disease, and germline findings.
• Germline BRCA1/2-associated disease: Patients with high-risk, HER2-negative early breast cancer and a pathogenic germline BRCA1/2 variant may be candidates for adjuvant olaparib.^[19]
• Advanced/metastatic disease: Stage IV or unresectable disease is managed primarily with subtype-directed systemic therapy. Detailed treatment sequencing belongs in the dedicated medical-therapy microchapter.

Prognosis is stage- and biology-dependent. Prognostic staging refines anatomic TNM with tumor grade and biomarker status, while treatment response and residual disease provide additional prognostic information.^[14]

• Classify every invasive tumor by ER, PR, and HER2 status at diagnosis.
• Do not confuse biennial screening with twice-yearly screening; biennial means once every 2 years.
• Do not treat HER2-low or HER2-ultralow expression as clinically irrelevant in advanced disease.
• Do not assume that mastectomy is oncologically safer than breast-conserving surgery when breast-conserving surgery and appropriate radiation are suitable.
• Apply high-risk screening pathways to patients with a lifetime risk of at least 20%, pathogenic hereditary variants, or prior chest radiation rather than using average-risk screening recommendations.
• Male breast cancer is uncommon and is usually hormone-receptor positive; evaluation for hereditary risk is important when clinically indicated.^[20]

This chapter summarizes the major discoveries and trials that transformed breast cancer care from a predominantly radical-surgery model into biology-directed, multimodal treatment. The milestones are presented for historical context; current screening, staging, and treatment recommendations belong in their dedicated microchapters.

William Halsted described and popularized radical mastectomy in a landmark 1894 publication. The procedure became the dominant surgical model because breast cancer treatment was centered on progressively removing more local and regional tissue to achieve control of presumed contiguous spread.^[1]

During the 1970s, the systemic disease hypothesis challenged the assumption that increasingly extensive local surgery could prevent distant relapse. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial, initiated in 1971, found no significant survival advantage for radical mastectomy over less extensive surgical approaches at long-term follow-up.^[2]

The introduction of adjuvant combination chemotherapy in the mid-1970s, notably cyclophosphamide, methotrexate, and fluorouracil (CMF), operationalized the systemic-disease hypothesis pharmacologically and established systemic therapy as a component of multimodal treatment.^[1]

NSABP B-06 and the Milan quadrantectomy trial subsequently established that breast-conserving surgery followed by radiation could achieve survival outcomes comparable to mastectomy in appropriately selected early breast cancer.^[3][4]

The 1990 NIH Consensus Development Conference helped establish breast conservation as an accepted treatment approach for early-stage disease. This marked a fundamental shift from maximal local surgery toward combined surgery, radiation, and systemic therapy.^[5]

Parallel to de-escalation of breast surgery, axillary surgery was progressively minimized. Sentinel lymph node biopsy was introduced by Giuliano in 1994 and was subsequently validated in clinically node-negative disease, reducing the need for routine axillary lymph node dissection in many patients.^[6][7]

The adoption of mammography as a population detection tool shifted breast cancer diagnosis toward earlier-stage disease and became a central milestone in modern breast cancer control. Detailed screening-trial chronology, screening intervals, and current society recommendations belong in the Screening microchapter.

The increasing use of estrogen receptor (ER), progesterone receptor (PR), and later HER2 testing changed breast cancer classification from anatomy alone to a combined anatomic, histologic, and biomarker-based framework. This development established the basis for subtype-directed systemic therapy.^[8]

Tamoxifen was synthesized in 1963 and became a landmark endocrine therapy and breast cancer prevention agent. The NSABP P-1 Breast Cancer Prevention Trial began accrual in 1992 and was reported in 1998. Five years of tamoxifen at 20 mg/day reduced invasive breast cancer incidence by 49% in women at increased risk; the preventive benefit was concentrated in estrogen receptor-positive tumors.^[9]

Third-generation aromatase inhibitors later expanded endocrine-treatment options for postmenopausal patients and became an important subsequent milestone in the endocrine era.^[10]

The Women’s Health Initiative changed understanding of menopausal hormone therapy by demonstrating opposing, regimen-dependent effects. Estrogen-plus-progestin therapy significantly increased invasive breast cancer incidence, with a cumulative hazard ratio of 1.28 (95% confidence interval, 1.13–1.45), whereas estrogen-alone therapy in women with prior hysterectomy decreased incidence, with a hazard ratio of 0.78 (95% confidence interval, 0.65–0.93).^[11][12]

Recognition of HER2/ERBB2 amplification and overexpression introduced a clinically actionable molecular target. The association between HER2 amplification and breast cancer biology was reported in the 1980s, including a 1987 report identifying amplification in approximately 20–30% of breast cancers and associating it with poorer prognosis.^[13]

Trastuzumab received FDA approval for metastatic HER2-positive breast cancer in 1998 and, following the 2005 joint analysis of the NSABP B-31 and NCCTG N9831 adjuvant trials, for adjuvant treatment of operable disease in 2006.^[14][15]

The HER2 era demonstrated that a biomarker could define both prognosis and treatment sensitivity, accelerating the transition from histology-based treatment to molecularly targeted therapy.^[16]

The hereditary basis of breast cancer became more clearly defined through the discovery of BRCA1 and BRCA2. BRCA1 was mapped to chromosome 17q in 1990 and positionally cloned in 1994; BRCA2 was identified in 1995.^[17][18]

These discoveries connected inherited cancer susceptibility with DNA-repair biology and supported the later development of PARP-inhibitor therapy for selected patients.

The development of multigene assays, including the 21-gene recurrence score, introduced genomic recurrence biology into adjuvant decision-making. The TAILORx and RxPONDER trials subsequently refined the role of chemotherapy in selected hormone receptor-positive/HER2-negative disease.^[19][20]

More recent treatment history is defined by the integration of immune checkpoint inhibition and DNA-repair–targeted therapy into selected early breast cancers. KEYNOTE-522 established a landmark immunotherapy paradigm for high-risk TNBC, while OlympiA demonstrated the clinical importance of adjuvant olaparib for selected patients with germline BRCA1/2-associated, high-risk HER2-negative disease.^[21][22]

These developments completed the transition from a predominantly anatomy-driven model to a framework integrating stage, histology, receptor status, inherited genetics, genomic assays, immune biology, and treatment response.

Breast cancer classification uses three complementary axes: histopathologic type, biomarker-defined clinical subtype, and intrinsic gene-expression subtype. These categories describe different features and are not interchangeable.^[1][2]

Breast epithelial lesions are classified as in situ or invasive. In situ categories include Ductal carcinoma in situ (DCIS) and lobular neoplasia, including Lobular carcinoma in situ (LCIS). Classic LCIS is generally regarded as a risk marker/non-obligate precursor rather than invasive carcinoma.^[1]

Invasive carcinomas are classified by morphology:

• Invasive carcinoma of no special type (IBC-NST): the most common invasive histotype; formerly termed invasive ductal carcinoma.
• Invasive lobular carcinoma (ILC): commonly shows discohesive, single-file growth. Loss of E-cadherin supports lobular differentiation but is not required for diagnosis.
• Special histologic types: include tubular, cribriform, mucinous, micropapillary, apocrine, metaplastic, adenoid cystic, secretory, neuroendocrine, tall cell carcinoma with reversed polarity, and salivary gland-type carcinomas.

A special histologic type generally requires at least 90% of the tumor to show that morphology; otherwise, report a mixed IBC-NST and special-type carcinoma. Core biopsy may not establish whole-tumor purity.^[3][4]

Invasive carcinoma grade is reported separately from histologic type. The Nottingham (Elston-Ellis) system scores tubule formation, nuclear pleomorphism, and mitotic count to assign grade 1–3.^[3] DCIS is classified by nuclear grade as low, intermediate, or high.^[4]

The 2026 WHO classification recognizes ILC with extracellular mucin and updates criteria for mucinous and neuroendocrine carcinoma, among other refinements.^[5]

ER, PR, and HER2 should be assessed on every new primary and newly metastatic invasive breast cancer using validated ASCO/CAP methodology.^[6][7][4] ER and PR are positive when at least 1% of tumor-cell nuclei stain. HER2 status is determined by validated immunohistochemistry (IHC) and in situ hybridization (ISH) criteria.^[6][7]

Clinical category	Biomarker definition	Approximate frequency
Hormone receptor-positive (HR-positive), HER2-negative	ER and/or PR positive (≥1%); HER2-negative by IHC/ISH.	~70%
HER2-positive	HER2 IHC 3+, or IHC 2+ with ISH amplification; may be HR-positive or HR-negative.	~15%
Triple-negative breast cancer (TNBC)	ER <1%, PR <1%, and HER2-negative by IHC/ISH.	~15%

Frequency estimates vary by cohort. HER2-low and HER2-ultralow are cross-cutting expression categories and are not mutually exclusive with HR status.^[1][4]

An ER result of 1–10% is reported as ER-low-positive; results below 1% are ER-negative.^[6] ER-low tumors are heterogeneous, and some have biology resembling ER-negative/TNBC disease. The endocrine benefit remains uncertain: the ASCO/CAP-recommended comment notes limited data, while recent observational meta-analyses associate endocrine therapy with improved outcomes. These findings do not establish the magnitude of benefit for an individual patient.^{[6][8][9][10]}

HER2 IHC scores are 0, 1+, 2+, and 3+. IHC 2+ is equivocal and requires reflex ISH testing; amplification establishes HER2-positive status.^[7][4]

HER2 result	Classification
IHC 3+: intense, complete membrane staining in >10% of tumor cells	HER2-positive
IHC 2+	Equivocal; perform ISH. If ISH is negative, the tumor is HER2-negative and falls in the HER2-low expression category.
IHC 1+	HER2-negative; HER2-low expression category.
IHC 0 with faint, incomplete membrane staining in ≤10% of tumor cells (sometimes recorded as 0+)	HER2-ultralow expression category.
IHC 0 with no membrane staining	HER2-null; HER2-negative with no detectable membrane staining.

HER2-low generally denotes IHC 1+ or IHC 2+/ISH-negative disease; HER2-ultralow denotes IHC 0 with faint, incomplete membrane staining in ≤10% of tumor cells. These are expression/reporting categories within HER2-negative disease, not separate intrinsic gene-expression subtypes. Reported estimates suggest HER2-low expression occurs in roughly half of breast cancers, and about 88% of HER2-low tumors are HR-positive; estimates vary by cohort and assay.^[11][12][13]

Document the specific IHC score and staining pattern, including the distinction between HER2-null (IHC 0/absent staining) and HER2-ultralow (IHC 0+/faint incomplete staining in ≤10%). This distinction can affect biomarker eligibility for trastuzumab deruxtecan in certain metastatic settings; HER2-null does not meet the HER2-low/ultralow expression criterion for that indication.^[4][14][15]

Scoring near the IHC 0/1+ boundary has limited reproducibility in reported cohorts. One report found a change between IHC 0 and HER2-low in approximately 40% of paired primary/metastatic samples; in an expert re-review series, approximately 55% of initially IHC 0 cases were reclassified as HER2-ultralow.^[7][16]

Re-review with consideration of repeat or consultative HER2 testing is recommended when a grade 1 tumor of any histologic type, or a pure mucinous, tubular, or cribriform carcinoma, tests HER2-positive, because the result is biologically unexpected.^[4]

Gene-expression classifiers such as PAM50 define intrinsic molecular subtypes. They describe tumor biology and are distinct from the IHC-defined clinical categories.^[2][1]

Intrinsic subtype	Gene-expression pattern
Luminal A	Higher estrogen-related expression and lower proliferation-related expression.
Luminal B	Higher proliferation-related expression and lower estrogen-related expression than luminal A.
HER2-enriched	Enrichment of HER2-amplicon-related gene expression; this subtype is not synonymous with HER2-positive IHC/ISH status.
Basal-like	Basal-associated gene-expression pattern; it overlaps substantially with, but is not synonymous with, TNBC.
Normal-like	Normal-breast-like expression pattern; may reflect low tumor cellularity or admixture of normal tissue.

IHC-based surrogate schemes may subdivide HR-positive/HER2-negative cancers into luminal A-like (lower proliferation) and luminal B-like (higher proliferation) groups. These are approximations and do not reproduce PAM50 subtyping exactly. No standardized Ki-67 cutoff separates luminal A-like from luminal B-like; 14% and 20% thresholds have both been used. Ki-67 in an intermediate range should not be used as the sole basis for assigning a subtype.^[17][18]

Clinical and intrinsic molecular subtypes are not interchangeable; a meaningful minority of tumors are discordant between IHC-based classification and gene-expression classification.^[19][20]

Genes involved in the pathogenesis of breast cancer include BRCA1, BRCA2 and p53. On microscopic histopathological analysis, minimal tubule formation, marked pleomorphism, and numerous mitotic figures are characteristic findings of breast cancer.

The primary function of mammary glands is to nurture young by producing breast milk. The production of milk is called lactation. (While the mammary glands that produce milk are present in the male, they normally remain undeveloped.) The orb-like shape of breasts may help limit heat loss, as a fairly high temperature is required for the production of milk. Alternatively, one theory states that the shape of the human breast evolved in order to prevent infants from suffocating while feeding.^[1] Since human infants do not have a protruding jaw like human evolutionary ancestors and other primates, the infant’s nose might be blocked by a flat female chest while feeding.^[1] According to this theory, as the human jaw receded, the breasts became larger to compensate.^[1]

Milk production unrelated to pregnancy can also occur. This galactorrhea may be an adverse effect of some medicinal drugs (such as some antipsychotic medication), extreme physical stress or endocrine disorders. If it occurs in men it is called male lactation. Newborn babies are often capable of lactation because they receive the hormones prolactin and oxytocin via the mother’s bloodstream, filtered through the placenta. This neonatal liquid is known colloquially as witch’s milk.

• Majority of breast malignancies arise from epithelial cells and hence are carcinomas.
• Microscopic appearance and biologic behavior divide breast carcinomas to several diverse groups.
• Based upon the growth pattern and cytologic features of the lesions,the in situ carcinomas of the breast divide into ductal (also known as intraductal carcinoma) or lobular.
• Surprisingly their anatomic location within the mammary ductal-lobular system.

• The table below shows the invasive breast carcinomas several histologic subtypes; based on a series of 135,157 women with breast cancer reported to the SEER database o between 1992 and 2001.

Histologic subtypes of invasive breast carcinomas
Infiltrating ductal	76 %
Invasive lobular	8 %
Ductal/lobular	7 %
Mucinous (colloid)	2.4 %
Tubular	1.5 %
Medullary	1.2 %
Papillary	1 %
Other subtypes, including: ● Metaplastic breast cancer ● Invasive micropapillary breast cancer	less than 5 %

• Ductal carcinoma in situ (DCIS) is described as a proliferation of abnormal cells confined within the mammary ductal system.
• DCIS is commonly classified with respect to architectural and cytologic features as well as cell necrosis as follows:

• Low and intermediate grade (papillary, cribriform, and solid)
• High grade (comedo).

• DCIS signifies a herald to invasive breast cancer.

• The invasive breast carcinomas comprise numerous histologic subtypes.

• Infiltrating ductal carcinoma (the most common)
• Infiltrating lobular carcinoma (the second most common)

• Compared to the infiltrating ductal carcinomas, infiltrating lobular carcinomas are:

• Generally multicentric or may be bilateral
• Usually more differentiated
• Hormone receptor-positive
• May arise in older women
• As a role they metastasize later but if metastasize,
• Sometimes spread to unusual locations, such as:

• The meninges
• The peritoneum
• The gastrointestinal tract

• On gross pathology, a discrete mass within the breast tissue that infiltrates stroma and or surrounding adipose tissue, creating a stellate, scar-like appearance (scirrhous carcinoma) is characteristic of Invasive ductal carcinoma (the most common type of invasive breast cancer).
• Important: The gross appearance of invasive ductal carcinoma might be similar to the fat necrosis.
• The following is a comprehensive description of probable gross findings:
  • Firm, poorly circumscribed, contracts from surrounding tissue, hard cartilaginous consistency, grating sound when scraped, streaks of chalky white elastotic stroma penetrating surrounding stroma (“crab like”), calcification
  • Large tumors have hemorrhage, necrosis and cystic degeneration
  • May be fixed to chest wall and cause skin dimpling or nipple retraction
    
• Shown below is a typical gross appearance of the breast cancer: a pale area in the yellow texture of the normal breast.

• On microscopic histopathological analysis, Mitotic figures, and pleomorphism are characteristic findings of high-grade breast cancers.
• The following is the microscopic description of breast tumors:

• Sheets, nests, cords or individual cells
• Tubular formations are prominent in well-differentiated tumors but absent in poorly differentiated tumors
• Tumor cells are more pleomorphic than lobular carcinoma
• Stroma usually desmoplastic and may obscure tumor cells
• Calcification in 60% of cases, variable necrosis
• Elastosis involves wall of vessels and ducts and causes grossly noted chalky streaks
• Often DCIS (up to 80%), perineural invasion (28%)
• Mitotic figures are often prominent
• Mast cells are associated with low-grade tumors
• Uncommon features: eosinophils (BMC Cancer 2007;7:165), intraluminal crystalloids (Arch Pathol Lab Med 1997;121:593)
• No myoepithelial cell lining (as seen in DCIS or benign lesions)

• Angiolymphatic invasion:

• In 35% – differs from tissue retraction because:
• Occurs outside margin of carcinoma
• Does do not conform precisely to space it is in
• The endothelial lining is present and is CD31+, Factor VIII+
• Blood vessels are in the vicinity

• Shown below are micrographs of breast cancer.

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• Breast cancer, like other cancers, occurs because of an interaction between the environment and a defective gene.

• Normal cells divide as many times as needed and stop; they attach to other cells and stay in place in tissues.
• Cells become cancerous when mutations destroy their ability to stop dividing, to attach to other cells, and to stay where they belong.

• Normal cells will commit cell suicide (apoptosis) when they are no longer needed.
• Until then, they are protected from cell suicide by several protein clusters and pathways.
• One of the protective pathways is the PI3K/AKT pathway; another one is the RAS/MEK/ERK pathway. *Sometimes the genes along these protective pathways are mutated in a way that turns them permanently “on”, rendering the cell incapable of committing suicide when it is no longer needed. This is one of the steps that cause cancer in combination with other mutations.
• Normally, the PTEN protein turns off the PI3K/AKT pathway when the cell is ready for cell suicide.
• In some breast cancers, the gene for the PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the “on” position, and the cancer cell does not commit suicide.^[2]
• Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure^[3] and failure of immune surveillance, the removal of malignant cells throughout one’s life by the immune system.^[4]
• Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth.^[5][6] In breast adipose tissue, overexpression of leptin leads to increased cell proliferation and cancer.^[7]
• In the United States, 10 to 20 % of patients with breast cancer or ovarian cancer have a first- or second-degree relative with one of these diseases.
• The familial tendency to develop these cancers is called hereditary breast—ovarian cancer syndrome.
• The best known of these, the BRCA mutations, confer a lifetime risk of breast cancer of between 60 and 85 % and a lifetime risk of ovarian cancer of between 15 and 40 %.
• Some mutations associated with cancer, such as p53, BRCA1 and BRCA2, occur in mechanisms to correct errors in DNA.
• These mutations are either inherited or acquired after birth. Presumably, they allow further mutations, which lead to uncontrolled division, lack of attachment, and metastasis to distant organs.^[8][9]
• However, there is strong evidence of residual risk variation that goes well beyond hereditary BRCA gene mutations between carrier families; this is caused by unobserved risk factors.^[10]
• It implicates that environmental factors and other causes are triggers for breast cancer.
• The inherited mutation in BRCA1 or BRCA2 genes can interfere with repair of DNA cross links and DNA double strand breaks (known functions of the encoded protein).^[11]
• Because of this repair deficit, risks from carcinogenic chemicals and ionizing radiation can increase.^[12]
• These carcinogens cause DNA damage, such as to DNA cross links and double strand breaks that often require repairs by pathways containing BRCA1 and BRCA2.^[13][14]
• But it is these repair pathways that can be crippled by inherited mutation.
• There is evidence that cancer risks increase in mutation carriers exposed to such opportunistic carcinogens.^[15]
• Thus, risks for cancers may be reduced by avoiding or compensating for carcinogens that exploit the inherited BRCA gene deficiency^[16]
• However, mutations in BRCA genes account for only 2 to 3 % of all breast cancers.^[17]
• About half of hereditary breast–ovarian cancer syndromes involve unknown genes.

• Today, breast cancer, like other forms of cancer, is considered to be the final outcome of multiple environmental and hereditary factors. Some of the effects of environmental and hereditary factors that ultimately cause breast cancer are:

1. Lesions to DNA such as genetic mutations. Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer.^[3] Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of ionizing radiation.
2. Failure of immune surveillance, which usually removes malignancies at early phases of their natural history.
3. Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells. For example: in the angiogenesis, it is necessary to promote new blood vessel growth near new cancers.
4. Inherited defects in DNA repair genes, such as BRCA1, BRCA2 and p53.

• The followings are genes that might be associated with an increased risk for breast cancer. Nevertheless, the risk associated with these genes is not well understood yet.

• CHEK2
• BRIP1
• ATM
• PALB2

8RAD51

• BARD1

8MRE11A

• 8NBN
• RAD50

• In the’Associated conditions below, you will find the known hereditary syndromes with an increased risk of breast cancer.

• Hereditary Breast and Ovarian Cancer (HBOC) Syndrome: mutations in the BRCA1 or BRCA2 gene
• Cowden syndrome: mutations in the PTEN gene
• Li Fraumeni syndrome: mutations in the TP53 gene
• Hereditary Diffuse Gastric Cancer: mutations in the CDH1 gene
• Peutz-Jeghers syndrome: mutations in the STK11 gene

• Bone is the most common site of breast cancer distant spread. Bone metastases due to breast cancer cause major morbidity, decrease survival and reduce quality of life of many patients.

Cancer influence on the skeleton results in two main negative consequences: pain and Skeletal-Related events (SREs), defined as any of the following:

• Pathologic fracture,
• A requirement for surgical intervention and palliative radiotherapy to bone lesions,
• spinal cord compression,
• hypercalcemia of malignancy ^[18].

In fact, SREs constitute readily measured clinical parameters that are employed in clinics and clinical trials.

• Many disciplines should be involved in the management of breast cancer bone metastases, including medical oncology, pain and palliative care, radiation oncology, orthopedic surgery and neurosurgery. Systemic therapy delays the progression of bone metastases and provides palliation; it includes endocrine therapy, biologic agents, chemotherapy, bisphosphonate therapy and the new osteoclast inhibitors.
• A thorough knowledge of the molecular basis of bone metastasis caused by breast cancer is essential for the understanding of the therapeutic approach. In fact, The normal balance between bone resorption and deposition is significantly affected by cancer. Bone metastases due to breast cancer are mostly osteolytic lesions, though predominant osteoblastic disease can occur ^[19].

The breast cancer cells and the bone microenvironment interact extensively through many chemical mediators resulting in bone destruction and tumor growth. These molecular mediators (pimarily Osteopontin, CXCR4, CTGF and Interleukin-11) exert their effect on osteoclasts which in turn cause bone resorption. This osteoclast-mediated bone resorption is thought to be the product of the action of numerous molecules including:

• PTHrP (Parathyroid Hormone–related Peptide),
• Tumor Necrosis Factor α (TNF-α),
• Cytokines such as Interleukin-1, Interleukin-6, Interleukin-8, and interleukin-11

• These factors signal osteoblasts (the bone-building cells) to induce osteoclast differentiation through the RANKL (the ligand for the receptor activator of nuclearfactor-κB [RANK])- RANK signaling. When Osteoclasts lyse bone, they cause the release of growth factors such as bone morphogenetic proteins (BMPs), IGF-I and TGF-β from the bone matrix which stimulate and maintain tumor cell proliferation and induce further release of PTHrP ^[20].

The cause of breast cancer is not yet known exactly, though many risk factors can increase the chance of developing breast cancer.

The cause of breast cancer is not yet known exactly, though many risk factors can increase the chance of developing breast cancer.^[1] BRCA1 or BRCA2 tumor suppressor genes and less commonly PALB2, ATM or CHEK2 are among known genes that may increase the risk of developing breast cancer, nevertheless none of the above mentioned genes can cause developing breast cancer.^[1]

Breast cancer must be differentiated from other diseases such as malignancy, cysts, inflammation and non-inflammatory solid lumps. Breast symptoms such as nipple discharge and mastalgia require assessment as well. Differentiating breast cancer different types of breast lumps are based on imaging findings and breast clinical exam results.

ABBREVIATIONS
LAP=Lymphadenopathy, HRT=Hormonal replacement therapy, FNA=Fine needle aspiration, DCIS=Ductal carcinoma in-situ

Diseases	Benign or Malignant	Clinical manifestation								Paraclinical findings		Gold standard diagnosis
		Demography	History	Symptoms			Signs			Histopathology	Imaging
				Mass	Mastalgia	Nipple discharge	Breast exam	Skin changes	LAP
Fibroadenoma[1]	Benign Very slight increased risk of breast cancer in complex fibroadenoma	Most common benign tumor, women aged 20-30 years	Increases in size during pregnancy or with estrogen therapy, and regress after menopause	+	±	–	Solitary Well-defined Mobile mass	–	–	Proliferative breast lesion without atypia	Ultrasound: Well-defined Solid mass	Mammography Ultrasound Biopsy
Breast cyst[2]	Benign No increased risk of malignancy for simple cyst <1% for complicated cyst <1% to 23% for complex cyst	Common masses found in premenopausal, perimenopausal, and postmenopausal women Mostly seen among HRT users	May resolve after aspiration Further evaluation for unresolved masses	+	±	–	Solitary Cluster of small masses or an ill-defined mass Smooth, firm, and frequently tender	–	–	Nonproliferative breast lesions	Ultrasound: Simple cyst: Well circumscribed, posterior acoustic enhancement without internal echoes Complicated cyst: Homogenous low-level internal echoes due to without solid components Complex cyst: Thick walls greater than 0.5 mm with solid component	Ultrasound Fine needle aspiration (FNA)
Fibrocystic change[3]	Benign No increased risk of malignancy Slightly increased risk of malignancy in presence of positive familial history of breast cancer	Unknown prevalence among adolescents >50% in women of reproductive age	Present before menses and improve during menstruation	+	+	±	Painful breast tissue Tender, nodular swelling	–	–	Nonproliferative breast lesions	Ultrasound: Small cysts in mammary zone Fibroglandular tissue around the mass	Ultrasound Mammography (it is not recommended for adolescents)
Galactocele[4][5]	Benign No increased risk of malignancy	Milk retention cysts with fluid collection among pregnant women and during breast-feeding	After ending lactation, the cysts resolve	+	±	±	Soft masses Cystic masses	–	–	Inflammation of lactate ducts due to extension, results in wall fibrosis	Mammography: Intermediate mass in absence of classic fat-fluid level Ultrasound: Complex mass	Ultrasound Mammography
Cysts of montgomery[6]	Benign No increased risk of malignancy	Most common in age of 10-20 years old	More than 80% resolve spontaneously Drainage is essential in rare cases	+	±	±	Asymptomatic subareolar mass Drainage of clear to brownish fluid	±	–	Acute inflammation due to obstruction of the Montgomery’s gland	Ultrasound: Single cystic lesion in retroareolar area	Ultrasound
Hamartoma[7]	Benign Coexisting malignancy may be present	Common in women older than 35 years old	Asymptomatic ones found incidentally or painless breast lump Usually excised	±	–	–	Soft breast lump Breast enlargement without palpable mass	±	–	Benign proliferation of fibrous, glandular, and fatty tissue Thin capsule of connective tissue	Mammography: Well-described Discrete, solid, and encapsulated lesion	Ultrasound Mammography
Breast abscess[8][9]	Benign No increased risk of malignancy	Complication of lactational mastitis in 14% of cases Common among African-American women, heavy smokers , and obese patients	Resolve after drainage/antibiotic therapy	+	+	–	Localized inflammation of breast Tenderness	+	–	Mixed inflammatory feature by neutrophils. Granulation tissue and chronic inflammation feature caused by Gram-positive cocci	Ultrasound: Fluid collection	Ultrasound
Mastitis[10][11]	Benign No increased risk of malignancy	Common among lactating women (first three months of breast-feeding) Periductal mastitis among smokers and associated with squamous metaplasia	Resolve after drainage/antibiotic therapy	±	+	±	Breast tenderness Swollen breast tissue	+	–	Breast parenchyma inflammation: Acute mastitis: Staphylococcus infection Granulomatous mastitis: Tuberculosis or sarcoidosis infection	Ultrasound: Ill-defined area with hyperechogenicity with inflamed fat lobules Skin thickening	Ultrasound
Diseases	Benign or Malignant	Demography	History	Mass	Mastalgia	Nipple discharge	Breast exam	Skin changes	LAP	Histopathology	Imaging	Gold standard diagnosis
Breast carcinoma[12][13][14]	Malignant	Most common diagnosed cancer among women Leading cause of cancer death in women 40-49 years old	Positive family history	+	–	±	Hard Immobile Solitary Irregular margin	±	±	Molecular alteration in epithelial cells Ductal Lobular Ductal/lobular Mucinous Tubular Medullary Papillary	Mammography: Spiculated soft tissue, mass microcalcification Ultrasound: Spiculated, hypoechoic lesion, shadowing, internal calcification	Ultrasound Mammography
Ductal carcinoma in situ (DCIS)[15][16]	Malignant	Approximately 25% of all breast cancers Increase risk with ageing	Positive family history Nulliparity Obesity	±	–	±	May have normal physical exam	–	–	Noninvasive breast cancer Heterogenous group of neoplastic lesions	Mammography: Suspicious microcalcification	Mammography
Microinvasive breast cancer[17]	Malignant	Rare Commonly referred to DCIS with microinvasion Average age 50-60 years old	Nulliparity Positive family history	+	–	±	Solitary Firm palpable mass	–	±	Associated with high grade DCIS	Mammography: A mass with or without calcification Stromal reaction	Mammography
Breast sarcoma[18]	Malignant	Rare type, < 1% of all breast malignancies Average age of between 45-50 years	Positive history of breast cancer Rapid increase in size	+	–	–	Well-defined Firm mass	±	–	Heterogeneous nonepithelial malignancies from connective tissue of breast	Mammography: Noncalcified oval mass Indistinct margins	Mammography
Phyllodes tumor[19][20]	Benign or Malignant	Most common in premenopausal women (40-50 years)	Represent 1% of breast tumors Grow aggressively Classify in benign, borderline, and malignant groups	±	–	–	Smooth and multinodular Well-defined Firm mass Mobile	–	–	Nonepithelial breast neoplasm with average size of 5 cm	Ultrasound: Solid mass Hypoechoic Well-circumscribed Mammography: Smooth mass Polylobulated mass	Ultrasound Mammography
Lymphoma[21][22]	Malignant	Extremely rare ( 0.04%-0.5%) Average age 55-60 years	Unilateral mass in older women In childbearing women, bilateral and similar to inflammatory breast cancer, possibly having Burkitt lymphoma	+	–	–	Well-defined, firm mass Multiple	–	±	Diffuse growth pattern with large cells like immunoblast associated with neutrophils	Mammography: Nonspecific circumscribed masses Without calcification	Mammography Core biopsy
Duct ectasia[23]	Benign	Common among perimenopausal women	Usually resolve spontaneously	±	±	±	Usually asymptomatic	–	–	Distention of subareolar ducts	Ultrasound: Dilated milk ducts Fluid-filled ducts	Ultrasound
Intraductal papilloma[24]	Benign	Common in women between 35-55 years old	Possibly benign Harbor areas of atypia or DCIS Surgical excision is recommended	+	±	±	Solitary or multiple lesion Large lump near nipple	–	–	Growth of papillary cell into a lumen	Ultrasound: Well-defined Solid nodule	Core needle biopsy
Lipoma[25]	Benign	Common between age of 40-60 years old	Benign tumors May experience recurrence	+	–	–	Solitary Mobile Soft mass	–	–	Mature adipocytes without lipoblasts or atypia	Ultrasound: Well-Circumscribed Hypoechoic lesion	Core needle biopsy Excisional biopsy
Sclerosing adenosis[26][27]	Small risk of malignancy	Recurrent pain during mensturation	May present as a mass or incidental finding on mammogram No treatment is needed	±	+	–	Multiple lesion Firm Tender nodules	±	–	Proliferative disease	Mammography: Well-defined or irregular mass Microcalcification	Mammography
Pseudoangiomatous stromal hyperplasia[28][29]	Benign	Common in reproductive age women	Benign stromal proliferation Stimulation of vascular lesion	+	–	–	Solitary firm mass Thickening	–	–	Slit-like spaces between glandular units Maybe confused with mammary angiosarcoma	Mammography and ultrasound: Well-defined Solid mass Noncalcified	Ultrasound Mammography
Mondor’s disease[30][31]	Benign	Uncommon benign disease Occur on outer side of breast or under nipple	Benign and self-limiting disease Resolve after 4-6 weeks	+	+	–	Thick and tender cord on breast skin	+	–	N/A	Ultrasound: Tubular anechoic structure Multiple narrowing areas	Clinical examination Ultrasound
Diseases	Benign or Malignant	Demography	History	Mass	Mastalgia	Nipple discharge	Breast exam	Skin changes	LAP	Histopathology	Imaging	Gold standard diagnosis
Diabetic mastopathy[32]	Benign	Lymphocytic mastitis or mastopathy Common among premenopausal women Longstanding diabetes mellitus type 1	Suspicious breast mass After diagnosis, excision is not required	+	–	–	Ill-defined mass Immobile	–	–	Dense keloid-like fibrosis Periductal, lobular, and perivascular lymphocytic infiltration	Ultrasound: Irregular mass Hypoechoic Dense lesion	Ultrasound Core needle biopsy
Gynecomastia[33][34]	Benign	Benign breast tissue swelling among men and boys around puberty	Benign proliferation of the male breast glandular tissue Usually underlying nipple mass At least 0.5 cm	+	±	±	Unilateral or bilateral firm mass Breast swelling Rubbery mass	–	–	Glandular breast changes	Ultrasound: Nodular pattern Dendritic pattern Diffuse glandular pattern	Ultrasound
Sarcoidosis[35]	Benign	Rare in patients with systemic involvement	Benign palpable mass May mimic malignancy feature	+	–	–	Firm mass Hard mass	–	–	Epithelioid granulomas with multinucleated giant cell with rare necrosis	Mammography: Irregular Ill-defined Spiculated solid mass	Biopsy
Fat necrosis[36]	Benign	Common among women May mimic malignancy features	Benign breast lumps develop after trauma/ surgery Suspicious lumps required biopsy No excision in established diagnosis	+	±	–	Hard or smooth mass Solitary mass Mobile	–	–	Collections of liquefied fat	Ultrasound: Collections of liquefied fat Oil cysts	Ultrasound

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The prevalence of breast cancer is approximately 124.8 per 100,000 women per year. The number of deaths was 21.9 per 100,000 women per year, based on 2010-2012 data. About 1 out of 8 women in United states will develop invasive breast cancer. Annually (i . e in 2019) around 268,600 and 62,930 new cases of invasive and non-invasive (in situ) breast cancer are expected to be diagnosed respectively. In men, life time likelihood of developing breast cancer is about 1 in 883. Annually 2,670 new cases of invasive breast cancer are expected to be diagnosed in males. Breast cancer increasing pattern of incidence rates began decreasing after year 2000 in US.

• About 1 out of 8 women in United states will develop invasive breast cancer.
• Annually (i . e in 2019) around 268,600 and 62,930 new cases of invasive and non-invasive (in situ) breast cancer are expected to be diagnosed respectively.
• In men, life time likelihood of developing breast cancer is about 1 in 883.
• Annually 2,670 new cases of invasive breast cancer are expected to be diagnosed in males.
• Breast cancer increasing pattern of incidence rates began decreasing after year 2000 in US.
• According to the results of the Women’s Health Initiative study ,published in 2002, reduced use of hormone replacement therapy (HRT) by US women might explain the observed decreasing pattern of incidence.
• Around 42000 women in the U.S. are expected to die annually from breast cancer.
• Women under 50 have experienced larger decreases.
• A decreasing pattern of death rates has been observed since 1989 which might be explained by treatment advances, earlier cancer detection courtesy of screening programs, and increased awareness.^[1]
  • In the subgroup of women under 45, African-American women breast incidence of breast cancer is higher compared to the white women, and they are more likely to die of breast cancer.
  • Asian, Hispanic, and Native-American women, have a lower risk of developing and dying from breast cancer.

• The following tables represent age-adjusted SEER incidence rates, 2011-2015.

Age at Diagnosis	All Races, Females	White Females	Black Females
All ages	31.1	30.8	32.1
Under 65	23.1	22.9	21.9
65 and over	86.7	85.3	102.9
All ages (WHO world std)b	25.3	25.0	25.

Age at Diagnosis	All Races, Females	White Females	Black Females
<1	–	–	–
1-4	–	–	–
5-9	–	–	–
10-14	–	–	–
15-19	–	–	–
20-24	0.2	0.2	–
25-29	0.7	0.6	0.8
30-34	2.7	2.4	3.1
35-39	9.6	9.7	8.6
40-44	40.7	40.5	34.5
45-49	62.5	62.9	49.4
50-54	70.5	70.6	62.9
55-59	73.1	71.4	79.2
60-64	86.6	84.0	101.7
65-69	108.4	105.9	122.0
70-74	103.4	101.1	123.2
75-79	88.0	87.0	112.8
80-84	64.3	64.2	74.9
85+	28.4	28.2	34.4

Footnotes: ^a SEER 18 areas. Rates are per 100,000 and are age-adjusted to the 2000 US Std Population (19 age groups – Census P25-1130), unless noted.

^b Rates are per 100,000 and are age-adjusted to the world (WHO 2000-2025) standard million.

– Statistic not shown. Rate based on less than 16 cases for the time interval.

• Estimated new breast cancer cases in 2018 was 266,120 which made 15% of all new caner cases.
• The incidence of breast cancer varies greatly around the world: it is lowest in less-developed countries and greatest in the more-developed countries.
• In the twelve world regions, the annual age-standardized incidence rates per 100,000 women are as follows:

• in Eastern Asia,18;
• South Central Asia, 22;
• Sub-Saharan Africa, 22;
• South-Eastern Asia, 26;
• North Africa and Western Asia, 28;
• South and Central America, 42;
• Eastern Europe, 49;
• Southern Europe, 56;
• Northern Europe, 73;
• Oceania, 74;
• Western Europe, 78;
• and in North America, 90.^[2]

• In 2019, around 3.1 million women are living with breast cancer in the United States.
• Approximately 12.3 percent of women will be diagnosed with female breast cancer at some point during their lifetime.

• Worldwide, breast cancer is the most common invasive cancer in women. (The most common form of cancer is non-invasive non-melanoma skin cancer; non-invasive cancers are generally easily cured, cause very few deaths, and are routinely excluded from cancer statistics.) Breast cancer comprises 22.9% of invasive cancers in women and 16% of all female cancers.^[3]

• In the United States, breast cancer is the third most common cause of cancer death (after lung cancer and colon cancer). In 2007, breast cancer caused approximately 40,910 deaths (7% of cancer deaths; almost 2% of all deaths) in the U.S.^[4]
• Among women in the U.S., breast cancer is the most common cancer and the second- most common cause of cancer death (after lung cancer). Women in the U.S. have a 1 in 8 lifetime chance of developing invasive breast cancer and a 1 in 33 chance of breast cancer causing their death.^[5] A U.S. study conducted in 2005 by the Society for Women’s Health Research indicated that breast cancer remains the most feared disease,^[6] even though heart disease is a much more common cause of death among women.^[7]

• Since the 1970s, The number of cases has significantly increased, a phenomenon partly blamed on modern lifestyles in the Western world.^[8][9]
• According to the results of the Women’s Health Initiative study ,published in 2002, reduced use of hormone replacement therapy (HRT) by US women might explain the observed decreasing pattern of incidence.
• Because the breast is composed of identical tissues in males and females, breast cancer also occurs in males, although it is less common.^[10]

• Estimated death due to breast cancer in 2018 was 40,920 which made 6.7% of all caner induced death.
• The number of deaths was 21.9 per 100,000 women per year, based on 2010-2012 data.
• A decreasing pattern of death rates has been observed since 1989 which might be explained by treatment advances, earlier cancer detection courtesy of screening programs, and increased awareness.

• While the overall age-adjusted incidence of invasive breast cancer among males and females in the United States between 2007 and 2011 is 67.1 per 100,000, the age-adjusted incidence of invasive breast cancer by age category is:^[11]
  • Under 65 years: 41.9 per 100,000
  • 65 and over: 241.6 per 100,000

• Among females, only, the overall age-adjusted incidence of invasive breast cancer in the United States between 2007 and 2011 is 124.5 per 100,000, whereas the age-adjusted incidence of invasive breast cancer by age category is:^[11]
  • Under 65 years: 81.7 per 100,000
  • 65 and over: 420.3 per 100,000

• Shown below is an image depicting the incidence of breast cancer by age and race in the United States between 1975 and 2011.^[11]

• Among females only, the overall age-adjusted incidence of in-situ breast cancer in the United States between 2007 and 2011 is 31.7 per 100,000, whereas the age-adjusted incidence of invasive breast cancer by age category is:^[11]
  • Under 65 years: 23.6 per 100,000
  • 65 and over: 87.7 per 100,000

• Shown below is an image depicting the incidence of in-situ versus invasive breast cancer in females in the United States between 1975 and 2011.

• In the United States, the age-adjusted prevalence of invasive breast cancer by gender in 2011 is:^[11]
  • In males: 8.3 per 100,000
  • In females: 1222.3 per 100,000

Men have a lower risk of developing breast cancer (approximately 1.08 per 100,000 men per year), however, this risk appears to be rising.^[12]

According to the American Cancer Society, between the years of 2008 and 2012, breast cancer incidence rates increased among black women and Asian/Pacific Islanders. Conversely, incidence rates remained stable amongst white women, Hispanic and American Indian/Alaska Natives, for the same years.

White women have traditionally had the highest incident rate for breast cancer. However, in 2012, the incidence rates for white women and black women converged.^[13]

In the 2013 statistics, the incidence rate remains quite close. White women have an incidence rate of 124.4 per 100,000 and black women, just a little less at 122.9 per 100,000.

Although incidence rates are similar now among black and white women, there remain differences based on age and stage at diagnosis.

• Shown below is a table depicting the age-adjusted prevalence of invasive breast cancer by race in females and males in 2011 in the United States.^[11]

	All Races	White	Black	Asian/Pacific Islander	Hispanic
Age-adjusted prevalence	666.3 per 100,000	700.1 per 100,000	592.9 per 100,000	510.9 per 100,000	460.5 per 100,000

• Shown below is a table depicting the age-adjusted prevalence of invasive breast cancer by race in females in in 2011 in the United States.^[11]

	All Races	White	Black	Asian/Pacific Islander	Hispanic
Age-adjusted prevalence	1222.3 per 100,000	1300.2 per 100,000	1026.1 per 100,000	916 per 100,000	835.9 per 100,000

• Shown below is an image depicting the incidence of breast cancer by race in the United States between 1975 and 2011.^[11]

API: Asian/Pacific Islander; AI/AN: American Indian/ Alaska Native

• Breast cancer is a major public health issue in less developed countries, such as those in South America.
• Breast cancer is the leading cause of cancer-related deaths in women in countries such as Uruguay, Argentina, and Brazil.
• For example, the expected numbers of new cases and deaths due to breast cancer in South America for the year 2001 were approximately 70,000 and 30,000, respectively.^[14]
• Unfortunately, due to lack of funding and resources, treatment is not always available to those suffering with breast cancer.

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Common risk factors in the development of breast cancer are family history, dense breast, obesity, radiation therapy, older age at first birth or never having given birth, hormone replacement therapy, and alcohol.

• Although less than 15 percent of women with breast cancer have a positive family history, a woman’s risk of breast cancer nearly doubles if she has a first-degree relative (mother, sister, daughter) with the history of breast cancer.
• Around 5-10 percent of breast cancers are due to inherited gene mutations either from one’s mother or father.
• BRCA1 and BRCA2 mutations are the most common genetic abnormality in breast cancer.^[1]

• Women with a BRCA1 and BRCA2 mutation have up to a 72% and 69% lifetime risk of developing breast cancer respectively.
• Patients with BRCA1 or BRCA2 are often younger compared to their counterparts without these mutations.
• There is also an increased risk of developing ovarian cancer risk in subjects with mutated BRCA1 andBRCA2.
• Although BRCA1mutations are barely correlated to breast cancer in men, a 6.8% increased risk of developing breast cancer has been observed in men with BRCA2 mutations.

• We should keep in mind that around 85% of women with breast cancers have no family history.
• Sensitivity of commercial BRCA mutation tests like 23andMe is debated. For example 23andMe’s testing formula is based on solely three genetic variants, most prevalent among Ashkenazi Jews, while most people carry other mutations of the gene. This will result in false negative results. As accurately stated by Prof. Mary-Claire King, who discovered the BRCA1, “The F.D.A. should not have permitted this out-of-date approach to be used for medical purposes. Misleading, falsely reassuring results from their incomplete testing can cost women’s lives.”

A personal history of breast cancer or benign (noncancer) breast disease^[2]

• Women with any of the following have an increased risk of breast cancer:

• A personal history of invasive breast cancer, ductal carcinoma in situ (DCIS), or lobular carcinoma in situ (LCIS).
• A personal history of benign (noncancer) breast disease.

A family history of breast cancer

• Women with a family history of breast cancer in a first-degree relative (mother, sister, or daughter) have an increased risk of breast cancer.^[3]

Inherited gene changes

• Women who have inherited changes in the BRCA1 and BRCA2 genes or in certain other genes have a higher risk of breast cancer, ovarian cancer, and maybe colon cancer.

• The risk of breast cancer caused by inherited gene changes depends on the type of gene mutation, family history of cancer, and other factors.

• Men who have inherited certain changes in the BRCA2 gene have a higher risk of breast, prostate, and pancreatic cancers, and lymphoma.

Dense breasts

• Having breast tissue that is dense on a mammogram is a factor in breast cancer risk.^[4]

• The level of risk depends on how dense the breast tissue is.
• Women with very dense breasts have a higher risk of breast cancer than women with low breast density.
• Increased breast density is often an inherited trait, but it may also occur in women who:

• Have not had children
• Have the first pregnancy late in life
• Take postmenopausal hormones (HRT)
• Drink alcohol

Exposure of breast tissue to estrogen made in the body

• Estrogen is a hormone made by the body. It helps the body develop and maintain female sex characteristics. Being exposed to estrogen over a long time may increase the risk of breast cancer. Estrogen levels are highest during the years a woman is menstruating.^[5]
• A woman’s exposure to estrogen is increased in the following ways:

• Early menstruation: Beginning to have menstrual periods at age 11 or younger increases the number of years the breast tissue is exposed to estrogen.
• Starting menopause at a later age: The more years a woman menstruates, the longer her breast tissue is exposed to estrogen.
• Older age at first birth or never having given birth: Because estrogen levels are lower during pregnancy, breast tissue is exposed to more estrogen in women who become pregnant for the first time after age 35 or who never become pregnant.

Taking hormone therapy for symptoms of menopause

• Hormones, such as estrogen and progesterone, can be made into a pill form in a laboratory. Estrogen, progestin, or both may be given to replace the estrogen no longer made by the ovaries in postmenopausal women or women who have had their ovaries removed. This is called hormone replacement therapy (HRT) or hormone therapy (HT). Combination HRT/HT is estrogen combined with progestin. This type of HRT/HT increases the risk of breast cancer. Studies show that when women stop taking estrogen combined with progestin, the risk of breast cancer decreases.^[6]

Radiation therapy to the breast or chest

• Radiation therapy to the chest for the treatment of cancer increases the risk of breast cancer, starting 10 years after treatment. The risk of breast cancer depends on the dose of radiation and the age at which it is given.^[7] The risk is highest if radiation treatment was used during puberty when breasts are forming.
• Radiation therapy to treat cancer in one breast does not appear to increase the risk of cancer in the other breast.
• For women who have inherited changes in theBRCA1 and BRCA2 genes, exposure to radiation, such as that from chest x-rays, may further increase the risk of breast cancer, especially in women who were x-rayed before 20 years of age.

Obesity

• Obesity increases the risk of breast cancer, especially in postmenopausal women who have not used hormone replacement therapy.^[8]

Drinking alcohol

• Drinking alcohol increases the risk of breast cancer. The level of risk rises as the amount of alcohol consumed rises.^[9]

• Most studies have not found an increased risk of breast cancer from active tobacco smoking, although a number of studies suggest an increased risk of breast cancer in both active smokers and those exposed to secondhand smoke compared to women who reported no exposure to secondhand smoke.^[10]

• Women who have received high-dose ionizing radiation to the chest (for example, as treatments for other cancers) have a relative risk of breast cancer between 2.1 to 4.0.^[10]
• Serial mammography might slightly increase the risk of developing breast cancer in high-risk patients such as patients with a family history of breast cancer and patients with known genetic carcinogenic mutations.

• According to a recently published study by Jansen-van der Weide et.al. average increased the risk of breast cancer because of low-dose radiation exposure was (OR between 1.3 and 2 with respect to the patients’ risk and exposure) observed compared to that of high-risk women not exposed to low-dose radiation.^[11]
• Pooled OR revealed an increased risk of breast cancer among high-risk women due to low-dose radiation exposure (OR = 1.3, 95% CI: 0.9- 1.8).
• Exposure before age 20 (OR = 2.0, 95% CI: 1.3-3.1)
• A mean of ≥5 exposures (OR = 1.8, 95% CI: 1.1-3.0)
• When using low-dose radiation among high-risk women, a careful approach is needed, by means of

• They recommended careful approach in these subgroup of patients as follows:

• Reducing repeated exposure,
• Avoidance of exposure at a younger age
• Using non-ionising screening techniques.

• According to another study by Diana L. Miglioretti et.al. radiation-induced breast cancer incidence and mortality from digital mammography screening are impacted by:^[12]

• Dose variability from screening and resultant diagnostic work-up,
• Initiation age
• Screening frequency.
• Women with large breasts may be at higher risk of radiation-induced breast cancer;

• However, we should keep in mind that “the benefits of screening outweigh these risks”.

• Although environmental exposures are not generally cited as risk factors for the disease (except for diet, pharmaceuticals, and radiation), a substantial and growing body of evidence indicates that exposures to certain toxic chemicals and hormone-mimicking compounds, including chemicals used in pesticides, cosmetics, and cleaning products, contribute to the development of breast cancer.
• A recent Canadian study concluded that female farm workers are three times more likely to have breast cancer.^[13]

The increasing prevalence of these substances in the environment may explain the rising incidence of breast cancer, though direct evidence is sparse.

• Although not well-quantified, there has long been a concern about the risk associated with environmental estrogenic compounds, such as dioxins. ^[14][15]

• Researchers at the National Cancer Institute and National Institute of Environmental Health Sciences have conducted a study that suggests that artificial light during the night can be a factor for breast cancer.^[16]

According to the the U.S. Preventive Service Task Force (USPSTF), screening for breast cancer by mammogram is recommended for women aged 50-74 years, twice a year.

Three tests are used by health care providers to screen for breast cancer:^[1]

• Mammography is the most common screening test for breast cancer. A mammogram is an x-ray of the breast. This test may find tumors that are too small to feel. Mammograms are less likely to find breast tumors in women younger than 50 years than in older women. This may be because younger women have denser breast tissue that appears white on a mammogram.
• The following may affect whether a mammogram is able to detect (find) breast cancer:

• Size of the tumor
• How dense the is breast tissue?
• The radiologist knowledge and expertness

• Women aged 40 to 74 years who have screening mammograms have a lower chance of dying from breast cancer than women who do not have screening mammograms.

• A clinical breast exam is an exam of the breast by a doctor or other health professional. The doctor will carefully feel the breasts and under the arms for lumps or anything else that seems unusual. It is not known if having clinical breast exams decreases the chance of dying from breast cancer.
• Doing breast self-exams has not been shown to decrease the chance of dying from breast cancer.
• The USPSTF recommends against teaching breast self-examination (BSE). There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.

• MRI is a procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. MRI does not use any x-rays.
• MRI is used as a screening test for women who have one or more of the following:

• Certain gene changes, such as in the BRCA1 or BRCA2 genes.
• A family history (first degree relative, such as a mother, daughter or sister) with breast cancer.
• Certain genetic syndromes, such as Li-Fraumeni or Cowden syndrome.

• MRIs find breast cancer more often than mammograms do, but it is common for MRI results to appear abnormal even when there isn’t any cancer. (False positive)

• Women should begin yearly mammogram by the age of 45 years.
• At age 55 years, women should have mammogram every other year should continue as long as the women is in good health.
• Breast exams are no longer recommended.^[2]
• Because of variation in life style, genes as well as the other risk factors of breast cancer, national studies in each country is warranted in order to precisely determine the cut of point for age of starting screening.

Breast cancer screening: summary of recommendations
Population	Recommendation	Grade (please refer to the next table below)
Women, Age 50-74 Years	The USPSTF recommends biennial screening mammography for women 50-74 years.	B
Women, Before the Age of 50 Years	The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take patient context into account, including the patient’s values regarding specific benefits and harms.	C
Women, 75 Years and Older	The USPSTF concludes that the current evidence is insufficient to assess the benefits and harms of screening mammography in women 75 years and older. Go to the Clinical Considerations section for information on risk assessment and suggestions for practice regarding the I statement.	I
All Women	The USPSTF recommends against teaching breast self-examination (BSE).	D
Women, 40 Years and Older	The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of clinical breast examination (CBE) beyond screening mammography in women 40 years or older. Go to the Clinical Considerations section for information on risk assessment and suggestions for practice regarding the I statement.	I
All Women	The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of either digital mammography or magnetic resonance imaging (MRI) instead of film mammography as screening modalities for breast cancer. Go to the Clinical Considerations section for information on risk assessment and suggestions for practice regarding the I statement.	I

	Grade definitions after July 2012
Grade	Definition	Suggestions for Practice
A	The USPSTF recommends the service. There is high certainty that the net benefit is substantial.	Offer or provide this service.
B	The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.	Offer or provide this service.
C	The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small.	Offer or provide this service for selected patients depending on individual circumstances.
D	The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.	Discourage the use of this service.
I	The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.	Read the clinical considerations section of USPSTF Recommendation Statement. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms.

Level of certainty
Level of Certainty*	Description
High	The available evidence usually includes consistent results from well-designed, well-conducted studies in representative primary care populations. These studies assess the effects of the preventive service on health outcomes. This conclusion is therefore unlikely to be strongly affected by the results of future studies.
Moderate	The available evidence is sufficient to determine the effects of the preventive service on health outcomes, but confidence in the estimate is constrained by such factors as: The number, size, or quality of individual studies. Inconsistency of findings across individual studies. Limited generalizability of findings to routine primary care practice. Lack of coherence in the chain of evidence.As more information becomes available, the magnitude or direction of the observed effect could change, and this change may be large enough to alter the conclusion.
Low	The available evidence is insufficient to assess effects on health outcomes. Evidence is insufficient because of: The limited number or size of studies. Important flaws in study design or methods. Inconsistency of findings across individual studies. Gaps in the chain of evidence. Findings not generalizable to routine primary care practice. Lack of information on important health outcomes.More information may allow estimation of effects on health outcomes.

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If left untreated, 22% of patients with breast cancer may regress. Common complications of breast cancer include metastasis. Prognosis is generally good with treatment. Breast cancer used to be staged according to the TNM system. Recently, the American Joint Committee on Cancer (AJCC) Staging Manual (8th edition, last updated 1/25/2018) extensively revised their staging system. The 8th edition of the AJCC TNM breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data. Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on classic TNM anatomic factors. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice. Bone is the most common site of breast cancer distant spread. Bone metastases due to the breast cancer cause major morbidity, decrease survival and reduce the quality of life of many patients. Rather than systemic chemotherapy, bisphosphonates like Pamidronate, Alendronate, Ibandronate, Risedronate, and Zoledronic acid , RANKL-RANK inhibitors like Denosumab, also has been recommended and studied for the treatment of bone metastases..Additionally, External beam radiotherapy (EBRT) has been, and continues to be, the mainstay for the treatment of painful, uncomplicated bone metastases.

• There is a theory that up to 22% of small (radiographically detected) breast tumors regress, based on an analysis in a large population.^[1] The study is supported by NCI’s SEER data.^[2]
• The natural history of breast cancer is extremely variable ranging from indolent cancers to aggressive cancers that can metastasize with fatal consequences.^[3]

The prognosis and treatment options depend on the following:

• The stage of the cancer (the size of the tumor and whether it is in the breast only or has spread to lymph nodes or other places in the body)
• The type of breast cancer
• Estrogen receptor and progesterone receptor levels in the tumor tissue
• Human epidermal growth factor type 2 receptor (HER2/neu) levels in the tumor tissue
• Whether the tumor tissue is triple negative (cells that do not have estrogen receptors, progesterone receptors, or high levels of HER2/neu)
• How fast the tumor is growing
• How likely the tumor is to recur (come back)
• A woman’s age, general health, and menopausal status (whether a woman is still having menstrual periods)
• Whether the cancer has just been diagnosed or has recurred (come back)

The Nottingham prognostic index (NPI) is used to determine prognosis following surgery for breast cancer. Its value is calculated using three pathological criteria: the size of the lesion; the number of involved lymph nodes; and the grade of the tumor.^[4]

The index is calculated using the formula:

NPI = [0.2 x S] + N + G

Where:

• S is the size of the index lesion in centimetres
• N is the node status: 0 nodes = 1, 1-4 nodes = 2, >4 nodes = 3
• G is the grade of tumour: Grade I =1, Grade II =2, Grade III =3

Score	5-year survival
2.0 to 2.4	93%
2.5 to 3.4	85%
3.5 to 5.4	70%
> 5.4	50%

Estimated five year survival rates:^[5]

stage I: ~87%

stage II: ~75%

stage III: ~46%

stage IV: ~13%

AJCC clinical prognosis categorization

• The 8th revision of AJCC staging system for breast cancer has been extensively modified.
• Rather than classic TNM system, other characteristics of tumors such as pathologic grade, the presence of ER, PR, hormone receptors as well as presence of certain genetic mutations such as HER2 has been integrated into the latest revision. Among multi gene panels only RS score (Oncotype DX) has been integrated into AJCC 8th edition of breast cancer staging system. It is recommended solely for the pathologic groupings of the patients whom surgery is the initial treatment for them. For more information please refer to the staging section of this chapter.
• Patients has been assigned to clinical prognosis stages with respect to the above-mentioned criteria.

Approach to determine the prognostic stage group of the patients according to the AJCC staging recommendations for breast cancer (8th edition)

Adopted and modified from AJCC 8th Edition staging system.

In a nutshell, rather than classic TNM staging system, the following biological factors were incorporated into the prognostic staging system of the eighth edition of the AJCC staging manual:

• Estrogen receptor (ER) and progesterone receptor (PR) expression
• Human epidermal growth factor receptor 2 (HER2)
• Histologic grade
• Recurrence Score (RS):Oncotype DX

In addition to the above-mentioned factors, the AJCC mentioned several other factors that might help to determine the prognosis in patients with breast cancer, although the followings were not formally included in the current staging system:

• Ki-67 :

• Cellular proliferation and tumor balk marker

• Multigene expression assays other than RS:

• Mammaprint, EndoPredict, PAM50 Risk of Recurrence (ROR), and the Breast Cancer Index (level II evidence)

• Risk assessment models:

• Adjuvant! Online
• PREDICT-Plus

• Circulating tumor cells (CTCs):

• Cancer cells that separate from solid tumors and enter the bloodstream
• The cutoff for an unfavorable prognosis is ≥5 cells/7.5 mL

• Disseminated tumor cells (DTCs):

• Disseminated tumor cells in the bone marrow
• Might predict the likelihood of relapse at the time of initial tumor resection
• The relevant cutoff is ≥1 cell.

Breast cancer used to be staged according to the TNM system. Recently, the American Joint Committee on Cancer (AJCC) Staging Manual (8th edition, last updated 1/25/2018) extensively revised their staging system. The 8th edition of the AJCC TNM breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data. Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on classic TNM anatomic factors. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice.

• The 8th edition of the AJCC TNM breast cancer staging system delivers a flexible platform for prognostic classification based on traditional anatomic factors, which may be modified and enhanced with respect to patient biomarkers and other prognostic panel data.^[6]
• Nevertheless, in order to maintain worldwide value, AJCC tumor staging system remained based on the classic TNM anatomic factors.
• Major changes in the 8th edition of AJCC TNM staging system were discussed below.^[7]
• AJCC panel incorporated biologic factors into the staging system as follows:

• Tumor grade
• Proliferation rate
• Estrogen and progesterone receptor expression
• Human epidermal growth factor 2 (HER2) expression
• Gene expression prognostic panels

• Hence components of recent breast cancer staging system are as follows:

• The extent (size) of the tumor (T)
• The spread to nearby lymph nodes (N)
• The spread (metastasis) to distant sites (M)
• Estrogen receptor (ER) presence
• Progesterone receptor (PR) presence
• Her2/neu (HER2) presence
• Histopathologic grade of the cancer (G):
• In certain circumstances, gene expression panels might also be used such as The Oncotype DX® and the MammaPrint® .

• Oncotype DX®:

• For small hormone receptor-positive tumors that have not spread to more than 3 lymph nodes
• Also may be used for more advanced tumors
• Might be used for DCIS (ductal carcinoma in situ or stage 0 breast cancer). as well looks at a set of 21 genes in tumor biopsy samples to get a “recurrence score,” which is a number between 0 and 100.
• The score reflects the risk of breast cancer coming back (recurring) in the next 10 years and how likely you will benefit from getting chemo after surgery.
• The lower the score (usually 0-10) the lower the risk of recurrence.
• Benefit from chemotherapy is in doubt in most women with low scores
• An intermediate score (usually 11-25): intermediate risk of recurrence.
• Benefit from chemotherapy is in doubt in most women with intermediate-recurrence scores,
• Nevertheless chemotherapy is believed to be beneficial for women younger than 50 with a higher intermediate score (16-25)
• The possible risks and benefits of chemo should be weighted and discussed prior to decision making.
• A high score (usually 26-100): higher risk of recurrence.Chemotherapy is recommended for women with high scores in order to help lower the chance of cancer *recurrence.
• OncotypeDx is the only multigene panel with level I of evidence, and hence has been incorporated in the AJCC staging system

• MammaPrint®:

• To determine the likelihood of cancer recurrence in a distant part of the body after treatment.
• May be used in any type of breast cancer with stage 1 or 2 that has spread to no more than 3 lymph nodes.
• Hormone and HER2 status are also evaluated in this test. Seventy different genes are examined in this test to determine the 10 years cancer recurrence
• The test results are reported as either “low risk” or “high risk.”
• Unlike OncotypeDx has not been incorporated in the AJCC staging system yet.

According to the AJCC statement “Content is available for user’s personal use. It can not be sold, published or incorporated into any software, product or publication with a written license agreement with ACS.” Hence, we may not provide the details of their recent staging system here.

You may find more information for your personal use here.

• This system is solely recommended for countries with no/limited access to the other mentioned biochemical and genetic tests.
• This system is the classic Tumor(T) Lymph Node(N), Metastasis (M) system.

• Patients has been assigned to clinical prognosis stages with respect to the above-mentioned criteria.
• The clinical prognostic stage applies to all patients with breast cancer.
• It is the primary prognostic staging system for patients who receive neoadjuvant treatment or for those who do not receive surgery.
• It is based on clinical T, N, and M; grade; and HER2 and hormone receptor status and does not include genomic profile information.

• For patients who receive surgical resection as initial treatment,
• Based on:

• Pathologic T, N, and M;
• Pathologic grade;
• HER2
• Hormone receptor status
• and for T1 to T2 N0, ER-positive, HER2-negative disease:

• Genomic testing.  

• Bone is the most common site of breast cancer distant spread. Bone metastases due to the breast cancer cause major morbidity, decrease survival and reduce the quality of life of many patients. Rather than systemic chemotherapy, bisphosphonates like Pamidronate, Alendronate, Ibandronate, Risedronate, and Zoledronic acid , RANKL-RANK inhibitors like Denosumab, also has been recommended and studied for the treatment of bone metastases..Additionally, External beam radiotherapy (EBRT) has been, and continues to be, the mainstay for the treatment of painful, uncomplicated bone metastases.

• Bone is the most common site of breast cancer distant spread. Bone metastases due to the breast cancer cause major morbidity, decrease survival and reduce the quality of life of many patients.

Cancer influence on the skeleton results in two main negative consequences: pain and Skeletal-Related events (SREs), defined as any of the following:

• Pathologic fracture,
• A requirement for surgical intervention and palliative radiotherapy to bone lesions,
• spinal cord compression,
• hypercalcemia of malignancy ^[8].

In fact, SREs constitute readily measured clinical parameters that are employed in clinics and clinical trials.

• Many disciplines should be involved in the management of breast cancer bone metastases, including medical oncology, pain and palliative care, radiation oncology, orthopedic surgery and neurosurgery. Systemic therapy delays the progression of bone metastases and provides palliation; it includes endocrine therapy, biologic agents, chemotherapy, bisphosphonate therapy and the new osteoclast inhibitors.
• A thorough knowledge of the molecular basis of bone metastasis caused by breast cancer is essential for the understanding of the therapeutic approach. In fact, The normal balance between bone resorption and deposition is significantly affected by cancer. Bone metastases due to breast cancer are mostly osteolytic lesions, though the predominant osteoblastic disease can occur ^[9].

The breast cancer cells and the bone microenvironment interact extensively through many chemical mediators resulting in bone destruction and tumor growth. These molecular mediators (pimarily Osteopontin, CXCR4, CTGF and Interleukin-11) exert their effect on osteoclasts which in turn cause bone resorption. This osteoclast-mediated bone resorption is thought to be the product of the action of numerous molecules including:

• PTHrP (Parathyroid Hormone–related Peptide),
• Tumor Necrosis Factor α (TNF-α),
• Cytokines such as Interleukin-1, Interleukin-6, Interleukin-8, and interleukin-11

• These factors signal osteoblasts (the bone-building cells) to induce osteoclast differentiation through the RANKL (the ligand for the receptor activator of nuclearfactor-κB [RANK])- RANK signaling. When Osteoclasts lyse bone, they cause the release of growth factors such as bone morphogenetic proteins (BMPs), IGF-I and TGF-β from the bone matrix which stimulate and maintain tumor cell proliferation and induce further release of PTHrP ^[10].

Bisphosphonates constitute a mainstay therapy for patients with bone metastases, they can prevent skeletal complications and palliate bone pain. It should be noted that there is no proven survival benefit. Therapy with high dose bisphosphonates should be initiated after a documented diagnosis of osseous metastases because it has been shown that they do not decrease the incidence of skeletal events in women without metastatic disease.

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption through multiple mechanisms, including downregulation of osteoclast activity, promotion of osteoclast apoptosis and inhibition of osteoclast maturation and differentiation ^[11]. Furthermore, they may trigger the apoptosis of cancer cells, inhibit matrix metalloproteinase 1 (an enzyme that degrades extracellular matrix proteins), reduce angiogenesis and disturb the adhesion of tumour cells to bone ^[12]. The bisphosphonates are analogs of pyrophosphate, with carbon replacing the central oxygen. Their affinity for hydroxyapatite, the main bone mineral, is made possible by the side chains (R1 and R2) from the central carbon ^[13].

There are two classes of bisphosphonates, non-nitrogen containing and nitrogen containing, that are different in their action on the osteoclasts. The nitrogen containing bisphosphonates (Pamidronate, Alendronate, Ibandronate, Risedronate, and Zoledronic acid) are more potent osteoclast inhibitors than the non-nitrogen containing bisphosphonates which include Etidronate, Clodronate, and Tiludronate.

In the United States, only the intravenous pamidronate and zoledronic acid are approved by the FDA for treatment of osseous metastases. The American Society of Clinical Oncology (ASCO) recommends that:

• Osteoclast inhibitors including bisphosphonates be initiated in the management of patients with metastatic breast cancer and evidence of bone destruction on plain radiographs, CT, or MRI (but not bone scans) even if asymptomatic
• Bisphosphonates administration: Intravenous pamidronate 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks
• There is no clear difference between oral or intravenous formulations of bisphosphonates and no clear superiority of either zoledronic acid or pamidronate ^[14].

Another important concept is that bone modifying agents including bisphosphonates should be adjunctive for bone pain control and not a replacement for analgesics, radiotherapy, or surgery ^{[15] [16]}. There is no recommended duration of treatment; the ASCO guidelines suggest that bone modifying agents be continued until evidence of substantial decline in a patient’s general performance status ^[14].

• Phase III studies have shown that less than 2 percent of patients experience serious toxicity from bisphosphonates ^[17].

• Side effects include inflammatory reactions including the acute phase reaction, phlebitis and ocular inflammation (conjunctivitis, uveitis, scleritis). The acute phase reaction is a flu-like syndrome with fever, chills, myalgias and arthralgias occuring in approximately half of the patients; it is more common in non-Japanese Asians, younger subjects, and nonsteroidal antiinflammatory drug users and less common in smokers, patients with diabetes, previous users of oral bisphosphonates, and Latin Americans ^[18]. It is classically seen within 3 days after infusion and is self limiting within 1 to 3 days. Acetaminophen or non-steroidal antiinflammatory drugs intake prior to infusion may decrease symptom severity ^[17]. The occurence of the acute phase reaction and its intensity tends to lessen after subsequent infusions.

• Renal insufficiency is another complication of bisphosphonate therapy and it is both dose- and infusion time-dependent. Nephrotoxicity can be reduced by slow infusion durations, providing adequate hydration prior to bisphosphonate infusion and withholding concomitant nephrotoxic medications. The ASCO recommends no change in dose, infusion time, or interval if creatinine clearance is superior to 60 mL/min. For patients receiving IV bisphosphonates, the creatinine level should be monitored before each infusion ^[14].

• Electrolyte disturbances can occur in patients on bisphosphonates which necessitates regular monitoring of serum calcium, magnesium, and phosphate during therapy.

Osteonecrosis (avascular necrosis) of the jaw (ONJ) is a more common complication with zoledronic acid compared with pamidronate. It is defined as an area of exposed bone in the maxillofacial or mandibular region that does not heal within 8 weeks of identification by a healthcare provider, in a patient who has been exposed to a bone-modifying agent administered either IV or orally, and has not had radiation therapy to the craniofacial region ^[19]. The pathophysiology is unclear. The most common complaints are pain and/or numbness in the affected region, tooth mobility, and soft tissue swelling. Conservative management with debridement, mouth rinses and antibiotics could result in healing ^[20].

US FDA labeling and ASCO guidelines for bone-modifying agents (including Bisphosphonates and Denosumab) suggest dental examination and necessary preventive dentistry for cancer patients before initiating therapy with these agents ^[14]. Maintaining oral hygiene and avoiding dental procedures of the mandible, maxilla or periosteum should be advised. Patients receiving therapy with bisphosphonates should get calcium and vitamin D supplementation to reduce the risk of bisphosphonate-induced hypocalcemia. Also, it should be noted that vitamin D deficiency increases the risk for bisphosphonate-induced hypocalcemia.

As mentioned in the pathogenesis section, the RANKL-RANK signaling pathway is a main molecular tool used by osteoclasts to resorb bone. Denosumab is a monoclonal antibody to the RANKL that inhibits it from binding to RANK leading to osteoclast inhibition. Denosumab is FDA approved to prevent SREs in patients with bone metastases from solid tumors at a dose of 120 mg subcutaneously every four weeks. In a randomized double-blind phase III trial comparing the efficacy of Denosumab to zoledronic acid in delaying time to first SRE, Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001) ^[21]. This trial also showed that overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. Renal toxicity and acute-phase reactions occurred more frequently with zoledronic acid but hypocalcemia occurred more frequently with denosumab ^[21]. The most common side effects of denosumab are fatigue, nausea and hypophosphatemia; dyspnea is the most common serious side effect. The Combination of denosumab with an IV bisphosphonate for the treatment of bone metastases is not recommended. Calcium and vitamin D supplementation is recommended during therapy with denosumab to prevent hypocalcemia.

According to the American Society of therapeutic Radiation Oncology (ASTRO):^[22]

• External beam radiotherapy (EBRT) has been, and continues to be, the mainstay for the treatment of painful, uncomplicated bone metastases

• Although various fractionation schemes can provide good rates of palliation, numerous prospective randomized trials have shown that 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction can provide excellent pain control and minimal side effects. The longer course has the advantage of a lower incidence of repeat treatment to the same site, and the single fraction has proved more convenient for patients and caregivers

• Repeat irradiation with EBRT might be safe, effective, and less commonly necessary in patients with a short life expectancy

• Bisphosphonates do not obviate the need for EBRT for painful sites of metastases and might, indeed, act effectively when combined with EBRT

• Surgical decompression and stabilization plus postoperative RT should be considered for selected patients with single-level spinal cord compression or spinal instability unless the patients have an anticipated life expectancy that is too short. Kyphoplasty and vertebroplasty might be useful for the treatment of lytic osteoclastic spinal metastases or in cases of spinal instability for which surgery is not feasible or indicated. They do not obviate the need for EBRT, and no data are available to suggest that the addition of vertebroplasty or kyphoplasty further improve symptoms or has a greater effect on clinically significant endpoints than EBRT alone. Additional prospective trials are needed to better define whether a patient population exists that would benefit from treatment with kyphoplasty or vertebroplasty, and, if so, how those procedures should best be sequenced with EBRT.

The mainstay of breast cancer treatment is surgery when the tumor is localized, with possible adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor), chemotherapy, and/or radiotherapy. At present, the treatment recommendations after surgery (adjuvant therapy) follow a pattern. This pattern is subject to change, as every two years, a worldwide conference takes place in St. Gallen, Switzerland, to discuss the actual results of worldwide multi-center studies. Depending on clinical criteria (age, type of cancer, size, metastasis) patients are roughly divided to high risk and low risk cases, with each risk category following different rules for therapy. Treatment possibilities include radiation therapy, chemotherapy, hormone therapy, and immune therapy.

In planning treatment, doctors can also use PCR tests like Oncotype DX or microarray tests like MammaPrint that predict breast cancer recurrence risk based on gene expression. In February 2007, the MammaPrint test became the first breast cancer predictor to win formal approval from the Food and Drug Administration. This is a new gene test to help predict whether men or women with early-stage breast cancer will relapse in 5 or 10 years, this could help influence how aggressively the initial tumor is treated.^[1]

Depending on the staging and type of the tumor, just a lumpectomy (removal of the lump only) may be all that is necessary, or removal of larger amounts of breast tissue may be necessary. Surgical removal of the entire breast is called mastectomy.

Lumpectomy techniques are increasingly utilized for breast-conservation cancer surgery. However, mastectomy may be the preferred treatment in certain instances:

• Two or more tumors exist in different areas of the breast (a “multifocal” cancer).
• The breast has previously received radiation (XRT) treatment.
• The tumor is large relative to the size of the breast.
• The patient has had scleroderma or another disease of the connective tissue, which can complicate XRT treatment.
• The patient lives in an area where XRT is inaccessible.
• The patient is apprehensive about the risk of local recurrence after lumpectomy.

Standard practice requires the surgeon to establish that the tissue removed in the operation has margins clear of cancer, indicating that the cancer has been completely excised. If the removed tissue does not have clear margins, further operations to remove more tissue may be necessary. This may sometimes require removal of part of the pectoralis major muscle, which is the main muscle of the anterior chest wall.

During the operation, the lymph nodes in the axilla are also considered for removal. In the past, large axillary operations took out 10 to 40 nodes to establish whether cancer had spread. This had the unfortunate side effect of frequently causing lymphedema of the arm on the same side, as the removal of this many lymph nodes affected lymphatic drainage. More recently, the technique of sentinel lymph node (SLN) dissection has become popular, as it requires the removal of far fewer lymph nodes, resulting in fewer side effects. The sentinel lymph node is the first node that drains the tumor, and subsequent SLN mapping can save 65-70% of patients with breast cancer from having a complete lymph node dissection for what could turn out to be a negative nodal basin. Advances in Sentinel Lymph Node mapping over the past decade have increased the accuracy of detecting Sentinel Lymph Node from 80% using blue dye alone to between 92% and 98% using combined modalities.^[2] SLN biopsy is indicated for patients with T1 and T2 lesions (<5cm) and carries a number of recommendations for use on patient subgroups.^[2]

Radiation therapy involves using high-powered X-rays or gamma rays (XRT) that precisely target the area being treated. These X-rays or gamma rays are very effective in destroying the cancer cells that might recur where the tumor was removed. The X-rays are delivered by a machine called a linear Accelerator or LINAC. Alternatively, the use of implanted radioactive catheters (brachytherapy), similar to those used in prostate cancer treatment, is being evaluated. Radiation therapy for breast cancer is usually performed after surgery and is an essential component of breast-conserving therapy. The purpose of radiation is to reduce the chance that the cancer will recur.

Radiation therapy eliminates the microscopic cancer cells that may remain near the area where the tumor was surgically removed. The dose of radiation must be strong enough to ensure the elimination of cancer cells. However, radiation affects normal cells and cancer cells alike, causing some damage to the normal tissue around where the tumor was. Healthy tissue can repair itself, while cancer cells do not repair themselves as well as normal cells. For this reason, radiation treatments are given over an extended period, enabling the healthy tissue to heal. Treatments are typically given over a period of five to seven weeks, performed five days a week. Each treatment takes about 15 minutes.

Although radiation therapy can reduce the chance of breast cancer recurrence, it is much less effective in prolonging patient survival. According to a review of six studies by the National Cancer Institute, none of them found a survival benefit for radiation therapy.^[3] Patients who are unable to have radiation therapy after lumpectomy should consult with a surgeon who understands this research and who believes that lumpectomy (or partial mastectomy) alone is a reasonable treatment option.

Indications for radiation treatment are constantly evolving. Patients treated in Europe have been more likely in the past to be recommended adjuvant radiation after breast cancer surgery. Radiation therapy is usually recommended for all patients who had (lumpectomy, quadrant-resection). Radiation therapy is usually not indicated in patients with advanced (stage IV disease) except for palliation of symptoms like bone pain.

In general recommendations would include:

• As part of breast conserving therapy when the whole breast is not removed (lumpectomy or wide local excision)
• After mastectomy: Patients with higher chances of cancer recurring because of conditions such as a large primary tumor or involvement of four or more lymph nodes.

Other factors which may influence adding adjuvant radiation therapy:

• Tumor close to or involving the margins on pathology specimen
• Multiple areas of tumor (multicentric disease)
• Microscopic invasion of lymphatic or vascular tissues
• Microcopic invasion of the skin, nipple/areola, or underlying pectoralis major muscle
• Patients with <4 LN involved, but extension out of the substance of a LN
• Inadequate numbers of axillary LN sampled

Radiotherapy can be delivered in many ways. The most common delivery method is linear accelerators.

There have been many improvements in the techniques that deliver radiation to the breast. One such new technology is using IMRT (intensity modulated radiation therapy), in which the radiation oncologist can change the shape and intensity of the radiation beam at different points across and inside the breast. This allows for a more focused beam of radiation directed at the tumor cells and leaves most of the healthy tissue unaffected by the radiation.

Another new procedure involves a type of brachytherapy, where a radioactive source is temporarily placed inside the breast in direct contact with the tumor bed (area where tumor was removed). This technique is called a Mammosite and is currently undergoing clinic trials.

New technology has also allowed more precise delivery of radiotherapy in a portable fashion — for example in the operating theatre. Targeted intraoperative radiotherapy (TARGIT)^[4] is a method of delivering therapeutic radiation from within the breast using a portable X-ray generator called Intrabeam. It is undergoing clinical trials in several countries to test whether it can replace the whole course of radiotherapy in selected patients.^[5] It may also be able provide a much better boost dose to the tumor bed and appears to provide superior control.^[6] This will be tested in a TARGIT-B trial.^[7]

The side effects of radiation have decreased considerably over the past decades. Aside from general fatigue caused by the healthy tissue repairing itself, there will probably be no side effects at all. Some patients develop a suntan-like change in skin color in the exact area being treated. As with a suntan, this darkening of the skin will fade with time. Other side effects experienced with radiation include the fact that radiation therapy can and often does cause permanent changes in the color and texture of skin, in addition to:

• reddening of the skin
• muscle stiffness
• mild swelling
• tenderness in the area
• long-term shrinking of the irradiated breast

The use of adjuvant radiation has significant potential effects if the patient has to later undergo breast reconstruction surgery. Fibrosis of chest wall skin from radiation negatively affects skin elasticity and makes tissue expansion techniques difficult. Traditionally most patients are advised to defer immediate breast reconstruction when adjuvant radiation is planned and are most often recommended surgery involving autologous tissue reconstruction rather than breast implants.

Systemic therapy uses medications to treat cancer cells throughout the body. Any combination of systemic treatments may be used to treat breast cancer. Systemic treatments include chemotherapy, immune therapy, and hormonal therapy.

Chemotherapy (drug treatment for cancer) may be used before surgery, after surgery, or instead of surgery in those patients who are unsuitable for surgery.

See breast cancer chemotherapy.

Patients with estrogen receptor positive tumors will typically receive hormonal therapy after chemotherapy is completed. Typical hormonal treatments include:

• Tamoxifen is typically given to premenopausal women to inhibit the estrogen receptors
• Aromatase inhibitors are typically given to postmenopausal women to lower the amount of estrogen in their systems
• GnRH-analogues
• ovarian ablation or suppression is used in premenopausal women

In patients whose cancer expresses an over-abundance of the HER2 protein, a monoclonal antibody known as trastuzumab (Herceptin ®) is used to block the activity of the HER2 protein in breast cancer cells, slowing their growth. In the advanced cancer setting, trastuzumab use in combination with chemotherapy can both delay cancer growth as well as improve the recipient’s survival.^[8] More recently, several clinical trials have also confirmed that in the adjuvant setting i.e. postoperative following breast cancer surgery, the use of trastuzumab for up to one year also delays the recurrence of breast cancer and improves survival.^[9][10][11]

A commercially available monoclonal antibody that blocks the activation of the VEGF receptor, bevacizumab, underwent testing in a randomized clinical trial whose preliminary results were announced by the National Cancer Institute in 2005.^[12] The preliminary data indicated that bevacizumab delays disease progression for up to five months over conventional chemotherapy, but survival was no better. Genentech, manufacturer of bevacizumab, has filed a supplemental biological application with the FDA for approval of bevacizumab in the setting of metastatic breast cancer, on the strength of the improvement in progression-free survival.

In the March 2007, edition of the scientific journal, Nature Genetics, researchers from Canada’s McGill University reported that they have developed a potential drug target for treating up to 40 percent of breast cancers by blocking an enzyme called protein tyrosine phosphatase 1B (PTP1B), which has been implicated in the onset of breast cancer in mouse models of the disease.^[13] Elevated levels of PTP1B have also been found in diabetes and obesity. A drug to block the activity of PTP1B is under development by Merck, and was found to delay the development of breast tumors and prevent lung cancer up to two months from the administration of the drug. The researchers hope to continue further research in mouse models which are also HER-2 positive (responsive to Herceptin) so that the drug could benefit a significant population of women.^[14]

Preliminary research into flax seeds indicate that flax can significantly change breast cancer growth and metastasis, and enhance the inhibitory effect of tamoxifen on estrogen-dependent tumors.^{[15][16][17][18]}

The use of traditional Chinese medicine to treat breast cancer has been claimed, but no successful clinical trials have yet been reported.

Recently, the acceleration of gene expression profiling research has made available additional markers to predict disease recurrence. Beyond conventional TNM staging, doctors can now order a gene expression profile on tumors to predict whether a breast cancer patient will have a high chance of developing breast cancer again. There are currently 2 commercial tests on the market, MammaPrint and Oncotype DX. Oncotype DX is not used in every clinical setting; for example, in a patient with positive lymph nodes who is a candidate for chemotherapy, the test would not change therapy decisions. The most useful setting for Oncotype DX testing is where there are negative lymph nodes, and the benefit of chemotherapy is felt to be small. In up to 10% of patients, there will be disease recurrences, but treating every patient with chemotherapy is overkill. In this setting, a high-risk score on the Oncotype DX can help doctors decide whether to recommend chemotherapy.

Breast carcinoma is considered an absolute contraindication to the use of the following medications:

• Conjugated estrogens/bazedoxifene
• Norethindrone acetate and Ethinyl estradiol
• Drospirenone and Ethinyl estradiol
• Norgestimate and Ethinyl estradiol
• Norgestrel and Ethinyl estradiol
• Norelgestromin and Ethinyl Estradiol
• Progesterone
• Hydroxyprogesterone caproate

Carcinoma of the breast in male is considered an absolute contraindication to the use of the following medications:

• Nandrolone
• Androderm
• Oxandrolone

Carcinoma of the breast in females with hypercalcemia is considered an absolute contraindication to the use of the following medications:

• Nandrolone

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