Breast Cancer

AUTHOR: Bharti Rathore, MD

Definition

Breast cancer refers to epithelial carcinoma arising from the ducts (ductal) or the lobules (lobular) of the breast that is initially in situ but can progress to become invasive in nature.

Classification ¹

Carcinomas make up the majority of breast malignancies and originate in the epithelium of the collecting ducts (ductal) or the terminal lobular ducts (lobular). Sarcomas are rare, constituting less than 1% of primary breast cancers, and arise from stromal or connective tissue. Tumor grade is based on tubule formation, nuclear pleomorphism, and mitotic counts using the Nottingham score to determine low, intermediate, or high grade. Higher grade is associated with a poorer long-term prognosis.

Initially, breast carcinoma may be divided into invasive and in situ lesions (Table 1). Invasive ductal carcinoma accounts for the majority, approximately 80%, of invasive carcinomas. Invasive lobular carcinomas constitute approximately 10% to 15% of cases. Other subtypes include mucinous, tubular, medullary, micropapillary, and papillary. Both in situ and invasive carcinomas are often found in the same quadrant of the breast. Additionally, multifocal carcinomas are not uncommon, and bilateral breast carcinomas occur in 1% to 2% of newly diagnosed cases.

TABLE 1 Simplified Classification of Breast Carcinoma Based on Histology

Type of Carcinoma		Percentage of All Cases Diagnosed
Ductal carcinoma
In situ		5
Infiltrating		70
Infiltrating with uniform histologic appearance		10
Medullary, colloid, comedo, tubular, papillary
Lobular carcinoma
In situ		3
Infiltrating		9
Inflammatory carcinoma		2
Paget disease		1

From Gershenson DM et al: Comprehensive gynecology, ed 8, Philadelphia, 2022, Elsevier.

Genomic Profiling ¹

Historically, the treatment of breast cancer was based on tumor histologic characteristics, axillary node status, tumor size, receptor patterns, and grade of differentiation. In addition to simplified histologic classification, a classification based on gene expression or profiling, including the presence of hormone receptors, has evolved. Identification of tumor receptor status is critical because endocrine therapy is used both for adjuvant therapy and in the management of advanced disease. The genomic analysis of tumors has led to the molecular subtyping of breast cancers. In the early 2000s, breast tumors were classified into four different molecular subtypes: luminal, basal, HER2, and normal. Subsequently, the luminal group was further differentiated into luminal-A and luminal-B subgroups. Basal-like tumors include triple-negative tumors, tumors that are estrogen, progesterone, and HER2 negative by immunohistochemistry. A more aggressive subtype of triple-negative tumors, claudin-low tumors, has also been described. These divisions are detailed in Table 2.

TABLE 2 Classification of Breast Carcinoma Based on Gene Profiling and Hormone Receptor

Expression Type	Grade	Characteristic Behavior	Hormone Receptor Status ∗
Luminal A	Usually low grade	Good prognosis	E and P+
Luminal B	All grades	Mixed prognosis	E and P+, Her2 (Neu)+
Her2 (Neu)	Higher grades	Poor prognosis	E and P-, Her2 (Neu)+
Basal	Usually grade 3	Poor prognosis	Triple negative
Normal breast ^†	Usually low grade	Good prognosis	Triple negative

^∗E, Estrogen receptor; P, progesterone receptor.

^†Normal breast does not express gene profiling of basal elements and myoepithelial gene expression.

From Gershenson DM et al: Comprehensive gynecology, ed 8, Philadelphia, 2022, Elsevier.

Synonym

Carcinoma of the breast

ICD-10CM CODES
C50.911		Malignant neoplasm of unspecified site of right female breast
C50.912		Malignant neoplasm of unspecified site of left female breast
C50.919		Malignant neoplasm of unspecified site of unspecified female breast
C50.921		Malignant neoplasm of unspecified site of right male breast
C50.922		Malignant neoplasm of unspecified site of left male breast
C50.929		Malignant neoplasm of unspecified site of unspecified male breast

Epidemiology & Demographics

In the U.S., there were an estimated 290,560 new patients and an estimated 43,780 deaths in 2022.²
Hormone-receptor-positive cancers are the most common type and their incidence has increased, particularly among young women.
Only 1% of breast cancers occur in males.
Table 3 describes risk factors for breast cancer.
Factors associated with a decreased risk for breast cancer are summarized in Table 4.
Known genetic mutations in breast cancer are described in Table 5. Genetically defined group of women with BRCA1 or BRCA2 genes (Table 6) carry lifetime risk as high as 85%.

TABLE 5 Known Genetic Mutations in Breast Cancer and Their Management

Genetic Mutation	Breast Cancer Risk	Management
ATM	Increased by 15%-40%	Annual mammography starting at age 40 with consideration for breast tomosynthesis/magnetic resonance imaging (MRI)
BARD1	Limited evidence for increased risk but stronger for triple-negative breast cancer	Annual mammography starting at age 40 with consideration for breast tomosynthesis/MRI
BRCA1 BRCA2	Both carry increased absolute risk greater than 60%	Breast awareness starting at age 18 Clinical breast examination every 6-12 mo starting at age 25 yr Breast screening: Age 25-29 yr: Annual breast MRI screening with contrast or mammogram with consideration of tomosynthesis, only if MRI is unavailable or individualized based on family history if a breast cancer diagnosis before age 30 is present Age 30-75 yr: Annual mammogram with consideration of tomosynthesis and breast MRI screening with contrast Age >75 yr: Management should be individualized Consider risk-reducing mastectomy
BRIP1	Potential increase in risk	Management based on family history
CDH1	Increased absolute risk 41%-60%	Annual mammogram with consideration of tomosynthesis or breast MRI with contrast starting at age 30
CHECK2	Increased absolute risk 15%-40%	Annual mammography starting at age 40 with consideration for breast tomosynthesis/MRI
MSH2 MLH1 MSH6 PMS2 EPCAM	Limited evidence of increased risk, absolute risk is <15%	Management based on family history
NBN	Increased risk of breast cancer with variant 657del5	Management based on family history
NF1	Increased absolute risk 15%-40%	Annual mammography starting at age 30 with consideration for breast tomosynthesis/MRI
PALB2	Increased absolute risk 41%-60%	Annual mammography starting at age 30 with consideration for breast tomosynthesis/MRI Consider risk-reducing mastectomy
PTEN	Increased absolute risk 40%-60%	Breast awareness starting at age 18 Clinical breast examination every 6-12 mo starting at age 25 yr (or 5-10 yr before earliest known breast cancer in the family) Breast screening: Age 25-29 yr: Annual breast MRI screening with contrast or mammogram with consideration of tomosynthesis, only if MRI is unavailable or individualized based on family history if a breast cancer diagnosis before age 30 is present Age 30-75 yr: Annual mammogram with consideration of tomosynthesis and breast MRI screening with contrast Age >75 yr: Management should be individualized Consider risk-reducing mastectomy
RAD51C	Increased absolute risk 15%-40%	Management based on family history
RAD51D	Increased absolute risk 15%-40%	Management based on family history
STK11	Increased absolute risk 40%-60%	Annual mammography alternating with breast MRI every 6 mo starting at age 30 and clinical breast examination every 6 mo
TP53	Increased absolute risk >60%	Breast awareness starting at age 18 Clinical breast examination every 6-12 mo starting at age 20 yr Breast screening: Age 20-29 yr: Annual breast MRI screening with contrast or mammogram with consideration of tomosynthesis, only if MRI is unavailable or individualized based on family history if a breast cancer diagnosis before age 30 is present Age 30-75 yr: Annual mammogram with consideration of tomosynthesis and breast MRI screening with contrast Age >75 yr: Management should be individualized Consider risk-reducing mastectomy

From Gershenson DM et al: Comprehensive gynecology, ed 8, Philadelphia, 2022, Elsevier.

TABLE 6 Major Inherited Gene Mutation Syndromes Associated With Breast Cancer

Syndrome	Gene	Incidence	Lifetime Breast Cancer Risk	Associated Cancer Risks
BRCA1	BRCA1	1/500-1/1000	85%	Ovary and pancreas
BRCA2	BRCA2	Unclear	85%	Ovary and pancreas
Cowden	PTEN	1/100,000-1/200,000	50%	Thyroid and endometrium
Li-Fraumeni	TP53	1/20,000	90%	Sarcoma, brain, and leukemia

Other syndromes, including Peutz-Jeghers syndrome, ataxia telangiectasia, CHEK2 gene mutation, and Fanconi syndrome, have much smaller lifetime risks with poorer penetrance.

From Gershenson DM et al: Comprehensive gynecology, ed 8, Philadelphia, 2022, Elsevier.

TABLE 4 Factors Associated With a Decreased Risk for Breast Cancer

Demographic	Qualification	Relative Risk
Born and living outside Western countries
Late menarche	After age 14
Oophorectomy	Yes vs. no	0.3
Lactation	>16 mo vs. none	0.73
Parity	≥5 vs. 0	0.73
Postmenopausal body mass (kg/m²)	<22.9 vs. >30.7	0.63
Physical activity	Yes vs. no	0.70
Vitamin D	Low levels associated with risk
Intake of vitamin D	Associated with decreased risk
Olive oil and omega-3 fatty acids
Low-fat diet	Results suggestive but not yet conclusive
Aspirin	>1×/wk for ≥16 mo vs. no use	0.79

From Gershenson DM et al: Comprehensive gynecology, ed 8, Philadelphia, 2022, Elsevier.

TABLE 3 Risk Factors for Breast Cancer

Risk Factor	Qualification	Relative Risk
Age	≤49 yr 50-59 yr Age 60-69 yr ≥70 yr	2.0 2.3 3.5 6.7
Geographic	Common in Western countries
Age at menarche	>14 yr (low risk) vs. <12 yr	1.5
Age at first full-term pregnancy	<20 yr (low risk) vs. >30 yr	1.9-3.5
Late menopause	<45 yr (low risk) vs. >55 yr (high risk)	2.0
Hormone replacement therapy	No use vs. current	1.2
Contraceptive pill use	None vs. past or current use	1.07-1.2
Alcohol use	None vs. 2-5 drinks/day	1.4
Postmenopausal weight gain	Women with a higher body mass index (BMI)	1.1 per 5 BMI units
Bone density	Lowest vs. highest quartile	2.7-3.5
Nightshift work	Exposed to nightshift work	1.48
Smoking	History of smoking	1.10 ∗
Benign breast disease	None vs. positive biopsy result	1.7
Breast density (as measured by mammography)	0% vs. ≥75%	1.8-6.0
Hyperplasia with atypia	None vs. positive biopsy result	3.7
Multiple relatives, not first degree, with breast cancer
One first-degree relative with breast cancer (mother or sister)	None vs. yes	2.6
Two or more first-degree relatives	Increased risk if the cancers are premenopausal
Deleterious BRCA1/BRCA2 genes	Negative vs. positive	2.0-7.0
Mantle radiation for treatment of malignancy	Very high risk, which increases with age

^∗Summary relative risk.

From Gershenson DM et al: Comprehensive gynecology, ed 8, Philadelphia, 2022, Elsevier.

Physical Findings & Clinical Presentation

Increasing number of small breast cancers are found by mammograms, in which case patients are usually completely free of symptoms or physical findings.
Palpable lump or mass which can be self- or physician-detected.
Skin and/or nipple retraction and skin edema, erythema, ulcer, satellite nodule.
Nodal enlargement in axilla and supraclavicular areas.
Nipple discharge may be serous or bloody.
Generalized symptoms and signs, including fatigue, weight loss, jaundice, and anorexia, may be present in metastatic cases.

Etiology

Endogenous and exogenous estrogen exposure is key to the development of receptor-positive breast cancer
Breast cancer is no longer perceived as a single disease. Molecular classification based on gene expression profiling has shown breast cancer to be of the following types ³:
1. Luminal A type: Endocrine responsive with favorable prognosis
2. Luminal B type: Endocrine responsive with less favorable prognosis
3. Normal type: Resemble normal epithelium and prognosis similar to luminal B type
4. HER2 amplified type: HER2 gene amplification occurs in 15% to 20% of cases
5. Basal type: Hormone receptor and HER2 negative cancers with poor prognosis
Approximately 10% of all women with breast cancer have a germline mutation of BRCA1, BRCA2, P53, or other mutations
Possibly interaction of ovarian estrogen, nonovarian estrogen, estrogens of exogenous origin with breast tissue of varied carcinogenic susceptibility to develop cancer
Other known or suspected variables: Childbearing, breastfeeding practice, diet, physical activity, body mass, alcohol intake

Diagnosis ⬆ ⬇

Differential Diagnosis

Benign disease is summarized in Table 7. Noninvasive neoplasms of the breast were previously broadly divided into two major types, LCIS and DCIS (Box 1). LCIS is no longer regarded as a neoplasm of the breast in the eighth edition of the AJCC staging system but is regarded as a risk factor for the development of breast cancer.

BOX 1 Transverse Rectus Abdominis Muscle Flap Reconstruction

Indications
- Breasts of all sizes
- Breast ptosis
Relative Contraindications
- Smoking
- Abdominal liposuction
- Previous abdominal surgery
- Pulmonary disease
- Obesity
Contraindications
- Previous abdominoplasty
- Patient unable to tolerate 4- to 6-week recovery period
- Patient unable to tolerate longer procedure

From Townsend CM et al: Sabiston textbook of surgery, ed 21, St Louis, 2022, Elsevier.

TABLE 7 American Board of Pathology Histologic Classification of Benign Disease

Histopathologic Findings		Approximate Relative Risk
Nonproliferative		No added risk
Cysts
Duct ectasia
Calcification
Fibroadenoma
Milk ductal epithelial hyperplasia
Sclerosing adenosis		No added risk
Papillomatosis		Slight added risk
Radial scars
Complex sclerosing lesions		?
Moderate florid hyperplasia		1.5:1-2:1
Atypical hyperplasia (ductal and lobular)		4:1
Extensive ductal involvement of atypical hyperplasia		7:1
Lobular carcinoma in situ		10:1
Ductal carcinoma in situ		10:1

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

The following nonmalignant breast lesions can simulate breast cancer on both physical and mammogram examinations:

Fibrocystic changes
Fibroadenoma
Hamartoma

Workup

Initial workup:
1. Mass and axillary nodal assessment by medical professional.
2. Diagnostic mammogram followed by breast ultrasound for suspicious lesions.
3. MRI (Fig. 1) detects suspicious lesions better than mammography in women with dense breasts or inherited predisposition to breast cancer.⁴ When MRI is used for screening, it should be used in addition to screening mammography. Although MRI is more sensitive than mammography, it may still miss some malignancies that a mammogram would detect. For routine MRI screening, the American Cancer Society has recommended a risk-adjusted model:
  1. Annual screening beginning at age 30 yr for women at high lifetime risk for breast cancer development (approximately 20% to 25% or greater) (Box 2).
  2. Discussion with physicians regarding the benefits and limitations of adding MRI screening for women at moderately increased lifetime risk (15% to 20%).
  3. MRI is not recommended for women with a lifetime risk of developing breast cancer of less than 15%.
  4. Table 8 summarizes guidelines for evaluation and treatment of nonpalpable ductal carcinoma in situ.
Diagnosis:
1. Positive aspiration cytology on a clinically and mammographically suspicious mass is highly accurate, but requires open biopsy confirmation.
2. Stereotactic, ultrasound-guided core-needle biopsy procedures are accurate and have low complication rates. Indications for stereotactic core biopsy are summarized in Box 3. Box 4 describes contraindications to stereotactic core biopsy.
3. Excisional surgical biopsy establishes diagnosis.

BOX 3 Indications for Stereotactic Core Biopsy

Certain probably benign lesions, BI-RADS 3, depending on clinical suspicion, patient or physician preference, or when short-term follow-up is not practical
Lesions suspicious, BI-RADS 4
Lesions highly suspicious, BI-RADS 5
New suspicious microcalcifications, developing asymmetries, or architectural distortions
Nonpalpable asymmetry, focal asymmetry, or solid mass on mammogram not seen on ultrasound
Mammographic lesions corresponding to suspicious areas of enhancement on MRI

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

BOX 4 Contraindications to Stereotactic Core Biopsy

Patient unable to lie prone or cooperate
Patient’s weight
Lesion location near nipple, too superficial to skin, or too posterior to chest wall
Lesion mammographically occult
Patient has severe kyphosis or movement disorders
Lack of breast tissue thickness for adequate compression

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

Figure 1 A 42-yr-old woman with BRCA2 mutation.

Magnetic resonance imaging (MRI) screening showed a 1.2-cm invasive ductal cancer in the lower outer left breast seen only on MRI (A and B) and subsequently on second-look ultrasound. C, The mammogram showed only dense breast tissue.

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

TABLE 8 Guidelines for Evaluation and Treatment of Nonpalpable Ductal Carcinoma In Situ

Careful multiview mammography with or without ultrasound and including magnification views
- Document extent of disease
- Identify other areas of microcalcification
Suspicious microcalcifications and densities cleared with needle localization biopsy
Specimen radiography with magnification techniques
Radiograph-directed histopathologic evaluation with orientation of specimen by surgeon using multicolored inked margins
Complete pathologic description to include:
- Type of DCIS and size of tumor
- Relation to microcalcifications
- Distance of lesion from inked margins
- Presence of multifocality
- Presence or risk of microinvasion
Repeat mammography with magnification to confirm successful clearing of suspicious areas
Repeat breast excision if:
- Residual microcalcifications are found
- Margins are unacceptable

DCIS, Ductal carcinoma in situ.

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

BOX 2 American Cancer Society MRI Breast Cancer Screening Recommendations

Women at High Lifetime Risk (Risk Criteria for Breast Magnetic Resonance Imaging Screening. ≈20%-25% or Greater) of Breast Cancer

Known BRCA1 or BRCA2 gene mutation
First-degree relative with BRCA1 or BRCA2 gene mutation, but have not had genetic testing themselves
Lifetime risk of breast cancer of ≈20%-25% or greater
Radiation therapy to the chest between the ages of 10 and 30
Li-Fraumeni syndrome or Cowden syndrome or a first-degree relative with one of these syndromes

Women at Moderately Increased (15%-20%) Lifetime Risk

Lifetime risk of breast cancer of 15%-20% according to risk assessment tools based mainly on family history
Personal history of breast cancer, ductal carcinoma in situ, lobular carcinoma in situ, atypical ductal hyperplasia, or atypical lobular hyperplasia
Extremely dense breasts or unevenly dense breasts when viewed by mammograms

From Townsend CM et al: Sabiston textbook of surgery, ed 21, St Louis, 2022, Elsevier.

Staging

Table 9 describes the pathologic staging of breast cancer.

TABLE 9 Pathologic Staging of Breast Cancer

T_X		Primary Tumor Cannot Be Assessed
T₀		No evidence of primary tumor
T_is		Carcinoma in situ
T_is (DCIS)		Ductal carcinoma in situ
T_is (LCIS)		Lobular carcinoma in situ
T_is (Paget)		Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted
T₁		Tumor ≤20 mm in greatest dimension
T_1mi		Tumor ≤1 mm in greatest dimension
T_1a		Tumor >1 mm but ≤5 mm in greatest dimension
T_1b		Tumor >5 mm but ≤10 mm in greatest dimension
T_1c		Tumor >10 mm but ≤20 mm in greatest dimension
T₂		Tumor >20 mm but ≤50 mm in greatest dimension
T₃		Tumor >50 mm in greatest dimension
T₄		Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)
T_4a		Extension to chest wall, not including only pectoralis muscle adherence/invasion
T_4b		Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d’orange) of the skin, which do not meet the criteria for inflammatory carcinoma
T_4c		Both T_4a and T_4b
T_4d		Inflammatory carcinoma
N_X		Regional lymph nodes cannot be assessed (e.g., previously removed)
N₀		No regional lymph node metastasis
N₁		Metastasis to movable ipsilateral level I, II axillary lymph node(s)
N₂		Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted or in clinically detected ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis
N_2a		Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures
N_2b		Metastases only in clinically detected ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastases
N₃		Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s), with or without level I, II axillary node involvement, or in clinically detected ipsilateral internal mammary lymph node(s) and in the presence of clinically evident level I, II axillary lymph node metastasis; or metastasis in ipsilateral supraclavicular lymph node(s), with or without axillary or internal mammary lymph node involvement
N_3a		Metastasis in ipsilateral infraclavicular lymph node(s)
N_3b		Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
N_3c		Metastasis in ipsilateral supraclavicular lymph node(s)
M₀		No clinical or radiographic evidence of distant metastasis
cM_0(i+)		No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases
M₁		Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven >0.2 mm
G_X		Grade cannot be assessed
G₁		Low combined histologic grade (favorable)
G₂		Intermediate combined histologic grade (moderately favorable)
G₃		High combined histologic grade (unfavorable)

Stage Groupings in Breast Cancer
Stage	T	N	M
0	T_is	N₀	M₀
I_A	T₁	N₀	M₀
I_B	T₀-T₁	N_1mi	M₀
II_A	T₀-T₁	N₁	M₀
	T₂	N₀	M₀
II_B	T₂	N₁	M₀
	T₃	N₀	M₀
III_A	T₀-T₂	N₂	M₀
	T₃	N₁-N₂	M₀
III_B	T₄	N₀-N₂	M₀
III_C	Any T	N₃	M₀
IV	Any T	Any N	M₁

From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders; AJCC 8th ed., 2018.

Imaging Studies

Mammograms (Fig. E2, Fig. E3): 30% to 50% of breast cancers are detected by screening mammograms as a spiculated mass, a mass with or without microcalcifications, or a cluster of microcalcifications. MRI is particularly useful in patients with breast implants and when there is a strong family history of breast cancer. MRI is better for assessing response to neoadjuvant chemotherapy and for identifying the primary tumor in patients presenting with axillary adenopathy.

Figure E2 Mammogram and ultrasound findings of breast disease.

A, A stellate mass in the breast. The combination of a density with spiculated borders and distortion of surrounding breast architecture suggests a malignancy. B, Clustered microcalcification. Fine, pleomorphic, and linear calcifications that cluster together suggest the diagnosis of ductal carcinoma in situ (DCIS). C, An ultrasound image of breast cancer. The mass is solid, containing internal echoes, and displaying an irregular border. Most malignant lesions are taller than they are wide.

From Townsend CM et al [eds]: Sabiston textbook of surgery, ed 17, Philadelphia, 2004, Saunders.

Figure E3 Digital mammography and workup of breast calcifications.

A, Craniocaudal (CC) view in a routine screening of a 43-yr-old woman. Digital mammography penetrates dense breast tissue better than film-screen mammography, clearly showing diffuse benign pattern of large and small calcifications throughout the breast. B, CC view in a routine screening of a 46-yr-old woman. Digital mammography shows two areas of very faint calcification in the outer breast that require further workup. C, Close-up view of B, showing the calcifications (arrows) to be variable in size and shape, which is worrisome for malignancy, particularly ductal carcinoma in situ. Such tiny calcifications in a background of dense breast stroma are easier to see on digital mammography than on film-screen mammography. Computer-assisted diagnosis programs also help the radiologist to locate even tiny groups of faint calcifications such as these. D, Mediolateral view in the same patient as in B, showing that the calcifications are in the lower breast. E, Image from stereo core biopsy procedure in the same patient as in B, showing the core needle immediately proximal to one of the groups of calcifications. Stereo core biopsy allows histologic sampling of tiny groups of calcifications, which can be very helpful in planning surgical approach. This interventional procedure can decrease the total number of surgeries that a patient must undergo to achieve definitive treatment. F, Radiograph of specimen from stereo core biopsy procedure on the same patient as in B, showing that there are several tiny calcifications (arrows) within some of the core samples. Pathologic analysis of the core biopsy revealed ductal carcinoma in situ, high grade, with comedo features.

From Skarin AT: Atlas of diagnostic oncology, ed 4, Philadelphia, 2010, Elsevier.

Treatment ⬆ ⬇

Nonpharmacologic Therapy

These approaches include various types of surgical resection and reconstruction (Box 5) as well as adjuvant radiotherapy.
For early breast cancer, the primary therapy is usually surgical with a choice between modified radical mastectomy and breast-conserving treatments, and axillary staging with sentinel node biopsy or axillary dissection. Breast-conserving surgery removes the malignancy with a surrounding rim of grossly normal breast parenchyma. This procedure is depicted in Fig. E4, which shows the completed lumpectomy and skin incision for the axillary component of the procedure. The breast specimen that is removed is oriented and its edges are inked before sectioning. Specimen radiography should be performed for all nonpalpable lesions or if there are microcalcifications associated with the palpable tumor. If a margin appears to be close or is positive histologically on intraoperative assessment, reexcision to achieve a clear margin is required. Orientation of the surgical specimen allows focal reexcision of involved margins rather than global reexcision and improves the cosmetic result by reducing the amount of normal breast parenchyma that is excised.
Table 10 compares ductal versus lobular carcinoma in situ. Adjuvant treatment guidelines for patients with early-stage invasive breast cancer are described in Table 11.
Among patients with limited sentinel lymph nodes (SLN) who are treated with breast conservation and systemic therapy, survival with sentinel lymph node dissection (SLND) is not inferior to axillary lymph node dissection (ALND).⁵
DCIS: Local breast-conserving therapy (lumpectomy plus radiation therapy) or mastectomy followed by endocrine therapy in estrogen receptor-positive cases.
Invasive breast cancer: Mastectomy or lumpectomy, along with sentinel lymph node evaluation followed by radiation therapy for large tumors.
Invasive breast cancer may require systemic therapy options including endocrine therapy and/or chemotherapy. Current guidelines use stage and biologic characteristics in the development of treatment recommendations to guide decisions regarding systemic therapy for breast cancer (Table 12). Endocrine therapy is recommended alone or after chemotherapy in patients with hormone-receptor positive tumors. Breast cancer intrinsic subtypes are summarized in Table 13. Treatment according to breast cancer subtypes is described in Table 14. Adjuvant hormone therapy with antiestrogen drugs reduces disease recurrence and mortality in women with breast cancer. Aromatase inhibitors (anastrozole, letrozole, exemestane, fulvestrant) decrease the agonist effect of estrogen by inhibiting estrogen synthesis and have become preferred first-line hormonal treatment agents over the selective estrogen receptor modulator tamoxifen.
The FDA recently approved the addition of the CDK inhibitor abemaciclib as adjuvant treatment for patients with hormone receptor-positive, HER2-negative, node-positive early breast cancer who are at high risk of recurrence.⁶
There is an improvement in disease-free survival with the adjuvant use of the PARP inhibitor Olaparib in addition to standard endocrine therapy in breast cancer patients with germline BRCA1/BRAC2 mutations.⁷
Standard adjuvant chemotherapy used in the U.S. include AC (cyclophosphamide plus doxorubicin), AC-T (doxorubicin and cyclophosphamide followed by a taxane), and TC (docetaxel and cyclophosphamide) regimens. In patients with HER2 expressing breast cancers, standard adjuvant regimens also include the addition of trastuzumab and pertuzumab for 1-yr duration. Fig. E5 illustrates considerations for adjuvant chemotherapy in breast cancer.
Neoadjuvant chemotherapy (same regimens as used in the adjuvant setting) results in pathologic complete responses in significant number of cases, causes downstaging, provides an assessment of chemosensitivity, and provides no deleterious effect on survival.
In patients with early-stage, triple-negative breast cancer, the FDA has approved the PD-1 inhibitor immunotherapy agent pembrolizumab in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgical resection.
The benefit of adjuvant chemotherapy or hormone therapy can be assessed by commercially available multigene assays (OncotypeDx, Mammaprint), which help in determining prognostic and predictive benefit associated with the use of both hormonal therapy and chemotherapy in breast cancer. Results from the prospective TAILORx trial support the routine use of multigene assays to identify intermediate-risk score patients in which chemotherapy can be safely omitted.⁸ Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower based on the 21-gene breast cancer assay, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women did not have any benefit from adjuvant chemotherapy.
Metastatic breast cancer is treated based on the extent of bone-only or visceral disease sites as well as the rate of symptomatic progression. All management of metastatic breast cancer is palliative. Table 15 summarizes median survival of patients with metastatic breast cancer by location of metastases.
Typically, bone-only metastatic disease is approached with upfront, sequential hormonal therapy with tamoxifen or aromatase inhibitors. The combination of CDK4/CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) with aromatase inhibitors is typically used as up-front therapy and improves overall survival. Second-line therapy with aromatase inhibitor plus mTOR inhibitors (everolimus) is used.
Among patients with PIK3CA-mutated, hormone-receptor-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously, treatment with the combination of alpelisib plus fulvestrant prolonged progression-free survival, leading to the approval of this combination approach.⁹ Commonly used cytotoxic chemotherapy and anti-HER2 therapy drugs in metastatic breast cancer are summarized in Table 16.
Patients with progressive bone disease or those with visceral disease are treated with typically single-agent chemotherapy and occasionally with combination chemotherapy regimens. The chemotherapy agents are the same as those used in early stages of disease. Sequential chemotherapy with different classes of chemotherapy agents are usually used to provide palliation with improvement in survival and symptoms.
Patients whose tumors have germline BRCA1/2 mutations can be treated with the PARP inhibitors olaparib or talazoparib.
Patients with triple-negative breast cancer whose tumors express the program death ligand-1 receptor derive a survival benefit with the use of the combination of immune checkpoint inhibitor pembrolizumab plus chemotherapy.¹⁰
Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in most breast cancers, coupled to SN-38 (topoisomerase I inhibitor). Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among relapsed triple-negative breast cancer patients leading to its approval recently.¹¹
In patients with metastatic HER2/neu-positive breast cancer, the addition of the monoclonal antibody pertuzumab to the standard regimen of trastuzumab plus taxane chemotherapy has been demonstrated to significantly improve the median overall survival to >5 yr.¹² Also, the antibody-drug conjugates TDM-1 and trastuzumab dexrutecan improve survival in this group of patients.¹¹ The chimeric antibody margetuximab, which incorporates an engineered Fc region to increase immune activation, results in significant improvement in progression-free survival when used with chemotherapy in patients previously treated with two or more prior anti-HER2/neu therapies. In addition, oral HER2-directed inhibitors such as neratinib and tucatinib are active in previously treated patients with metastatic disease.
The FDA has approved elacestrant, an oral estrogen receptor antagonist for treatment of ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer in postmenopausal women or men who had disease progression following endocrine therapy.

TABLE 16 Commonly Used Cytotoxic Chemotherapy and Anti-HER2 Therapy Drugs in Metastatic Breast Cancer

Cytotoxic Chemotherapy
Albumin-bound paclitaxel Capecitabine Cisplatin Carboplatin Docetaxel Doxorubicin Epirubicin Eribulin Gemcitabine Ixabepilone Vinorelbine
*Anti-HER2* Therapy**
Ado-trastuzumab emtansine Lapatinib Pertuzumab Trastuzumab

HER2, Human epidermal growth factor receptor 2.

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

TABLE 15 Median Survival in Months of Patients With Metastatic Breast Cancer by Location of Metastases

Location		Survival (Months)
Liver (>30% replacement)		3
Lung (lymphangitic)		3
Lung (nodular)		22
Skin		27
Bones		36+

From Townsend CM et al: Sabiston textbook of surgery, ed 21, St Louis, 2022, Elsevier.

TABLE 12 Decision-Making for Systemic Therapy

Stage	Systemic Therapy	Comments
I (<1 cm)
Hormone receptor-positive	Endocrine therapy ± chemotherapy	Consider genomic testing
Hormone receptor-negative	Consider chemotherapy
HER-2-positive	Strongly consider trastuzumab and chemotherapy
I (>1 cm)
Hormone receptor-positive	Endocrine therapy ± chemotherapy	Consider genomic testing
Hormone receptor-negative	Chemotherapy
HER-2-positive	Trastuzumab and chemotherapy
II (Lymph Node-Negative)
Hormone receptor-positive	Endocrine therapy ± chemotherapy	Consider genomic testing
Hormone receptor-negative	Chemotherapy
HER-2-positive	Trastuzumab and chemotherapy
II (Lymph Node-Positive), III
Hormone receptor-positive	Chemotherapy + endocrine therapy	Endocrine therapy should be recommended for all patients
Hormone receptor-negative	Chemotherapy	Decision-making for chemotherapy may be influenced by results from ongoing clinical trials
HER-2-positive	Trastuzumab and chemotherapy	Consider neoadjuvant chemotherapy with dual HER-2-targeted therapy

HER-2, Human epidermal growth factor receptor 2.

From Townsend CM et al: Sabiston textbook of surgery, ed 21, St Louis, 2022, Elsevier.

TABLE 13 Breast Cancer Intrinsic Subtypes

Subtype	Characteristics	Markers
Luminal A	Low grade. High ER ∼40% of all breast cancer Good prognosis	ER+, PR+, HER2-Low Ki-67 (<14%)
Luminal B	Higher grade. Lower ER ∼20% of all breast cancer Poorer prognosis than luminal A	ER+, PR+/-, HER2+/-High Ki-67 (>14%)
HER2-enriched	High grade. Often node positive P53 mutations ∼10%-15% of all breast cancer	ER-, PR-, HER2+
Basal-like	High proliferation. BRCA dysfunction ∼15%-20% of all breast cancer Poor prognosis	ER-, PR-, HER2-CK5/6 Or EGFR+

CK, Cytokeratin; EGFR, epidermal growth factor receptor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

TABLE 14 Treatment According to Breast Cancer Subtype

Subtype		Treatment Response and Prognosis
Luminal A		Respond to endocrine therapy Premenopausal: SERMs (tamoxifen) Postmenopausal: AIs (exemestane, anastrozole, letrozole)
Luminal B		Response to endocrine therapy lower. Response to chemotherapy greater than luminal A
HER2-enriched		Respond to anti-HER2 agents (trastuzumab, pertuzumab, lapatinib)
Basal-like		No response to endocrine therapy or anti-HER2 agents. Chemotherapy only treatment outside of a clinical trial

AIs, Aromatase inhibitors; HER2, human epidermal growth factor receptor 2; SERMs, selective estrogen receptor modulators.

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

TABLE 10 Carcinoma In Situ: Lobular Versus Ductal

Feature	Lobular Carcinoma In Situ	Ductal Carcinoma In Situ
Age	Younger	Older
Palpable mass	No	Uncommon
Mammographic appearance	Not detected on mammography	Microcalcifications, mass
Immunophenotype	E-cadherin negative	E-cadherin positive
Usual manifestation	Incidental finding on breast biopsy	Microcalcifications on mammography or breast mass
Bilateral involvement	Common	Uncertain
Risk and site of subsequent breast cancer	25% risk for invasive breast cancer in either breast over remaining lifespan	At site of initial lesion; 0.5% risk/yr of invasive breast cancer in opposite breast
Prevention	Consider tamoxifen or raloxifene	Consider tamoxifen or raloxifene if estrogen-receptor positive
Treatment	Yearly mammography and breast examination	Lumpectomy ± radiation; mastectomy for large or multifocal lesions

From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

TABLE 11 Adjuvant Treatment Guidelines for Patients With Early-Stage Invasive Breast Cancer

Patient Group		Treatment
*Hormone Receptor-Positive and HER2* Positive Breast Cancer**
<0.5 cm		Consider adjuvant endocrine therapy
0.6-1 cm		Adjuvant endocrine therapy Consider adjuvant chemotherapy and trastuzumab
>1 cm		Adjuvant endocrine therapy Adjuvant chemotherapy and trastuzumab
Node positive		Adjuvant endocrine therapy Adjuvant chemotherapy with pertuzumab and trastuzumab
*Hormone Receptor-Positive and HER2* Negative Breast Cancer**
<0.5 cm		No adjuvant therapy
>0.5 cm		Adjuvant hormonal therapy Consider adjuvant chemotherapy based on 21-gene recurrence score
Node-positive		Adjuvant hormonal therapy + adjuvant chemotherapy
*Hormone Receptor-Negative and HER2* Positive Breast Cancer**
<0.5 cm		Consider adjuvant chemotherapy and trastuzumab
0.6-1 cm		Consider adjuvant chemotherapy and trastuzumab
>1 cm		Adjuvant chemotherapy and trastuzumab
Node positive		Adjuvant endocrine therapy Adjuvant chemotherapy with pertuzumab and trastuzumab
*Hormone Receptor-Negative and HER2* Negative Breast Cancer**
≤0.5 cm		No adjuvant therapy
0.6-1.0 cm		Consider adjuvant chemotherapy
>1 cm or node positive		Adjuvant chemotherapy

HER2, Human epidermal growth factor receptor 2.

Modified from National Comprehensive Cancer Network Guidelines. Available at www.nccn.org.

BOX 5 Options for Breast Reconstruction

Autogenous

Abdominal-based flaps
Transverse rectus abdominis muscle (TRAM)
Single pedicle
Double pedicle
Free flap
Deep inferior epigastric perforator flap ∗

Latissimus dorsi musculocutaneous flap

Gluteal flap ∗

Superiorly based
Inferiorly based

Rubens flap ∗

Thoracoepigastric flap

Lateral thigh flap ∗

Breast-splitting procedure

Alloplastic

Silicone gel implant
Silicone implant with saline fill
Smooth wall
Textured wall
Round
Anatomic shaped

Combination procedures

Latissimus dorsi flap with implant
TRAM flap with implant

From Townsend CM et al: Sabiston textbook of surgery, ed 21, St Louis, 2022, Elsevier.

Figure E4 Breast-conserving surgery.

A, Incisions to remove malignant tumors are placed directly over the tumor or around the areola. After the partial mastectomy has been completed, the parenchymal defect is closed (inset) to prevent a cosmetic deformity. B, A transverse incision below the axillary hairline is used for sentinel node biopsy or axillary dissection. The boundaries of the axillary dissection are the axillary vein superiorly, the latissimus dorsi muscle laterally, and the chest wall medially. The inferior dissection enters the tail of Spence (the axillary tail of the breast). In sentinel node biopsy, a similar transverse incision is made, which may be located by percutaneous mapping with the gamma probe to detect a hot spot from the radiolabeled colloid. It is extended through the clavipectoral fascia, and the true axilla is entered. The sentinel node is located by staining with blue dye (inset), radioactivity, or both and is dissected free as a single specimen.

From Townsend CM et al: Sabiston textbook of surgery, ed 21, St Louis, 2022, Elsevier.

Figure E5 Management of recurrent and metastatic breast cancer.

Considerations for adjuvant chemotherapy. ER, Estrogen receptor; HER2, human epidermal growth factor receptor 2.

From Cameron JL, Cameron AM: Current surgical therapy, ed 10, Philadelphia, 2011, Saunders.

Chronic Rx

Follow-up after treatment of early breast cancer stages includes:

Patient instruction in monthly breast self-examination.
Regular clinical evaluations as delineated by medical oncologist or surgeon.
Annual mammograms and breast MRI as indicated.
Laboratory tests as indicated.
Tumor markers and CT scans for surveillance are not recommended.
Adjuvant therapy: In premenopausal women with hormone receptor-positive early breast cancer, use of aromatase inhibitor exemestane plus ovarian suppression, compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. In postmenopausal women with hormone receptor-positive breast cancer, aromatase inhibitor therapy improves survival outcomes compared with tamoxifen. Women who take tamoxifen for 10 yr lower their recurrence risk by 25% and their dying of breast cancer risk by 27% compared with those who took it for just 5 yr. In postmenopausal women with hormone-receptor positive breast cancer, recent trial data showed that in women treated with 5 yr of adjuvant endocrine therapy, extending hormone therapy by 5 yr provided no benefit over a 2-yr extension but was associated with more bone fractures.
Retrospective analyses suggest that occult lymph-node metastases are an important prognostic factor for disease recurrence or survival; however, recent data indicate that the magnitude of the difference in outcome at 5 yr is small (1.2 percentage points) and do not favor additional evaluation of initially negative sentinel nodes.
Adding zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer.

Referral

Referral to a multidisciplinary team consisting of a breast surgeon, reconstructive surgeon, medical oncologist, and radiation oncologist is necessary as soon as breast cancer is suspected.

∗Requires microsurgical procedure and historical note only.

Pearls & Considerations ⬆ ⬇

Breast Cancer In Pregnancy and Lactation

Frequency in women 40 yr or younger reported to be 15%
May carry worse prognosis because disease discovery delayed by engorged and nodular breast changes and/or because disease progression more rapid in pregnancy
Survival is similar to nonpregnant early-stage patients in same age group
Expedient workup recommended, including mammography and sonography
Choice of mastectomy or lumpectomy with axillary dissection for treatment
Adjuvant chemotherapy and radiotherapy delayed until third trimester or after delivery
Other contraindications to radiation are summarized in Box 6

BOX 6 Contraindications to Radiation

Absolute

Pregnancy

Relative

Systemic scleroderma
Active systemic lupus erythematosus
Prior radiation to breast or chest wall
Severe pulmonary disease
Severe cardiac disease (if tumor is left sided)
Inability to lie supine
Inability to abduct arm on affected side
p53 mutation

From Townsend CM et al: Sabiston textbook of surgery, ed 21, St Louis, 2022, Elsevier.

Ductal Carcinoma In Situ (Dcis, Intraductal Carcinoma) (See TABLE 10

Discovered by mammogram as cluster of microcalcifications and/or density
Presents less often as a palpable mass or nipple discharge
With widespread mammogram screening, DCIS accounts for 15% to 20% of all breast cancers
Treated with lumpectomy with cure rates 98% to 99%
Higher-risk cases require breast radiation and adjuvant hormone therapy
Mastectomy is required with multifocal and/or high-grade DCIS

Inflammatory Carcinoma

Rare, rapidly progressive, and often lethal form of breast cancer
Presents as erythematous and edematous breast resembling mastitis
Biopsy required, including that of the skin
Treatment with upfront combination chemotherapy followed by surgery and radiotherapy
Prognosis is improved with 5-yr disease-free survival approaching 50% (Fig. E6)

Figure E6 A, 5-Yr Relative Survival by Race and Stage at Diagnosis of Breast Cancer (SEER Data, 1996-2002)

B, Female Breast Cancer Incidence by Race and Ethnicity (SEER Data). C, When Lobular Breast Cancer Metastasizes, It Can Often Infiltrate Serosal Surfaces, Mimicking Ovarian Cancer. This Patient Presented with Abdominal Bloating, Tightness, and Narrowing in Her Stool Caliber 9 Yr after the Diagnosis of a Stage I Breast Cancer. Note the Diffuse Thickening of the Rectal and Colonic Wall, Peritoneal Carcinomatosis, and Ascites. Fig. E6 (Continued)A Colonoscopy was Performed, and Biopsy Confirmed Diffuse Involvement with Metastatic Adenocarcinoma Consistent with a Breast Primary. On Restaging, She was Also Noted to have Multiple Osseous Metastases. D, In an Ultrasound-Guided Needle Biopsy, the Ultrasound Probe is Used to Localize the Lesion that was Identified Either on Physical Examination or on Mammogram. A Biopsy Needle is Passed through the Lesion Several Times to Obtain Tissue. Compared to a Stereotactic Biopsy, an Ultrasound-Guided Biopsy is Faster and Better Tolerated by Most Patients. However, Not All Lesions May Be Amenable to an Ultrasound-Guided Biopsy. E, The Premise Behind Stereotactic Needle Biopsy is that a Lesion Can Be Localized in 3D by Evaluating its Changes in Position in a Series of Angled Radiographic Views. First, a Radiograph Localizes the Suspicious Area; Then Two Additional Views, Angled 15 Degrees to Either Side of the Lesion, are Obtained. A Computer Calculates How Much the Lesion’s Position Appears to have Changed on Each of the Angled Views and Uses These Data to Estimate the Lesion’s Location Within 3D Space. With the Advent of Digital Mammography, These Images are Commonly Acquired Digitally. F, Positron Emission Tomography (PET) Involves Injection of a Substance Labeled with a Positron-Emitting Isotope (Commonly, Fluorine-18 Bound to D-Glucose, Called FDG for 2-([18F]fluoro-2-Deoxy-D-Glucose)). Metabolically Active Cells, Especially Malignant Ones, Preferentially Take Up Glucose and Therefore FDG, as Compared with Nonneoplastic Tissue. Sensitivity of PET Can Vary Considerably by Tumor Type and Size. False-Positive Results Can Occur in Areas of Inflammation or Infection. Many Machines Now Acquire CT Images in Tandem with PET Images, Which Can Then Be Fused Together to Provide Anatomic Correlation by CT with Metabolic Activity Measurements by PET. This Patient Presented with Palpable Axillary Adenopathy and a Large Breast Mass with Associated Erythema, Skin Edema, and Nipple Retraction. Note the Extremely Intense Areas of Uptake Within the Right Breast and Axilla Corresponding to the Patient’s Known Locally Advanced Breast Cancer. Also Note the Intense Uptake in the Right Supraclavicular, Paratracheal, Prevascular, Precarinal, and Hilar Lymph Nodes Suspicious for Metastatic Disease. Uptake in the Kidney, Bladder, and Ureters is Physiologic and Due to FDG Excretion. Uptake in the Right Adnexa and Jaw is Most Likely Physiologic and Benign. G, Panels 1 and 2: Accelerated Partial Breast Irradiation (APBI) Encompasses Techniques Including Intracavitary and Interstitial Brachytherapy as Well as 3D-Conformal, Intensity-Modulated, and Intraoperative External-Beam Radiation Therapy. One of the More Commonly Used Brachytherapy Methods in the U.S., the Mammosite Brachytherapy System (Hologic, Massachusetts), Involves Insertion of a Catheter with a Balloon Tip into the Lumpectomy Cavity at the Time of Surgery or Shortly Thereafter (Panel 1). The Balloon is Filled with Saline, and a High-Dose-Rate Radioactive Source is Introduced Twice Per Day for 5 Days by Computed Axial Tomography Scan-Based Treatment Planning, Permitting a Highly Conformal Dose to Be Delivered to the First Centimeter of Remaining Breast Tissue with Optimal Sparing of the Remaining Tissue and Other Regional Organs (Panel 2). The Balloon Catheter is Removed Upon Completion. APBI is an Option Only for Selected Patients, Mainly Older Women with Smaller, Node-Negative “low-Risk” Tumors and with Negative Margins. H, The HER Family of Receptors (Human Epidermal Growth Factor Receptor, Also Called ErbB, is a Group of Transmembrane Tyrosine Kinase Receptors that Regulate Cell Growth, Survival, and Differentiation Via a Variety of Pathways, Including RAS (Rat Sarcoma), RAF (Receptor Activation Factor), MAPK (Mitogen-Activated Protein Kinase), and MEK (Mitogen Extracellular Signal Kinase). The Tyrosine Kinase Domains are Activated by Dimerization. Current Therapeutics Involve Tyrosine Kinase Inhibitors (E.g., Lapatinib) and Antibodies Directed Against the HER2 Protein and VEGF (Vascular Endothelial Growth Factor) (E.g., Trastuzumab and Bevacizumab). Akt, Protein Kinase B; Pi3-K, Phosphatidylinositol 3-Kinase; SOS, Son of Sevenless.

From Skarin AT: Atlas of diagnostic oncology, ed 4, Philadelphia, 2010, Elsevier. Image courtesy of Drs. Pamela Dipiro and Wendy Chen, Dana Farber Cancer Institute, Boston, MA. Image courtesy of Robyn L. Birdwell, MD, Brigham and Women’s Hospital, Boston, MA, and Diagnostic Imaging Breast, Amirsys, Inc., Salt Lake City, UT, 2006. Courtesy of Phillip M. Devlin, MD, Dana Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, MA.

Comments

The U.S. Preventive Services Task Force (USPSTF) now recommends against automatic “routine” screening of younger women (age range 40 to 49). The task force recommends biennial screening mammography for all middle-aged women (age range 50 to 74). It also states that current evidence is insufficient to assess the benefits and harms of screening mammography in older women (aged 75 and older). The task force also discourages women from performing breast self-examination. Several other U.S. organizations, such as the American Congress of Obstetricians and Gynecologists, however, still recommend annual screening beginning at age 40 yr. Breast cancer screening recommendations by organization are summarized in Table 17.
The American Cancer Society screening guidelines are summarized in the following ¹³:
Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 yr or longer. (Qualified recommendation)
Women with an average risk of breast cancer should undergo regular screening mammography as below:
1. Women should have the opportunity to begin annual screening between the ages of 40 and 44 yr. (Qualified recommendation)
2. Women aged 45 to 54 yr should be screened annually. (Qualified recommendation)
3. Women 55 yr and older should transition to biennial screening or continue screening annually. (Qualified recommendation)
Women who are at high risk for breast cancer based on certain factors should get an MRI and a mammogram every year, typically starting at age 30 yr. This includes women who:
1. Have a lifetime risk of breast cancer of about 20% to 25% or greater, according to risk assessment tools that are based mainly on family history.
2. Have a known BRCA1 or BRCA2 gene mutation (based on genetic testing).
3. Have a first-degree relative (parent, brother, sister, or child) with a BRCA1 or BRCA2 gene mutation and have not had genetic testing themselves.
4. Had radiation therapy to the chest between the ages of 10 and 30 yr.
5. Have Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or have first-degree relatives with one of these syndromes.
Physicians should be familiar with the risks and benefits of these various competing recommendations in order to better counsel patients.
Breast radiologic evaluation, evaluation of nipple discharge, and evaluation of palpable mass are described in Section III.
Exposure of the heart to ionizing radiation during breast cancer radiotherapy increases risk of ischemic heart disease. The increased rate of ischemic heart disease begins within a few years of exposure and continues for at least 20 yr. The increase is proportional to the mean radiation dose to the heart.

TABLE 17 Breast Cancer Screening Recommendations by Organization

Organization	When to Initiate Screening	Frequency of Screening	When to Stop Screening
American Academy of Family Physicians (AAFP)	Follow U.S. Preventive Services Task Force (USPSTF) recommendations	Follow USPSTF recommendations	Follow USPSTF recommendations
American Cancer Society (ACS)	Opportunity to begin screening at ages 40-44 Regular screening starting at age 45	Annually from age 45-54 Biennially starting at age 55 with opportunity to continue annually	Continue screening mammography as long as overall health is good, and life expectancy is 10 yr or longer
American College of Obstetricians and Gynecologists (ACOG)	Annual screening starting at age 40	Annually	Not specified
American College of Physicians (ACP)	Individualized for women ages 40-49 Regular screening starting at age 50	Biennially	Age 75 yr or older Women of any age with life expectancy <10 yr
American College of Radiology (ACR)	Annual screening starting at age 40	Annually	Should be considered as long as the patient is in good health and is willing to undergo additional testing if an abnormality is detected
National Comprehensive Cancer Network (NCCN)	Annual screening starting at age 40	Annually	Upper age limit is not yet established Consider comorbid conditions limiting life expectancy (e.g., ≤10 yr) and whether therapeutic interventions are planned
U.S. Preventive Services Task Force (USPSTF)	Individualized for women ages 40-49 Regular screening beginning at age 50	Biennially	Insufficient evidence to recommend for or against screening at age 75 or older

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

Risk Reduction Strategies

Prophylactic bilateral mastectomy reduces the risk for invasive breast cancer by >90%.
Counseling points for women with average risk interested in contralateral prophylactic mastectomy (CPM) are summarized in Box 7.
Selective estrogen receptor modulators (SERM) reduce the incidence of hormone receptor-positive invasive breast cancer by 50%.
Ovarian failure is a common toxic effect of chemotherapy. Administration of the gonadotropin-releasing hormone (GnRH) agonist goserelin appears to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility.

BOX 7 Counseling Points for Women With Average Risk Interested in Contralateral Prophylactic Mastectomy (CPM)

There is a low annual contralateral breast cancer risk in women with average risk factors.
Risk of contralateral breast cancer is decreasing with use of adjuvant therapy.
Removing the contralateral breast does not decrease the risk for developing distant metastases.
Breast cancer does not commonly metastasize from one breast to the other.
CPM does not improve breast cancer-specific survival.
CPM does not decrease local recurrence.
Contralateral breast cancers tend to be at a lower stage than the initial primary cancer.
CPM increases the surgical complication risk.
Choice of CPM may influence reconstruction options.
There are alternatives to CPM, including chemoprevention and surveillance.

From Cameron JL, Cameron AM: Current surgical therapy, ed 12, Philadelphia, 2017, Elsevier.

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section name header

Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

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