Editing Breast cancer

== '''Epidemiology''' ==

* Second only to lung cancer for cancer-related deaths
* 2 million cases worldwide annually
* Recently decreasing incidence, probably due to screening and decreased use of HRT

== '''Risk factors''' ==

=== '''Un-modifiable''' ===

** Increasing age
*** Rare in women <20yo
*** Steadily increases with age, up to 1 in 8 by age 80
** Female sex
*** <1% occurs in men
*** Masses in men are more likely to be non-cancerous than cancerous
** Reproductive factors (increased lifetime oestrogen exposure - relatively small contribution to overall risk. Particularly hormone receptor-positive cancers. )
*** Early age at menarche (<12yo)
*** Older age at menopause (>55yo double risk)
*** Nulliparity
*** Age at first live birth (first full-term pregnancy >30yo is double risk of first pregnancy <18yo)
*** Parity
*** Lack of breastfeeding
** Family history of breast cancer
*** First degree relatives RR 2-3
*** Much higher risk with pre-menopausal onset and bilateral breast cancer
** Genetic disposition
*** See separate topic
** Personal history of breast cancer
*** Magnitude of risk depends on age at diagnosis of primary, use of adjuvant chemotherapy and endocrine therapy
*** Absolute risk as high as 0.5-1% in younger patients
** White race
** Radiation exposure
*** RR 2-4, especially increased with mantle radiation <30yo

=== '''Modifiable''' ===

** Obesity
** Alcohol
** Tobacco smoking
** HRT
*** Combination HRT (oestrogen and progesterone) for 5 years: RR 1.2
*** Oestrogen-only HRT: no significant increase in risk
** Sedentary lifestyle
** Shift work

=== '''Histologic''' ===

** Proliferative breast disease
*** Without atypia - sometimes called severe hyperplasia - RR 1.3-1.9
**** Fibrocystic change with hyperplasia greater than mild; papilloma; papillomatosis; sclerosing adenosis; radial scar; etc
*** With atypia - RR 3.7-4.2
**** Atypical ductal or lobular hyperplasia, or both
**** Annual risk 0.5-1% per year
**** With strong family history breast cancer RR 4-9
** Atypical ductal hyperplasia
** Atypical lobular hyperplasia
** Lobular carcinoma in situ (RR>7)
*** See separate topic

== '''Overall risk assessment''' ==

* <nowiki>https://bcrisktool.cancer.gov/</nowiki> (Gail model)
** Significantly underestimated risk for patients with a history of invasive cancer, DCIS or LCIS, and first-degree relatives with pre-menopausal or bilateral breast cancer or other mutation
* <nowiki>https://canrisk.org/canrisk_tool/</nowiki> can give risk of cancer and mutations

== '''Care of high-risk patients''' ==

* High-risk patient is defined as a 5-year calculated risk of >1.66% using Gail model, which is the average risk of a 60yo woman
* For patients with specific genetic mutations, see separate topic - this is for general high-risk
* Close surveillance
** Monthly self-examination
** Semi-annual clinical breast examination
** Annual mammography begging at age 25 or 10 years before the earliest age of onset of breast cancer in a family member
** Consider annual screening MRI
* Chemoprevention
** Tamoxifen can reduce the risk of OR-positive cancers, but at the cost of endometrial cancers and PEs, so probably quite a high risk level is necessary to consider it
* Bilateral prophylactic mastectomy
** Reduces the risk of breast cancer development in high-risk women by 90%

== '''Classification''' ==

* Non-invasive breast cancer
** DCIS - separate topic
** LCIS - separate topic
* Invasive epithelial cancers
** Invasive lobular carcinoma (10%)
*** Tends to permeate the breast in a single-file nature, so generally remains clinically occult and often escapes detection on mammography or physical examination until the disease is extensive
*** Loss of e-cadherin, single-file pattern, presence of small dis-cohesive tumour cells
*** Intermediate prognosis
** Invasive ductal carcinoma (50-70%)
*** Tends to grow as a cohesive mass
*** Appears as discrete abnormalities on mammograms and is often palpable as a discrete lump in the breast
*** Subtypes:
**** Invasive ductal carcinoma, not otherwise specified (50-70%)
**** Tubular carcinoma (2-3%)
***** Small glands lined by a single row of bland epithelium
***** Usually low-grade
***** Excellent prognosis
**** Mucinous or colloid carcinoma (2-3%)
***** Infiltrating cells secrete copious amounts of mucin and appear to float in this material
***** Usually low-grade
***** Excellent prognosis
**** Medullary carcinoma (5%)
***** Bizarre invasive cells with high-grade nuclear features, many mitoses and lack of an in-situ component
***** Pushes into the surrounding breast rather than infiltrating
***** Uniformly high-grade, triple negative
**** Invasive cribriform carcinoma (1-3%)
**** Invasive papillary carcinoma (1-2%)
**** Adenoid cystic carcinoma (1%)
**** Metaplastic carcinoma (1%)
***** Typically high-grade and triple-negative
***** Mostly node negative but still have high potential for de novo metastatic spread
* Mixed connective and epithelial tumours
** Phyllodes tumours, benign and malignant
** Carcinosarcoma
** Angiosarcoma
** Adenocarcinoma
* Multifocal - multiple tumours within the same quadrant
* Multicentric - multiple tumours in different quadrants

== '''Pathophysiological features''' ==

=== Molecular markers ===

** ER background
*** Positive in about 80% of breast cancers
*** Ligand-dependent transcription factor, member of the steroid hormone receptor superfamily. When oestrogen binds, promoter regions of DNA are triggered. Has two subunits - ER-alpha and ER-beta
**** See 'reproductive physiology' under 'O+G' for background on oestrogens
*** Clinical ER assays measure ER-alpha, and quantitate using immunohistochemistry, and level of expression predicts response to endocrine therapy - 70% of ER+/PR+ cancers respond
*** Graded on intensity of scoring (0 to 3+) and proportion of staining (percentage)
**** >1% staining is considered positive
**** 1-10% is low positive
**** Allred Score out of 8 combines intensity and positivity
*****[[File:Allred-score-guidelines-for-ER-and-PR-evaluation.png|none|Allred score for ER and PR evaluation|thumb|441x441px]]
*** 65% of ER+ cancers are also PR+
*** Some ER-/PR+ cancers also respond to endocrine therapy, but this is a rare combination
** HER2
*** Tyrosine kinase receptor which functions as a protooncogene when amplified
**** Based on ERBB2 gene, chromosome 17
**** External to internal signalling, influencing growth and differentiation via PI3K, MAPK, JAK/STAT pathways
**** Doesn't bind to ligands, but is activated when it dimerizes with itself or other EGFR family members
*** Associated with high-grade cancers with axillary involvement, and decreased ER/PR expression. HER2 overexpression is also a poor prognostic factor on its own.
*** Amplified '''(rather than mutated)''' in about 13% of breast cancers
*** Scored on a scale of 0 to 3+
**** 0 or 1+ is considered negative
**** 2+ is equivocal - send for ISH
**** 3+ is positive (>30% of cells)
*** Inhibiting the function of the HER-2 receptor slows the growth of HER-2 positive tumours

=== Molecular profiling - breast cancers can be broken down into four different groups depending on the 'molecular portrait' ===

** Note that the molecular profile is independent of histological subtype (e.g. ductal vs lobular)

** Oestrogen receptor (ER)
*** '''Luminal A''' (40%)
**** ER+, PR+, HER2-; Ki67 <14%
**** Low-grade and good prognosis
**** 'Luminal' refers to the similar molecular profile to luminal epithelium of normal breast tissue
**** This type has best response rate to endocrine therapy
**** PR positivity predicts response to endocrine therapy regardless of ER positivity
**** Doesn't typically respond well to chemotherapy
*** '''Luminal B''' (20%)
**** ER+, PR+/-, HER2+/-; Ki67 >14%
**** Worse prognosis than luminal A
**** Has a lower response to endocrine therapy than luminal A but higher response to chemotherapy
** '''HER-2 enriched''' (10%)
*** ER-, PR-, HER2+
*** Characterised by high expression of HER2 and proliferation gene clusters and low expression of luminal clusters
*** Some are ER+ but not that common
*** Often node-positive
*** P53 mutations
** '''Basal-like''' (15%)
*** ER-, PR-, HER2-
*** Gene cluster profile similar to basal epithelial cells, characterised by low expression of the luminal and HER2 gene clusters - typically triple negative, but about 20% are not.
*** Not the same as triple-negative, although there is a lot of overlap between the two categories
*** Most aggressive breast cancer, accounts for about 10-20% of cases.
*** More frequently affects younger patients <40 years.
*** Tumours tend to be larger, palpable, higher grade
*** Distant mets often occur at visceral sites and are seen within the first 3 years after diagnosis
*** 20% of triple negative cancers are BRCA1 positive, and 10% of basal-like tumours overall are BRCA1 positive

=== Genetic expression profile analysis ===

** Oncotype DX is the most well-validated score: 21 genes analysed and used to produce a Recurrence Score (RS) between 0 and 100 for '''ER+, HER2-, node negative''' cancers
*** 0-17 low risk: hormone therapy alone is likely sufficient
*** 18-30 intermediate risk - consider offering chemotherapy in addition to endocrine therapy, especially in younger patients
*** >30 high risk: chemotherapy followed by endocrine therapy

=== Prognostic factors ===

** Grade (Elston-Ellis system a.k.a. Nottingham Histologic System, which is a modification of the Scarff-Bloom-Richardson grading system)
*** Determined by percentage of tubule formation/cell differentiation, nuclear pleomorphism and mitotic activity - 'TNM' (tubules, nuclear, mitoses)
*** Each scored out of 3, then a total score out of 9
*** Well-differentiated (grade 1)
*** Moderately-differentiated (grade 2)
*** Poorly-differentiated (grade 3)
** LVI - independent risk factor
** Ki-67 - independent
** Hormone receptors
*** ER/PR+ is associated with improved outcomes
*** HER2 is unfavourable

* Metastases

** Can metastasise by both lymphatic and haematogenous routes
** Can affect any organ, but liver, lungs and bone are the commonest
** Luminal A tends to be bone-only, while HER2+ or triple negative tends to be visceral
** Lobular can go anywhere, but especially peritoneal or pleural

=== Synoptic report ===

** Macroscopic
*** Number of specimens
*** Intra-op consultation
*** Method of localisation
*** Type and laterality
*** Orientation
*** Size - medial-lateral, anterior-posterior, superior-inferior
*** Weight
*** Multiple macroscopically visible tumours?
*** Nature of tumour
*** Tumour size
*** Macroscopic margins
*** Skin
*** Muscle
** Microscopic
*** Multiple tumours?
*** Maximum invasive tumour size
*** Histologic grade
**** Tubules
**** Nuclear grade
**** Mitotic rate
*** Invasive carcinoma subtype
*** LVI
*** Skin involvement
*** Treatment effect
*** DCIS
*** Microcalcification
*** Paget disease
*** Margin involvement by invasive cancer or DCIS?
*** Distance from closest margin
*** Lobular neoplasm
*** Associated breast changes
** Sentinel nodes
*** Total number
*** Macro-metastases
*** Micrometastases
*** Isolated tumour cells
*** Extra-nodal spread
*** Treatment effect
** Ancillary tests
*** HR
*** PR
*** HER2

== Staging ==
'''Breast carcinoma TNM staging AJCC UICC 2010'''
{| class="wikitable"
|'''Primary tumor (T)*¶Δ'''
|
|
|
|-
|TX
|Primary tumor cannot be assessed
|
|
|-
|T0
|No evidence of primary tumor
|
|
|-
|Tis
|Carcinoma in situ
|
|
|-
|Tis (DCIS)
|Ductal carcinoma in situ
|
|
|-
|Tis (LCIS)
|Lobular carcinoma in situ
|
|
|-
|Tis (Paget's)
|Paget's disease (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's disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget's disease should still be noted.
|
|
|-
|T1
|Tumor ≤20 mm in greatest dimension
|
|
|-
|T1mi
|Tumor ≤1 mm in greatest dimension
|
|
|-
|T1a
|Tumor >1 mm but ≤5 mm in greatest dimension
|
|
|-
|T1b
|Tumor >5 mm but ≤10 mm in greatest dimension
|
|
|-
|T1c
|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)
|
|
|-
|T4a
|Extension to the chest wall, not including only pectoralis muscle adherence/invasion
|
|
|-
|T4b
|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
|
|
|-
|T4c
|Both T4a and T4b
|
|
|-
|T4d
|Inflammatory carcinoma§
|
|
|-
|'''Posttreatment ypT.¥''' The use of neoadjuvant therapy does not change the clinical (pretreatment) stage. Clinical (pretreatment) T will be defined by clinical and radiographic findings, while y pathologic (posttreatment) T will be determined by pathologic size and extension. The ypT will be measured as the largest single focus of invasive tumor, with the modifier "m" indicating multiple foci. The measurement of the largest tumor focus should not include areas of fibrosis within the tumor bed.
|
|
|
|-
|'''Regional lymph nodes (N)'''
|
|
|
|-
|'''Clinical'''
|
|
|
|-
|NX
|Regional lymph nodes cannot be assessed (eg, previously removed)
|
|
|-
|N0
|No regional lymph node metastases
|
|
|-
|N1
|Metastases 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 metastases
|
|
|-
|N2a
|Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures
|
|
|-
|N2b
|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 lymph node involvement; or in clinically detected‡ ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement
|
|
|-
|N3a
|Metastases in ipsilateral infraclavicular lymph node(s)
|
|
|-
|N3b
|Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
|
|
|-
|N3c
|Metastases in ipsilateral supraclavicular lymph node(s)
|
|
|-
|'''Pathologic (pN)†**'''
|
|
|
|-
|pNX
|Regional lymph nodes cannot be assessed (eg, previously removed, or not removed for pathologic study)
|
|
|-
|pN0
|No regional lymph node metastasis identified histologically
|
|
|-
|pN0(i-)
|No regional lymph node metastases histologically, negative immunohistochemistry (IHC)
|
|
|-
|pN0(i+)
|Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC including isolated tumor cell clusters (ITC))
|
|
|-
|pN0(mol-)
|No regional lymph node metastases histologically, negative molecular findings (RT-PCR)¶¶
|
|
|-
|pN0(mol+)
|Positive molecular findings (RT-PCR)¶¶, but no regional lymph node metastases detected by histology or IHC
|
|
|-
|pN1
|Micrometastases; or metastases in 1-3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected ΔΔ
|
|
|-
|pN1mi
|Micrometastases (greater than 0.2 mm and/or more than 200 cells, but none greater than 2.0 mm)
|
|
|-
|pN1a
|Metastases in 1-3 axillary lymph nodes, at least one metastasis greater than 2 mm
|
|
|-
|pN1b
|Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected ΔΔ
|
|
|-
|pN1c
|Metastases in 1-3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected
|
|
|-
|pN2
|Metastases in 4-9 axillary lymph nodes; or in clinically detected◊◊ internal mammary lymph nodes in the ''absence'' of axillary lymph node metastases
|
|
|-
|pN2a
|Metastases in 4-9 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm)
|
|
|-
|pN2b
|Metastases in clinically detected◊◊ internal mammary lymph nodes in the ''absence'' of axillary lymph node metastases
|
|
|-
|pN3
|Metastases in ten or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or in clinically detected◊◊ ipsilateral internal mammary lymph nodes in the ''presence'' of one or more positive level I, II axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected ΔΔ; or in ipsilateral supraclavicular lymph nodes
|
|
|-
|pN3a
|Metastases in ten or more axillary lymph nodes (at least one tumor deposit greater than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes
|
|
|-
|pN3b
|Metastases in clinically detected◊◊ ipsilateral internal mammary lymph nodes in the ''presence'' of one or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected ΔΔ
|
|
|-
|pN3c
|Metastases in ipsilateral supraclavicular lymph nodes
|
|
|-
|'''Posttreatment ypN'''
|
|
|
|-
|
** Post-treatment yp "N" should be evaluated as for clinical (pretreatment) "N" methods above. The modifier "sn" is used only if a sentinel node evaluation was performed after treatment. If no subscript is attached, it is assumed that the axillary nodal evaluation was by axillary node dissection (AND).
|
|
|
|-
|
** The X classification will be used (ypNX) if no yp posttreatment SN or AND was performed
|
|
|
|-
|
** N categories are the same as those for pN
|
|
|
|-
|'''Distant metastasis (M)'''
|
|
|
|-
|M0
|No clinical or radiographic evidence of distant metastases
|
|
|-
|cM0(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 larger than 0.2 mm
|
|
|-
|'''Posttreatment yp M classification.''' The M category for patients treated with neoadjuvant therapy is the category assigned in the clinical stage, prior to initiation of neoadjuvant therapy. Identification of distant metastases after the start of therapy in cases where pretherapy evaluation showed no metastases is considered progression of disease. If a patient was designated to have detectable distant metastases (M1) before chemotherapy, the patient will be designated as M1 throughout.
|
|
|
|-
|'''Anatomic stage/prognostic groups§§'''
|
|
|
|-
|0
|Tis
|N0
|M0
|-
|IA
|T1¥¥
|N0
|M0
|-
|IB
|T0
|N1mi
|M0
|-
|
|T1¥¥
|N1mi
|M0
|-
|IIA
|T0
|N1‡‡
|M0
|-
|
|T1¥¥
|N1‡‡
|M0
|-
|
|T2
|N0
|M0
|-
|IIB
|T2
|N1
|M0
|-
|
|T3
|N0
|M0
|-
|IIIA
|T0
|N2
|M0
|-
|
|T1¥¥
|N2
|M0
|-
|
|T2
|N2
|M0
|-
|
|T3
|N1
|M0
|-
|
|T3
|N2
|M0
|-
|IIIB
|T4
|N0
|M0
|-
|
|T4
|N1
|M0
|-
|
|T4
|N2
|M0
|-
|IIIC
|Any T
|N3
|M0
|-
|IV
|Any T
|Any N
|M1
|}


'''Breast carcinoma TNM clinical prognostic stage groups AJCC UICC 8th edition'''
{| class="wikitable"
|'''When TNM is...'''
|'''And grade is...'''
|'''And HER2 status is...'''
|'''And ER status is...'''
|'''And PR status is...'''
|'''Then the clinical prognostic stage group is...'''
|-
|Tis N0 M0
|Any
|Any
|Any
|Any
|0
|-
|T1* N0 M0

T0 N1mi M0

T1* N1mi M0
|G1
|Positive
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|Negative
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IB
|-
|T1* N0 M0

T0 N1mi M0

T1* N1mi M0
|G2
|Positive
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|Negative
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IB
|-
|T1* N0 M0

T0 N1mi M0

T1* N1mi M0
|G3
|Positive
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|Negative
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IB
|-
|
|
|
|Negative
|Positive
|IB
|-
|
|
|
|
|Negative
|IB
|-
|T0 N1¶ M0

T1* N1¶ M0

T2 N0 M0
|G1
|Positive
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|
|Negative
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|Negative
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|
|Negative
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIA
|-
|T0 N1¶ M0

T1* N1¶ M0

T2 N0 M0
|G2
|Positive
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|
|Negative
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|Negative
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|
|Negative
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIB
|-
|T0 N1¶ M0

T1* N1¶ M0

T2 N0 M0
|G3
|Positive
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|
|Negative
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|Negative
|Positive
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|
|Negative
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIB
|-
|T2 N1Δ M0

T3 N0 M0
|G1
|Positive
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|
|Negative
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|Negative
|Positive
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|
|Negative
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIB
|-
|T2 N1Δ M0

T3 N0 M0
|G2
|Positive
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|
|Negative
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|Negative
|Positive
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|
|Negative
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIIB
|-
|T2 N1Δ M0

T3 N0 M0
|G3
|Positive
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|
|Negative
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|Negative
|Positive
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|T0 N2 M0

T1* N2 M0

T2 N2 M0

T3 N1Δ M0

T3 N2 M0
|G1
|Positive
|Positive
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|Negative
|Positive
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|T0 N2 M0

T1* N2 M0

T2 N2 M0

T3 N1Δ M0

T3 N2 M0
|G2
|Positive
|Positive
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|Negative
|Positive
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|T0 N2 M0

T1* N2 M0

T2 N2 M0

T3 N1Δ M0

T3 N2 M0
|G3
|Positive
|Positive
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|Negative
|Positive
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIC
|-
|T4 N0 M0

T4 N1Δ M0

T4 N2 M0

Any T N3 M0
|G1
|Positive
|Positive
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|Negative
|Positive
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIC
|-
|T4 N0 M0

T4 N1Δ M0

T4 N2 M0

Any T N3 M0
|G2
|Positive
|Positive
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|Negative
|Positive
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIC
|-
|T4 N0 M0

T4 N1Δ M0

T4 N2 M0

Any T N3 M0
|G3
|Positive
|Positive
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|Negative
|Positive
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIC
|-
|
|
|
|Negative
|Positive
|IIIC
|-
|
|
|
|
|Negative
|IIIC
|-
|Any T Any N M1
|Any
|Any
|Any
|Any
|IV
|}


'''Breast carcinoma TNM pathologic prognostic stage groups AJCC UICC 8th edition'''
{| class="wikitable"
|'''When TNM is...'''
|'''And grade is...'''
|'''And HER2 status is...'''
|'''And ER status is...'''
|'''And PR status is...'''
|'''Then the pathological prognostic stage group is...'''
|-
|Tis N0 M0
|Any
|Any
|Any
|Any
|0
|-
|T1* N0 M0

T0 N1mi M0

T1* N1mi M0
|G1
|Positive
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|Negative
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|T1* N0 M0

T0 N1mi M0

T1* N1mi M0
|G2
|Positive
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|Negative
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IB
|-
|T1* N0 M0

T0 N1mi M0

T1* N1mi M0
|G3
|Positive
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|Negative
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IA
|-
|
|
|
|Negative
|Positive
|IA
|-
|
|
|
|
|Negative
|IB
|-
|T0 N1¶ M0

T1* N1¶ M0

T2 N0 M0
|G1
|Positive
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IB
|-
|
|
|
|Negative
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|Negative
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IB
|-
|
|
|
|Negative
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|T0 N1¶ M0

T1* N1¶ M0

T2 N0 M0
|G2
|Positive
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IB
|-
|
|
|
|Negative
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|Negative
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|
|Negative
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIA
|-
|T0 N1¶ M0

T1* N1¶ M0

T2 N0 M0
|G3
|Positive
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|
|Negative
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|Negative
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIA
|-
|
|
|
|Negative
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIA
|-
|T2 N1Δ M0

T3 N0 M0
|G1
|Positive
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|
|Negative
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|Negative
|Positive
|Positive
|IA
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|
|Negative
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIB
|-
|T2 N1Δ M0

T3 N0 M0
|G2
|Positive
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|
|Negative
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|Negative
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|
|Negative
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIB
|-
|T2 N1Δ M0

T3 N0 M0
|G3
|Positive
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|
|Negative
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|Negative
|Positive
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIB
|-
|
|
|
|Negative
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIIA
|-
|T0 N2 M0

T1* N2 M0

T2 N2 M0

T3 N1Δ M0

T3 N2 M0
|G1
|Positive
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|Negative
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIA
|-
|T0 N2 M0

T1* N2 M0

T2 N2 M0

T3 N1Δ M0

T3 N2 M0
|G2
|Positive
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|Negative
|Positive
|Positive
|IB
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|T0 N2 M0

T1* N2 M0

T2 N2 M0

T3 N1Δ M0

T3 N2 M0
|G3
|Positive
|Positive
|Positive
|IIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|Negative
|Positive
|Positive
|IIB
|-
|
|
|
|
|Negative
|IIIA
|-
|
|
|
|Negative
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIC
|-
|T4 N0 M0

T4 N1Δ M0

T4 N2 M0

Any T N3 M0
|G1
|Positive
|Positive
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|Negative
|Positive
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|T4 N0 M0

T4 N1Δ M0

T4 N2 M0

Any T N3 M0
|G2
|Positive
|Positive
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|Negative
|Positive
|Positive
|IIIA
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIC
|-
|T4 N0 M0

T4 N1Δ M0

T4 N2 M0

Any T N3 M0
|G3
|Positive
|Positive
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|
|Negative
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIB
|-
|
|
|Negative
|Positive
|Positive
|IIIB
|-
|
|
|
|
|Negative
|IIIC
|-
|
|
|
|Negative
|Positive
|IIIC
|-
|
|
|
|
|Negative
|IIIC
|-
|Any T Any N M1
|Any
|Any
|Any
|Any
|IV
|-
|''NOTES:''

*# For cases with lymph node involvement with no evidence of primary tumor (eg, T0 N1, etc) or with breast ductal carcinoma ''in situ'' (eg, Tis N1, etc), the grade, HER2, ER, and PR information from the tumor in the lymph node should be used for assigning stage group.
*# For cases where HER2 is determined to be "equivocal" by ISH (FISH or CISH) testing under the 2013 ASCO/CAP HER2 testing guidelines, the HER2 "negative" category should be used for staging in the pathological prognostic stage group table.
*# The prognostic value of these prognostic stage groups is based on populations of persons with breast cancer that have been offered and mostly treated with appropriate endocrine and/or systemic chemotherapy (including anti-HER2 therapy).
|
|
|
|
|
|}

=== Staging scans: ===

* '''CT CAP + PET if:'''
** Inflammatory breast cancer
** Stage IIIA or higher disease (T3 or N2)
** ''The indications for PET are not very well-defined, apart from inflammatory cancer''
* Bone scan if:
** Localised bone pain
** Raised ALP
** If further suspicion despite negative bone scan, do a localised MRI
* Chest CT/CXR if pulmonary complaints
* CT abdo/pelvis if abnormal LFTs, elevated ALP, abdominal pain, abnormal abdo exam
* CTB if neurological symptoms 
* Breast MRI for lobular cancer

== '''Treatment approach by stage''' ==

=== '''Early-stage (Stage I, IIA, and T2N1)''' ===

** Up-front surgery for local and regional staging and control
*** See below for choice in local control approach
** If clinical axillary node - biopsy with USS. If negative, proceed to SLNB. If positive, needs axillary clearance (level 1 and 2 clearance).
** If no clinical nodes, SLNB. If <3 pathologically involved sentinel nodes, probably won't need axillary dissection.
** CTX
*** ER or PR positive = endocrine adjuvant therapy
*** HER2 positive cancer >1cm in size = CTX plus HER2-directed therapy + endocrine therapy if indicated.
*** Triple-negative: adjuvant CTX if tumour >0.5cm

=== '''Locally advanced (T3N0, and stage IIIA to IIIC)''' ===

** Neoadjuvant CTX and HER2-directed therapy if indicated and endocrine therapy may be indicated as well
*** If neoadjuvant CTX is happening, do USS-guided biopsy of axillary nodes (ask them to put a clip in any positive nodes so they can be selectively removed later), and then SLNB after neoadjuvant CTX even if negative, along with removing any previously positive nodes (this is the 'targeted axillary dissection'). Guidelines suggest attempting to get 3 sentinel nodes in this situation.
**** Ample evidence that the axilla can be down-staged (up to 40% of biopsy positive nodes will become negative after neoadjuvant ctx)
**** We don't really know whether patients with persistently positive axillas after neoadjuvant CTX truly need an ALND, but definitely safest to provide this based on current evidence. In fact, they probably also need axilla RTX after ALND.
*** Do MRI before and after neoadjuvant CTX to assess response
** Then surgery
*** If breast-conserving, get RTX
** Adjuvant CTX depends on response to neoadjuvant, and type of CTX given

=== '''Metastatic (Stage IV)''' ===

** Palliative systemic therapy

== '''Surgical options''' ==

=== '''Local control''' ===

** Breast-conserving surgery is defined as WLE and whole-breast radiotherapy 
** Indications:
*** Single or multiple lesions that can be excised to leave a satisfactory cosmetic outcome
*** Most T1 and T2 cancers (consider neoadjuvant therapy first for 4-5cm cancers)
*** T3 cancers in larger breasts
** Relative contraindications (none are absolute):
*** T4, N2 or M1
*** Patient preference for mastectomy
*** Collagen vascular disease (especially scleroderma - increased complications from radiotherapy)
*** Large or central tumours in small breasts (that cannot be excised to leave a satisfactory cosmetic outcome - although consider neoadjuvant first)
*** Strong family history of breast cancer, or BRCA1/BRCA2 positive
*** ''Unable or unwilling to have the radiotherapy that should be part of BCS''
*** ''High nuclear grade, presence of lymphovascular invasion and negative steroid hormone receptor status are linked to higher recurrence rates, but are not contraindications to breast conservation''
** Margins
*** Invasive breast cancer: any negative margin is acceptable, i.e., 'no ink on tumour'
*** An involved posterior or anterior margin may not be fixable with surgery, if the original excision extended from right under breast skin back to pectoralis fascia. More often, radiotherapy is the answer.
** Alternative therapies to WLE (remains investigative)
*** Cryoablation
**** Can potentially replace WLE for patients with high surgical risk
**** Argon gas and multiple freeze-thaw cycles
*** RFA
**** RFA alone
**** Excision followed by RFA
***** Under investigation currently
*** Laser ablation
*** High-intensity focused US
*** Microwave ablation
*** Stereotactic radio-ablation

=== '''Regional control''' ===

** SLNB
*** Accurately predicts status of lymph node basin (reflects status of axilla in 97%, with 5% false negative rate)
**** Clinically, if SLNB is negative, ALND is not required
**** For patients with negative SLNB, no difference in overall survival or regional control rate between ALND or no ALND
*** Indications
**** Clinically node-negative T1 or T2 cancer who are undergoing surgery
**** Also consensus that it is appropriate for T3, multifocal/multicentric disease, prior radiation therapy, and prior breast or axillary surgery, but no hard evidence for these cohorts - likely equivalent accuracy to axillary dissection
**** DCIS whenever mastectomy is required, or high-grade, large (>5cm) or palpable DCIS (since there may be a subsequent upstaging based on pathological specimen, which happens about 15% of the time in this cohort). This is because DCIS can be upstaged with excisional biopsy in up to 50% of patients - there is sometimes co-existent cancer.
*** Contraindications
**** T4
**** Inflammatory breast cancer
**** Palpable biopsy-proven positive nodes
*** Previous neoadjuvant therapy
**** Significant controversy over whether SLNB is needed (see 'targeted dissection' below)
*** Outcomes
**** False negative rates <5%
**** Axillary recurrence is very rare after a negative SLNB
** Treatment of the positive sentinel node(s)
*** Estimating risk of having additional positive nodes left behind:
**** Proportional to size of primary tumour, presence of lymphatic vascular invasion, and size of the lymph node metastases
**** 53% of patients with a positive SLNB have more positive nodes at ALND
*** Micrometastases (>0.2mm but <=2mm): additional ALND/axillary radiation confers no advantage
**** 5-year disease-free survival 86.4% with micrometastases, and 89.2% without. Statistically significant, but not considered to be clinically significant.
**** 20% additional non-sentinel node involvement
*** 0, 1 or 2 positive nodes with deposits >2mm
**** If having BCS: post-operative adjuvant whole-breast radiation (which covers most of the axilla) and systemic therapy, but no dissection. Variable between centres as to whether the standard post-BCS radiotherapy fields are altered to include more axilla.

**** If having mastectomy: post-mastectomy radiation
**** ''Note that patients need to have T1 or T2 tumours, need to be CLINICALLY node negative, <3 positive nodes, no evidence of extracapsular extension in axilla, patient needs to commit to radiation and adjuvant systemic therapy '''(Z0011 study)'''.''
**** ''If these conditions are not met, patient will need an axillary dissection''
**** ''May be able to omit dissection too in patients with 2/2 involves nodes from SLNB, but would not give chemotherapy - main role for dissection would be to stage the axilla in patients who would then go on to have chemotherapy''

*** 3 or more pathologically involved nodes will need axillary dissection

**** Can be diagnosed radiologically, clinically or histologically

** Axillary dissection
*** Indications

**** Locally advanced
**** Positive SLNB who are scheduled for accelerated partial breast irradiation
**** Positive SLNB and don't meet Z11 criteria
**** Clinically positive nodes
**** Positive sentinel node after neoadjuvant chemotherapy

** Targeted axillary dissection
*** More for patients with 1-2 level I and II clinical nodes that have neoadjuvant therapy (one study has been done with up to 3 positive nodes). Any more should have dissection. 
*** Re-stage nodes with USS after neoadjuvant therapy - if looks normal, eligible for targeted dissection; if you suspect the axilla is still positive, then should do an ALND
*** Need some sort of localisation - clips, magseed or scoutseed
*** Do SLNB at the same time
*** If ANY node comes back with ANY cancer - generally go back and do ALND
*** No long-term survival data for targeted dissection vs clearance as of 2024
* '''Systemic control'''

== '''Other scenarios''' ==

=== '''Male breast cancer''' ===

** Epidemiology
*** Comprises 0.8% of all breast cancers
** Risk factors
*** Factors that increase effect of oestrogen - cirrhosis, obesity, exogenous oestrogen
*** Factors that decrease effect of testosterone - testicular non-descent, infection, trauma, 5alpha reductase inhibitors, Klinefelter's syndrome)
*** Genetics - BRCA2
*** Increasing age
*** Radiation exposure
*** ''Gynaecomastia is not a risk factor''
** Pathophysiology
*** 90% invasive ductal carcinoma
*** >90% hormone receptor positive
** Presentation
*** Local pain
*** Axillary lymphadenopathy
*** Nipple retraction
*** Ulceration
*** Bleeding
*** Discharge 
** Differential diagnosis
*** Primary breast cancer
*** Metastatic cancer
*** Gynaecomastia
*** Sarcoma
*** Breast abscess
** Staged and treated nearly the same
** Total mastectomy usually required because most of the tumours are subareolar, and it's also harder to give radiotherapy
** Chest wall resection required much more commonly since there is less breast tissue (modified radical mastectomy)
** SLNB is reliable. Axillary management is alike to in females.
** Since nearly 90% of cancers are hormone positive, and tamoxifen can be used (aromatase inhibitors raise testosterone levels)
** ALL patients with male breast cancer should be referred to genetics
** Contralateral breast cancer is almost unheard of in men, no need to perform routine screening mammography

=== '''Breast cancer in pregnancy''' ===

** Important to mention to respect wishes of patient with respect to fetus and discuss at MDM. 
*** Early termination of pregnancy does not improve breast cancer outcomes.
*** Delaying oncological treatment until birth is not usually a good option
*** Breastfeeding is safe and feasible from both breasts afterwards
*** Customary to recommend delaying conception for 2 years after initial treatment
** More likely to be ER/PR negative and HER2 + or -; more commonly high-grade; more commonly locally advanced
** Any breast lump discovered during pregnancy/lactation should be evaluated with mammogram (shielded), USS and biopsy
*** Usually start off with USS, especially if presenting complaint was lump
*** MRI is difficult to interpret without gadolinium due to pregnancy-related changes, but gadolinium is probably harmful to fetus, especially in first trimester
** Staging
*** Common approach for node-positive disease: 
**** CXR with shielding
**** USS abdo/liver
**** MRI liver/chest/brain/other area as required - without gadolinium
**** Low-dose bone scan only if there are symptoms of bony metastases
** Local treatment options:
*** Mastectomy usually the safest option, especially early on in pregnancy - radiation can't be given during pregnancy
*** BCS may be an option later in pregnancy when RTX can be given post-partum without too much delay
** Regional treatment:
*** SLNB can be done safely with 99mTc sulfur colloid like normal, but not blue dye
*** ALND is usually performed for the positive axilla
** Systemic treatment
*** Start chemotherapy once the first trimester is over
**** Neoadjuvant anthracycline is safe starting the second trimester - doesn't cross the placenta - series of 197 women with no increased risk of complications of birth or development
**** Taxanes appear safe - growing evidence base
*** Don't recommend delaying systemic therapy until after delivery
** Contraindicated:
*** Trastuzumab is not given - causes oligohidramnios in 50%
*** Tamoxifen is not safe for fetus
*** Immunotherapy
*** Blue dye
*** Radiotherapy
** Most common approaches:
*** First trimester: 
**** Early: mastectomy + SLNB, followed by CTX in second trimester if required and hormonal/HER2 therapy post-partum
**** Advanced: mastectomy + ALND + CTX in second trimester and hormonal/HER2 therapy +/- RTx post-partum
*** Second or third trimester
**** Early cancer: BCS with post-partum RTx vs mastectomy. SLNB. Endocrine/HER2 therapy post-partum.
**** Advanced: neoadjuvant + mastectomy + ALND + adjuvant trastuzumab/endocrine post-partum

=== '''Metastatic breast cancer of unknown primary''' ===

** Biopsy of involved node - might not be malignant, benign conditions can also cause lymphadenopathy
** Staging workup, CT CAP +/- PET
** Bilateral breast MRI will find a primary breast cancer in 75% of these patients
*** Then need MRI-guided USS
** Treatment will ALND +/- neoadjuvant CTX
** Management of ipsilateral breast is controversial
*** Best survival with mastectomy
*** Whole-breast RTX may give comparable survival, although only small retrospective reports to back it up

== '''Chemotherapy''' ==

* '''Systemic chemotherapy''' is a risk-based proposition - must be individualised, using the specific pathological subtype (see above under histopathology) - can use calculators.
** Systemic therapy (not necessarily CHEMOtherapy, could be endocrine) is indicated in '''any woman deemed to have a significant risk of micrometastatic disease'''
** Indications for CHEMOtherapy
*** Any evidence of metastases on CT or other imaging
*** Node positive disease regardless of hormone receptor status and/or primary tumour size
*** Triple negative breast cancer with primary tumour >1cm
*** HER2 cancers at least 1cm in size regardless of nodal status, in addition to HER2 targeted therapy
*** CTX is STRONGLY CONSIDERED for medically fit patients with HER2 overexpressing or triple negative cancers measuring 6-10mm
** Start 4-6 weeks after surgery
* '''Neoadjuvant chemotherapy:'''
** Theoretical advantages:
*** Downstage locoregional disease, and perhaps reduce extent of surgery
*** Prognosticate based on response
*** Increase proportion of patients getting to systemic therapy
*** Treat micrometastases earlier
*** Time - genetics, reconstruction, fertility planning
** Disadvantage - 3% progression despite therapy
** Indications
*** Locally advanced cancer
*** Stage I or II cancers where BCS is not possible due to tumour size or location
*** T1c or T2 triple negative or HER2+ tumours
*** Limited clinically node positive disease
*** Temporary contraindications to surgery (awaiting genetic testing)
*** In some circumstances if immediate reconstruction is planned (can delay adjuvant therapy, can prevent radiotherapy)
*** Some ER+/PR+ cancers with high Ki67% - aromatase inhibitors
** Background
*** Usually 3-6 months, most commonly 6
*** Review the patient after three months to ensure they're not progressing
* '''Adjuvant chemotherapy'''
** Aim to start by 4-6 weeks post-op
** Duration 3-6 months
** Earlier not necessarily better
** Delays of >3 months are likely detrimental
* '''Specific situations:'''
** Triple negative ('basal-like'): adjuvant chemotherapy
*** Triple negative paradox means primary tumours are more sensitive to CTX than others, and can achieve pathological complete response at a rate of about 20-45%, and if they do achieve that, have similar overall survival with other breast cancers.
*** Size >0.5cm or pathologically involved lymph nodes regardless of size = adjuvant CTX
*** CTX becomes more appropriate as risk of recurrence increases, meaning size of tumour, histological factors, nodal disease, etc
*** Most commonly TAC
*** Targeted therapy (PARP inhibitors, immune checkpoint inhibitors, pembrolizumab) are available, and there will probably be an increasing role for these in the future
*** Pembrolizumab given to patients with PD-L1 combined positive score >10, in combination with traditional chemotherapy
** ER/PR positive, HER2 negative - luminal subtype - individualise based on risk
*** Benefit of CTX is less clear - can use the Recurrence Score (see '''histopathology''' section above)
*** But should have endocrine therapy - see below
*** Neoadjuvant endocrine therapy has shown some promise - potential for downstaging, allowing breast-conserving surgery
*** CDK 4/6 inhibitors are usually better than traditional CTX
** HER2 positive disease often has neoadjuvant CTX
*** Trastuzumab plus CTX (if >1cm yes, and if 6-10mm likely)
*** Also likely have adjuvant - trastuzumab for a year
*** Pertuzumab (Perjeta) can be given in addition to trastuzumab in high-risk disease, and may improve outcomes
** '''Locally advanced: neoadjuvant'''
*** Luminal
**** Usually chemotherapy rather than endocrine therapy
**** Endocrine would only be used based on strong patient preference or serious comorbidities
*** HER2+
**** Trastuzumab with or without pertuzumab
**** Chemotherapy (docetaxel and carboplatin - drop the anthracyclines due to cumulative cardiac risk)
*** Triple negative
**** Chemotherapy (AC-T +/- carboplatin) +/- immunotherapy
** '''Metastatic'''
*** Luminal subtype
**** Mostly endocrine therapy followed by chemotherapy (AC-T) if progression
**** CDK 4/6 inhibitors
*** HER2+
**** Trastuzumab, pertuzumab and a taxane
**** Add endocrine therapy if amenable
*** Triple negative
**** First-line chemotherapy
**** AC-T + carboplatin
**** Add pembrolizumab if PD-L1 is overexpressed
**** Add PARP if BRCA
** Pre-menopausal women with incomplete families:
*** Goserelin - reduces ovarian failure from 22% to 8%
*** Egg harvesting
* Regimes and specific additional medications:
** Anthracyclines
*** Most common
*** Doxorubicin (Adriamycin) and epirubicin
*** Can be given at 3-week intervals or in an accelerated 2-week interval with G-CSF
*** Concern for cardiotoxicity - CCF; also nausea/vomiting, bone marrow suppression, febrile neutropaenia
*** Usually 4-6 cycles
** Taxanes
*** Paclitaxel and docetaxel
*** Often combine with anthracyclines
*** Especially in patients with ER-negative and/or HER2-positive disease
*** Hair loss, bone marrow suppression, diarrhoea, hand and foot syndrome, peripheral neuropathy
** Platinum-based
*** Carboplatin
*** Electrolyte imbalances, BM suppression
*** Often given with triple-negative cancers in combination with taxanes
** Cyclophosphamide
*** Alkylating agent
*** Myelosuppression, haemorrhagic cystitis, alopecia, gonadal suppression 
** Trastuzumab (Herceptin/Kadcyla)
*** Recombinant humanised monoclonal antibody directed against the extracellular domain of the HER2 protein, blocking signalling. Approved in 1998 in USA.
*** Significantly improved disease-free and overall survival for HER2 subtype.
*** Generally given for a year as monthly infusions. Current thinking is that is should be given concurrently with adjuvant chemotherapy.
*** HER2 resistance

**** Approximately 15% relapse after treatment
**** Other drugs assist with overcoming this - Lapatinib, Pertuzumab

*** Can get/worsen CCF - need TTE prior to trastuzumab - 3.6% get reduced EF

**** Need to give out of sequence with anthracyclines

** Pertuzumab (Perjeta)
*** Another anti-HER2 monoclonal antibody, binding to a different epitope than trastuzumab
*** Also risk cardiotoxicity
** Bisphosphonates
*** Zoledronic acid is the most potent
*** Routinely given with bone metastases - thought to alter the bone micro-environment, making it less favourable for dormant tumour cells
** CDK 4/6 inhibitors
*** Abemaciclib, ribociclic and palbociclib
*** Approved for metastatic hormone receptor positive, HER2- cancer
** PARP inhibitors
*** Olaparib, rucaparib, niraparib, talazoparib
*** Inhibitors the PARP protein which repairs cellular DNA
*** Particularly effective for BRCA cancers since these already have reduced DNA repair capabilities


== '''Radiotherapy''' ==

* Treatment protocol
** Typically 40Gy over about three weeks, in 15 minute sessions on weekdays
** Post-menopausal women with non-high grade, ER-positive, stage I breast cancer can be treated with a shorter 3 week course
** Partial breast irradiation focuses RTX around the tumour bed
* Contraindications to radiotherapy
** Absolute
*** Pregnancy
** Relative
*** Systemic scleroderma or active SLE ''(other collagen vascular diseases are not contraindications to radiation, although patients should not be taking immunosuppressants such as methotrexate because they are radiosensitisers)''
*** Prior radiation to breast or chest wall
*** Severe pulmonary disease
*** Severe cardiac disease (if tumour is left-sided)
*** Inability to lie supine
*** Inability to abduct arm on affected side
*** P53 mutation ''(highly susceptible to radiation-induced cancers)''
* To whole breast, after breast-conserving therapy
** Radiotherapy reduces local recurrence after WLE at 20 years from 39.2% to 14.3% in node-negative patients; and from 44.2% to 8.8% if the patient has positive nodes and therefore receives chemotherapy
** Improved breast cancer specific survival by 18%
** Can consider omitting RTX in patients age >70 with stage I hormone receptor positive breast cancer treated by partial mastectomy and tamoxifen (recurrence rate 2% with radiotherapy, 10% without)
** RT boost to tumour bed if high-risk factors are present:
*** Younger age
*** High-grade cancer
*** Margin involvement
*** Significant in-situ disease
*** Higher T stage
* Indications for axillary radiotherapy
** Instead of dissection in node-positive patients
*** AMAROS trial - ALND vs axillary RTX in T1/T2, pN1 - comparable long-term control, with less lymphoedema in the RTX group
** In patients with very high axillary tumour burden in addition to ALND
* To mastectomy site (PMRT - post-mastectomy radiotherapy)
** Indications
*** High-risk: Stage III breast cancer (decreased 15 year locoregional recurrence from 29% to 8% and breast cancer mortality from 60% to 55%)
*** Intermediate risk: Stage II disease with extracapsular extension, lymphovascular invasion, age <40yo, clear/positive surgical margins, nodal positivity ratio >20%
*** Also consider for close or involved margins
* Reconstruction and radiotherapy
** Oncological outcomes take priority
** Discuss in MDT
** Permanent silicon implants are high-risk of capsular contracture (pain, poor cosmesis, revision) in the setting of irradiated tissue, regardless of whether the silicon was in situ during radiotherapy
** Autologous tissue tolerates radiotherapy better
** [[File:Accelerated partial irradiation.png|none|thumb|693x693px|From Sabiston's Textbook of Surgery]]

* Intra-operative radiotherapy
** Immature technique, lacking robust long-term follow-up
** Probably offers advantages for appropriately chosen patients
** I don't think this is done in Australia
**[[File:Untitled picture.png|frameless|631x631px]]


== '''Endocrine therapy''' ==

* '''Rationale'''
** 60% of breast cancers express ER or PR or both
** Interruption of either production of oestrogen or of the ability of oestrogen to interact with the ER causes improved DFS and OS
** Reduces risk of death by about one third
** Risk of mortality from PE or uterine cancer is only 0.2% per 10 years
* '''SERMs (Selective ER Modulators)'''
** Tamoxifen
*** Competitively inhibits the binding of oestradiol to oestrogen receptors in the breast, but has agonist activity in endometrial tissue
*** Reduces the risk of breast cancer recurrence (by 41%) and death (by 30%) in premenopausal and postmenopausal women with ER+ tumours
*** Oral drug taken daily, typically 20mg, typically for 5 years (although some studies are showing good results from longer courses e.g. 10 years)
*** Tamoxifen can cause endometrial hyperplasia, fibroids, polyps, endometrial tumours, vaginal discharge, menstrual irregularities, sexual dysfunction.
*** Other side effects - hot flushes, VTE
** Raloxifene
*** Anti-oestrogenic in breast and endometrium
* '''Aromatase inhibitors (AIs)'''
** Only indicated for '''postmenopausal''' patients with ER+ tumours
*** Superior to SERMs due to improved effectiveness and lower toxicity
** Blocks the action of adrenal aromatase, and therefore prevents the conversion of adrenally-synthesised androgens to oestrogens, the final step in conversion to the active hormone. Does not interfere with production of corticosteroids or mineralocorticoids. 
** Does not block aromatase action outside the adrenal gland - ovarian synthesis of oestrogens continues unabated, and therefore, if the patient is pre-menopausal, aromatase inhibitors will be ineffective
** Will likely give them osteoporosis 
** Exemestane, anastrazole, letrozole
* Treatment approach:
** '''Postmenopausal''' (age > 60, or amenorrhoeic for 12 months without endocrine blockers) patients with ER/PR positive disease
*** Aromatase inhibitor is preferred, but if not tolerated, can use tamoxifen
**** Anastrazole/exemestane/letrozole
*** Treat for 5 years usually, but can be given for another 5 years if the cancer is high-risk (larger tumours or node-positive disease) and/or the therapy is well-tolerated, which has been shown to improve survival further
*** Start 4-6 weeks after surgery if no CTX
*** Start concurrently with RTX
*** Start after CTX if receiving CTX
** '''Premenopausal''' patients with ER/PR positive disease
*** Aromatase inhibitors will be ineffective due to ongoing ovarian function. If used, ovarian ablation must occur first.
*** Ovarian suppression (e.g. with goserelin)  leads to significant side effects in 30% - hot flushes, MSK pain, HTN
*** High-risk patients (younger <35, or those in whom CTX is indicated) should have ovarian suppression therapy and either aromatase inhibitors or tamoxifen
*** Otherwise use tamoxifen for 5 years
*** If the patient remains premenopausal after five years, offer an additional 5 years of endocrine therapy, which has been shown to reduce recurrence further
[[File:AdjvntendcrntxHRpsbrca.gif|none|frame|Algorithm for choice of ET - from UTD]]




== Prognosis ==

* Stage I: 5 year 98.7% survival rate
* Overall 5 year survival rate of 90%
* Most patients with metastatic disease die of breast cancer
* Local recurrence
** Older women with hormone receptor positive cancer: 0.4% per year
** Younger women with triple negative: 1% per year


'''Risk profile and associated survival outcomes, MD Anderson validation of biomarkers in TNM 8th edition staging'''
{| class="wikitable"
| 
|'''Five-year DSS'''

'''(%)'''
|'''Univariate analysis'''
|
|'''Multivariate analysis 2'''
|
|'''Assigned points'''
|-
|
|
|'''HR'''
|'''''p'''''
|'''HR'''
|'''''p'''''
|
|-
|'''Pathological stage'''
|
|
|
|
|
|
|-
|I
|99.1
|Referent
|
|Referent
|
|0
|-
|IIA
|98.0
|2.8
|0.002
|2.3
|0.01
|1
|-
|IIB
|95.6
|4.8
|<0.0001
|4.0
|<0.0001
|2
|-
|IIIA
|95.4
|6.8
|<0.0001
|7.2
|<0.0001
|3
|-
|IIIC
|79.5
|26.6
|<0.0001
|19.9
|<0.0001
|4
|-
|'''Nuclear grade'''
|
|
|
|
|
|
|-
|I
|99.8
|Referent
|
|Referent
|
|0
|-
|II
|98.9
|5.0
|0.1
|4.0
|0.2
|0
|-
|III
|95.3
|25.0
|0.001
|13.1
|0.01
|1
|-
|'''ER status'''
|
|
|
|
|
|
|-
|Positive
|98.8
|Referent
|
|Referent
|
|0
|-
|Negative
|92.9
|4.9
|<0.0001
|2.5
|0.001
|1
|-
|'''PR status'''
|
|
|
|
|
|
|-
|Positive
|98.8
|Referent
|
|Referent
|
|
|-
|Negative
|95.2
|4.0
|<0.0001
|
|NS
|
|-
|'''HER2 status'''
|
|
|
|
|
|
|-
|Positive
|97.5
|Referent
|
|Referent
|
|0
|-
|Negative
|98.0
|0.8
|0.5
|2.2
|0.04
|1
|-
|'''Factor'''
|'''0 points'''
|
|
|'''1 point'''
|
|
|-
|Grade
|Grade 1/2
|
|
|Grade 3
|
|
|-
|ER status
|ER positive
|
|
|ER negative
|
|
|-
|HER2 status
|HER2 positive
|
|
|HER2 negative
|
|
|-
|'''Stage'''
|'''Risk profile'''
|'''N'''
|'''Five-year DSS'''

'''(%)'''
|'''95% CI'''
|'''Five-year OS'''

'''(%)'''
|'''95% CI'''
|-
|I (IA and IB)
|0
|36
|100
|
|97
|80.4-99.6
|-
|
|1
|1173
|99.4
|98.7-99.7
|96.7
|95.4-97
|-
|
|2
|274
|98.8
|96.4-99.6
|94.6
|91-96.8
|-
|
|3
|119
|96.6
|91.1-98.7
|93.8
|87.5-97
|-
|IIA
|0
|31
|100
|
|96.8
|79.2-99.5
|-
|
|1
|634
|99.4
|97.5-99.8
|97.1
|94.7-98.4
|-
|
|2
|236
|97.5
|93.2-99.1
|94.1
|88.7-97
|-
|
|3
|98
|91
|81.8-95.7
|88.2
|78.5-93.8
|-
|IIB
|0
|11
|100
|
|100
|
|-
|
|1
|309
|96.9
|92.6-98.8
|94.6
|89.6-97.2
|-
|
|2
|107
|92.9
|83.6-97.1
|89.3
|80.1-94.4
|-
|
|3
|40
|91.5
|75.6-97.2
|91.5
|75.6-97.2
|-
|IIIA
|0
|3
|100
|
|100
|
|-
|
|1
|134
|98.3
|88.2-99.8
|91.5
|82.6-96
|-
|
|2
|50
|92.2
|77.2-97.5
|90.3
|75.7-96.3
|-
|
|3
|7
|68.6
|21.3-91.2
|68.6
|21.3-91.2
|-
|IIIC
|0
|0
|
|
|
|
|-
|
|1
|39
|92.2
|72.1-98.0
|84.4
|63.7-93.9
|-
|
|2
|16
|80.8
|51.4-93.4
|80.8
|51.4-93.4
|-
|
|3
|10
|33.3
|6.3-64.6
|33.3
|6.3-64.6
|}











[[Category:Breast]]