11 & 12 - Breast Cancer Flashcards
Most common cancer among women in the US
Breast Cancer
Leading cause of cancer death among women in the US
Lung Cancer
Second leading cause of cancer death among women in the US
Breast Cancer
Lifetime risk a woman has of developing breast cancer
1 in 8
Biggest risk factor for developing breast cancer (other than being a woman)
Age
Breast Cancer - Stage 0
DCIS - Cancer cells present in either lining of a breast lobule or a duct, but have not spread to the surrounding fatty tissue
Breast Cancer - Stage 1
Tumor
Breast Cancer - Stage 2
Tumor can range from 2 - 5 cm in diameter
OR
Breast Cancer - Stage 3
Locally advanced cancer
Tumor may be larger than 5 cm in diameter
OR >4 lymph nodes are involved
Breast Cancer - Stage 4
Known as metastatic
Cancer has spread to other parts of the body such as bone, liver, lung or brain.
Non-Metastatic Breast Cancer - Local Therapy
Surgery (lumpectomy)
Radiation therapy
If contraindications to this, then total mastectomy is treatment of choice
Non-Metastatic Breast Cancer - Systemic Therapy
Endocrine manipulations
Chemotherapy
Novel Therapies
Adjuvant Therapy
Chemotherapy after surgery
Neo-Adjuvant Therapy
Chemotherapy before surgery
Sentinel Lymph Node Biopsy
During surgery, surgeon injects dye
See lymph nodes that have uptake of that dye
Remove those lymph nodes to see if the cancer has spread there.
Adjuvant Systemic Therapy for Breast Cancer - Prognostic Factors
Estimate outcome independent of systemic treatment
Reflect tumor biology - Who should be treated?
Adjuvant Systemic Therapy for Breast Cancer - Predictive Factors
Reflect relative resistance or sensitivity to specific therapy
What specific treatments should be offered to an individual?
Breast Cancer Prognostic Factors
TNM Stage Axillary nodal status Tumor size Tumor Grade Lymphatic or vascular invasion
Breast Cancer Predictive Factors
Age
Estrogen Receptor
Grade
HER2
Estrogen Receptor (+)
Estrogen Dependent
That means on immunohistochemistry, you have Estrogen & Progesterone recepters >1%
More slow-growing
Can recur decades later
Estrogen Receptor (-)
Estrogen Independent
Commonly recurs within the first 5 years
If you hit the 5 year point without recurring, your likelihood of recurrence is very low.
Tamoxifen
PO
Once per day
Can give regardless of menopausal status
Selective Estrogen Receptor Modulator (SERM)
Risks:
Increased risk of endometrial cancer (1/1000)
Thromboembolic phenomena
Cataracts
Benefits:
Bone health
Lipid
Decreases risk of breast cancer recurrence of 50%
Also likelihood of this helping your breast cancer is directly proportional to how much Estrogen Receptor is found in your immunohistochemistry.
Aromatase Inhibitors (Anastrozole)
Decrease amount of systemic estrogen
Aromatase converts precursors to estradiol
Can only give to post-menopausal patients
Side effects: Hot flashes Vaginal dryness Fractures (unless their bone density was normal to begin with) Joint aches
After 5 years of Tamoxifen
Still see benefits 15 years later in terms of decreased rates of recurrence.
Tamoxifen - Who
Effective in all hormone receptor positive women (ER+/PR+, ER-/PR+, ER+/PR-)
Regardless of age, stage, tumor grade, menopausal state
Optimal duration: 5 years (these days it’s actually 10)
Anastrozole Vs Tamoxifen - Disease free survival
Anastrozole is better, when compared directly. You just can’t give it to everyone.
Breast Cancer Chemo - Which Regimen?
Polychemotherapy is superior to single agent chemotherapy
Anthracycline-based therapy is superior to CMF-based therapy
All women gain benefit
Younger women and those with poorly differentiated hormone receptor-negative tumors are more likely to benefit.
Triple Negative
ER-
PR-
HER2-
Typically are a bit more aggressive
Oncotype test
Only done with hormone receptor (+) and HER2 (-)
Tells us how well we’ll do with chemo
Main side effect of taxanes
Peripheral neuropathy (microtubule inhbitors)
Biologic Therapies
Used in HER2 type
Tyrosine Kinase TM growth factor receptor
Drugs that target HER2:
Trastuzumab (Herceptin)
Pertuzumab
TDM1
Trastuzumab - Side effects
Reversible decrease in cardiac function
Don’t give with doxorubicin too!
Metastatic Breast Cancer - Goals of Therapy
Cure Improve overall survival Improve time to progression Improve symptoms related to the disease Improve quality of life
Trastuzumab - Mechanism of action
Suppresses HER2 activity
Does not inhibit HER2 heterodimerization
Flags cells for destruction by the immune system (ADCC)
Pertuzumab - Mechanism of action
Inhibits HER2-forming dimer pairs
More complete HER2 blockade
Flags cells for destruction by the immune system
Pertuzumab - Side effect
Reversible impairment in pumping of the heart
TDM1
Trastuzumab (Herceptin) that is LINKED to a microtubule inhibitor
Palbociclib
Hormone Receptor (+) HER2 (-)
Give with aromatase inhibitor (Anastrozole) and it triples the time it takes for a tumor to grow
Interrupts cell cycle between G1 and S
HR(+), HER2(-) has only metastasized to the bone
Gurl can live for a decade
Functional unit of the duct
Terminal Duct Lobular Unit
Lined by myoepithelial cells (can contract as well as serving epithelial functions)
If we see myoepithelial cells at the periphery
The cancer is bounded (in situ)
Fibrocystic Changes - General description
Most common breast lesion
Misc changes of breast tissue involving ducts, lobules, stroma in any combination
Manifests in 40 - 50% of patients as lumps
Pathological incidence greater than 60 - 80%
Path - Reflects exaggerated changes occurring normally in menstrual cycle
Fibrocystic changes - Specifics
Fibrosis Cysts Apocrine metaplasia Adenosis (enlargement of TLDU) and sclerosing adenosis (scarring of TDLU) Intraductal and epithelial hyperplasia
Mild Hyperplasia (2 - 4 cells) indicates
No increased risk
Apocrine metaplasia indicates
No increased risk
Cysts (macro & micro) indicate
No increased risk
Duct ectasia indicates
No increased risk
Fibroadenomas indicate
No increased risk
Atypical ductal and lobular hyperplasia - borderline lesions indicate
Moderately increased risk (4 - 5x)
Hyperplasia, moderate or florid (ductal and lobular) indicates
Mild increased risk (1.5 - 2x)
Papilloma with fibrovascular core indicates
Mild increased risk (1.5 - 2x)
Adenosis (Sclerosing or florid) indicates
Mild increased risk (1.5 - 2x)
Atypical Ductal Hyperplasia
Borderline lesion
A proliferative lesion
Some of the cytologic and architectural criteria of carcinoma in situ are met, but not fully satisfied
Non-obligatory precursor of cancer, may or may not progress
Found in ~5% of biopsies
Indicates 4 - 5x increased risk of invasive cancer
Risk for cancer is bilateral and persists for more than 20 years
Prognosis is same as for cancers without this ADH
30% who have ADH on biopsy have cancer on excision
Malignant - Epithelial Derived Tumors
Intraductal and invasive ductal carcinoma
In situ and invasive lobular carcinoma
Malignant - Mesencymal neoplasm (sarcoma)
Cystosarcoma phyllodes
Angiosarcoma
Others
Breast carcinoma pathology
Most cancers (90%) show ductal epithelium differentiation 10% referred to as lobular type In situ and invasive components
Ductal Carcinoma In Situ (DCIS)
Neoplastic transformation of epithelium within ducts or lobules surrounded by myoepithelial cells
Non obligatory precursor to invasive cancer
Characterized by nuclear grade & histo patterns:
Comedo, Solid, Cribiform, Clinging, Papillary
May be detected by association with microcalcifications
May represent up to 25% of breast carcinoma
High grade and large size → multifocality & propensity for invasion
Relative risk for development of invasive carcinoma 8 - 10 fold greater than general population
Risk is primarily ipsilateral
Invasive Ductal Carcinoma
Infiltrative malignant epithelial cell process
Resembles cells lining TDLU
Most common breast carcinoma
Lacks myoepithelial cells at the periphery
Invasive Ductal Carcinoma - Histologic Classifications
Carcinoma no special type - Majority
Special good prognosis subtype including medullary carcinoma, colloid (mucinous) carcinoma & tubular carcinoma
Poor prognosis - inflammatory, metaplastic CA
Grade: Modified Scarff-Bloom Richardson based on extent of tubular formation, pleomorphism & mitoses
Inflammatory Breast Carcinoma
Poor prognosis
Orange peel appearance to the skin
Association with dermal lymphatic invasion
Lobular Carcinoma In Situ (LCIS)
Neoplastic transformation of epithelial cells lining terminal ducts and acini of small size
ER/PR+
E-cadherin negative
Surrounded by myoepithelium
Typically multifocal and bilateral
6 - 9 fold increased risk for development of invasive cancer
Bilateral risk of development of invasive cancer
3/4 of invasive cancers that ensue are DUCTAL. Weirdsies
Considered primarily a marker for invasion but is also non-obligatory precursor for invasive lobular carcinoma at a low rate.
Invasive Lobular Carcinoma
Infiltrating carcinoma resembling cells of LCIS
Histo - “Indian file” pattern and targetoid “bulls eye” pattern
Small cells with scanty cytoplasm, sometimes vacuolated
E-Cadherin negative
Represents 10% of breast cancer with higher-than-usual incidence of bilaterality (20%)
Prognostic Factors of Breast Cancer
Size of primary tumor (larger = worse)
Lymph node involvement and extent, distant metastasis (stage)
Grade - high grade worse
Histologic type
Oncotype Dx (for ER/PR+) predicting distant recurrence
HER2/NEU
ER/PR status
Luminal A Breast Cancers
Resembling normal luminal epithelium CK8/18 ER+ and associated genes Low Grade Excellent Prognosis Low p53 mutation rate (12%) PIK3CA Mutation (45%)
Luminal B Breast Cancers
ER+, but less than Luminal A Low-to-moderate expression of luminal specific genes Tumors have higher grade Proliferation Worse prognosis compared to Luminal A Some are HER2+ p53 mutation rate 29% PIK3CA Mutation 29%
HER2-Enriched Breast Cancers
Overexpression of HER2 & associated pathway genes ER (-) Poor prognosis 72% mutated for p53 39% PIK3CA
Basal-Like Cancers (Triple Negative)
Primitive High histologic grade Highly proliferative Pushing borders May contain necrosis Metaplastic changes Atypical medullary features Seen in the majority of BRCA1 carrier breast tumors 80% mutated for p53
Gynecomastia
Button-like subareolar swelling
Generally bilateral
Corresponds to intraductal epithelial hyperplasia & increased periductal stromal cellularity & edema
Physiological gynecomastia most common in puberty and old age
No clear cut association with development of carcinoma
Gynecomastia - Associated with
Relative estrogen excess Cirrhosis of the liver Klinefelter's Estrogen secreting tumor Estrogen therapy Digitalis therapy
Male Breast Carcinoma
Rare
Ratio of Male : Female breast cancer is 1 : 125
Occurs in advanged age
Identified in peri-nipple/areolar region
Presents in advanced stage
Resembles morphologically and biologically invasive carcinomas of the female breast
Associated with BRCA2 germ line mutations
Two benign tumors of the breast
Fibroadenoma
Intraductal papilloma
Fibroadenoma
Most common benign tumor or the female breast
Usually appears in young women
Peak incidence in third decade of life
Benign fibroepithelial tumor usually solitary, may be multiple
Rarely associated with carcinoma
Ball-like mass
Increased stroma in lobules
Intraductal Papilloma
Benign papillary neoplasm within a duct
Fibrovascular cores lined by benign epithelium and myoepithelium
Identified peripherally or centrally (nipple duct)
If central, may be associated with bloody nipple discharge
Mild increased risk (1.5 - 2x) of development of invasive cancer if you have multiple
Breast Cancer Risk Factors - Highest to Lowest
BRCA Mutation Prior chest wall irradiation Atypical hyperplasia Increased breast density Family history Nulliparity/Age at first birth > 30 Early menarche 55 Hormone replacement therapy >5 years Postmenopausal obesity Alcohol servings/day >2
Majority of breast cancer is
Sporadic
Hereditary Breast Cancers
5 - 10% of all breast cancer
1/2 of those are BRCA1
1/3 are BRCA2
BRCA1 & BRCA2
Red flags for Hereditary Breast and Ovarian Cancer Syndrome (HBOC) - Personal
Breast cancer
Red flags for Hereditary Breast and Ovarian Cancer Syndrome (HBOC) - Family History
Non-Ashkenazi Jewish:
2 first-degree relatives with breast cancer, 1 diagnosed
BRCA Genetic Testing Options
Multisite 3 (Ashkenazi mutations) Comprehensive (Full sequencing) BART (Large rearrangement test)
BRCA+
High risk
BRCA- but family member BRCA+
Average risk
No known mutation in family, BRCA-
Moderate risk
No known mutation & Variant of uncertain significance
Moderate risk
BRCA mutation carriers are at increased risk for
Breast Cancer Ovarian Cancer Prostate Cancer Male breast cancer Melanoma Pancreatic Cancer
Intensive screening - Self Breast Exam
Begin at age 18
Screen monthly
Intensive screening - Clinical Breast Exam
Begin at age 25
Screen every 6 - 12 months
Intensive screening - Mammogram
Begin at age 25
Screen yearly
Intensive screening - Breast MRI
Begin at age 25
Screen yearly
Who?
BRCA mutation carriers
Other hereditary breast cancer syndromes (Li-Fraumeni, Cowden’s)
Lifetime breast cancer risk >20 - 25% based on family history
Prior chest irradiation
Intensive screening - Pelvic exam
Begin at age 30 (No BSO)
Screen every 6 months
Intensive screening - Transvaginal ultrasound and CA-125
Begin at age 30 (No BSO)
Screen every 6 months
Risk-reducing surgery
Mastectomy reduces breast cancer risk by 90%
Oophorectomy reduces ovarian cancer risk by 79% and breast cancer risk by 55%
Chemoprevention
Tamoxifen
Risk reduction in BRCA (-) with high risk 45%
Risk reduction in BRCA (+) without cancer 62%
Risk reduction in BRCA (+) contralateral breast cancer (50%)
Only reduces the risk of hormone receptor positive cancers
OCPs reduce risk of ovarian cancer by 50%
