Carcinoma of the Breast Flashcards
How can breast cancers be separated into groups?
- Can be separated into three major groups defined by the expression of two proteins, ER and HER2
How do the three groups of breast cancer differ from each other?
- Patient characteristics
- Pathologic features
- Treatment responses
- Metastatic patterns
- Time to relapse
- Outcome
When does the incidence of breast cancer start to rise?
- After age 30
Who is at low risk of having breast cancer?
- Women younger than age 25
Who has the highest incidence of breast cancer?
- Women of European descent
What is the average age of onset of breast cancer in women of european descent?
- 63
What is the average age of onset of breast cancer in women of African descent?
- 59
What is the average age of onset of breast cancer in women of Hispanic descent?
- 56
Why has rate of mortality declined in breast cancer?
- Mammographic screening as well as more effective treatment modalities
Why has the rate of mortality not decreased as much in African Americans?
- Partly due to unequal access to healthcare
- Also more likely to be biologically aggressive and fall into molecular subtypes that are difficult to treat
What are some high rate risk factors for breast cancer?
- Female gender
- Increasing age
- Germline mutations of high penetrance
- Strong family history
- Personal history of breast cancer
- High breast density
What are some moderate rate risk factors for breast cancer?
- Germline mutations of moderate penetrance
- High-dose radiation to chest at young age
- Family history
What are some low rate risk factors for breast cancer?
- Early menarche
- Late menopause
- Late first pregnancy
- Nulliparity
- Absence of breastfeeding
- Exogenous hormone therapy
- Postmenopausal obesity
- Physical inactivity
- High alcohol consumption
What is believed to be the cause of 1/3 of breast cancers?
- Inheritance of a susceptibility gene or genes
What is the most common gene that produces TNBCs?
- BRCA1
What is the most common gene that produces luminal breast cancers (ER)?
- BRCA2
What is the difference between hereditary and familial?
- Hereditary: High penetrance genes
- Familial: Low penetrance genes
What is seen in hereditary cancers?
- Autosomal dominant traits
- Earlier age of onset
- Bilateral or multifocal cancers
- Multiple primary cancers
- Clustering of rare cancers in family members
What is seen in familial cancers?
- No classic features of hereditary cancer syndromes
- Variable age of onset
- More cases of a specific type of cancer in a family than statistically expected and no specific pattern
- May result from chance clustering of sporadic cases
- May result from common genetic background, similar environment, and/or lifestyle
What are the most important high penetrance susceptibility genes for breast cancer?
- BRCA1 and BRCA2
What do BRCA1 and BRCA2 do?
- Produce tumor suppressor proteins that help repair damaged DNA and, therefore, play a role in ensuring the stability of the cell’s genetic material
What happens when either BRCA1 or BRCA2 is damaged?
- The protein product is not made or does not function correctly causing the DNA damage to not be repaired properly
- As a result, cells are more likely to develop additional genetic alterations that can lead to cancer
What are the major risk factors for sporadic breast cancers?
- Hormone exposure
- Gender
- Age at menarche and menopause
- Reproductive history
- Breastfeeding
- Exogenous estrogens
What are some characteristics of the low proliferation ER+, HER2 luminal cancers?
- 40-50%
- Major type in older women and in men
- Many detected at early stage
- Usually low grade with lowest recurrence rate, often cured surgically
- Metastasizes after long period of time and usually to bone
- Responds well to anti estrogenic drugs
What are some characteristics of the high proliferation ER+, HER2 luminal cancers?
- 10%
- Increased nuclear staining for Ki67
- Most common form associated with BRCA2 mutation
- Higher expression of genes related to cellular proliferation
- 10% have complete response to chemotherapy
What is the difference in growth between ER+/PR+ cancers and ER-/PR- cancers?
- ER+/PR+ cancers are usually well differentiated and slow-growing
- ER-/PR- cancers are usually poorly differentiated and have a high proliferative rate
What is HER2?
- Proto-oncogene ERBB2 encodes HER2
- Member of the RTK family (a family of growth factor receptors)
How are HER2 carcinomas diagnosed?
- By detecting HER2 overexpression by immunohistochemistry or HER2 gene amplification by in situ hybridization
What does Herceptin do?
- MoAb that binds and inhibits HER2
- Not all HER2+ carcinomas respond to targeted therapy
How do TNBCs arise?
- Through an estrogen independent pathway that is not associated with HER2 gene amplification
What are some characteristics of TNBCs?
- Have a “basal-like” gene expression profile, so-called because many of the genes that comprise this signature are normally expressed in basally located myoepithelial cells
- Almost all tumors are poorly differentiated and several typical histological patterns are recognized
Who is most likely to have TNBCs?
- Young premenopausal women
- African Americans
- Hispanics
How does a TNBCs usually present?
- As a palpable mass in the interval between mammogram screenings because they grow at such a fast rate
What are all breast cancers?
- Adenocarcinomas
What do the terms ductal and lobular describe?
- Subsets of both in situ and invasive carcinomas
What was carcinoma in situ originally classified as?
- Ductal carcinoma in situ or lobular carcinoma in situ depending on the resemblance of the involved spaces
What does lobular refer to?
- Invasive carcinomas that are biologically related to LCIS
What does ductal refer to?
- Used more generally for adenocarcinomas that cannot be classified as a special histologic type
What is seen in LCIS and DCIS?
- No extension beyond basement membrane
- Myoepithelial cells preserved
- Detected mammographically as micro Ca++ can present as a mass if periductal fibrosis or in some subtypes as nipple discharge
What is the best treatment for DCIS?
- Not 100% sure, could be lumpectomy or mastectomy, + chemo
- Post op radiation + Tamoxifen
What can help decide the treatment in DCIS?
- Nuclear grade and necrosis
- Extent of disease
- Positive surgical margins
What is Paget disease of the nipple?
- Rare manifestation of breast cancer that usually presents as a unilateral erythematous eruption with a scale crust
What is common in Paget disease of the nipple?
- Pruritus is common
- Lesion may be mistaken for eczema
What occurs in Paget disease of the nipple?
- Malignant cells extend from DCIS within the ductal system via the lactiferous sinuses into nipple skin without crossing the basement membrane
- Tumor cells disrupt the normal epithelial barrier, allowing extracellular fluid to seep out onto the nipple surface
Is there a palpable mass in Paget disease of the nipple?
- Yes
What is the genetic makeup of Paget disease?
- ER- and overexpress HER2
What is LCIS?
- Clonal proliferation of cells that grow in a discohesive fashion due to mutation of CDH1 that leads to loss of tumor suppressor adhesion protein (E-cadherin negative)
How does LCIS present?
- Always an incidental finding
- BIlateral in 20-40% of cases
- What is LCIS a risk factor for?
- Invasive lobular carcinoma (either breast)
What does LCIS express?
- Always expresses ER and PR
- Overexpression of HER2 is not observed
What are some subtypes that are recognized with distinctive morphologies?
- Lobular carcinoma
- Carcinoma with medullary pattern
- Mucinous carcinoma
- Inflammatory
What is lobular carcinoma?
- Biallelic loss of CDH1 so loss of E-cadherin
- Most common type of breast cancer to present as an occult primary
What are some characteristics of metastasis of lobular carcinoma?
- Peritoneum and retroperitoneum
- Leptomeninges
- GI tract
- Ovaries (Krukenberg) and uterus
What is interesting about carcinomas with medullary pattern?
- Over half of BRCA1 associated carcinomas have this appearance
- Although the majority of carcinomas with medullary pattern are not assoicated with germline BRCA1 mutations, hypermethylation of the BRCA1 promoter leading to downregulation of BRCA1 expression is observed in 67% of tumors
What is seen in carcinomas with medullary pattern?
- These tumors have a better prognosis than other poorly differentiated carcinomas
- Have unusually high number of infiltrating T lymphocytes, suggesting that improved outcomes may be related to a host immune response to tumor antigens
What is inflammatory carcinoma?
- Only 3% of breast cancers
- Higher incidence in African Americans
- Very poor prognosis
What is a big clinical sign in inflammatory carcinoma? What causes it?
- Peau d’orange
- Due to extensive plugging of lymphovascular spaces of the dermis with carcinoma cells
What does the outcome of the breast cancer depend on?
- Biologic features of the carcinoma
- Extent to which the cancer has spread at the time of diagnosis
