Breast Disorders Flashcards

Question

Invasive Breast Carcinoma Assessment / Prognostic Factors

Answer 1

Two important groups of factors: * _Extent of Disease_ * **Grading** and **staging** * _Tumor Biology_: markers that play a role in determining prognosis and tx * **Estrogen Receptor (ER)** * **Progesterone Receptor (PR)** * **HER-2 protein overexpression** * **Proliferation marker (Ki-67) status** * **BRCA-1 or BRCA-2 gene status**

Answer 2

_TMN staging:_ * **Distant metastasis (M)** * **Most important ⊖ factor** * Metz mostly seen in **bone marrow, lung and pleura, liver, adrenal glands, CNS** * **Axillary lymph node status (N)** * 2^nd most important prognostic factor * Most common site for breast CA is _upper outer quadrant_ ⇒ **spreads to axillary nodes** * Tumor in _inner quadrant of breast_ ⇒ can metastasize to **internal mammary chain** * Sentinel node sampling is an important tool * _No nodes_: 10-yr disease-free survival 70-80% * _1-3+ nodes_: 10-yr disease-free survival 35-40% * _More than 10+ nodes_: 10-yr disease-free survival 10-15% * **Tumor size (T)** * More important prognostically for _ER ⊕ HER2_ _⊖_ _cancers_ * Others can metastasize even though small * **Lymphovascular invasion** * Often associated with node metz

Answer 3

* **Molecular subtype** * Determined by expression of ER and HER2 & proliferation * **Special histologic types of invasive carcinoma** * Better survival rate for _tubular, mucinous, lobular, papillary_ * **Histologic grade** * Use the **Nottingham Histologic Score** * Assesses _Nuclear Grade, tubule (gland) formation, mitotic rate_ * Add up points for grade I, II, III * **Proliferative Rate** * Can use **Ki-67** * **ER/PR receptors** * ⊕ ⇒ likely to respond to hormonal therapy, but not chemotherapy * ⊖ ⇒ vice versa * **HER2 overexpression** * Poorer survival * Status predicts response to agents that target the receptor

Answer 4

* **ER-⊕ pathway** * Most common * Recognizable precursor lesions include **flat epithelial atypia** and **atypical hyperplasia** * Luminal gene expression profile * **HER2-⊕ pathway** * May be ER-⊕ or ER-⊖ * Amplification of HER2 gene also present in a **subset of atypical apocrine lesions** * May represent a precursor lesion * HER2-enriched gene expression profile * **ER-⊖ and HER2-⊖ pathway** * Less common * No precursor lesion identified * Basal-like gene expression profile

Answer 5

**“Luminal Breast CA”** * **50-65%** of Breast CA * Most similar to nl breast luminal cells in mRNA expression pattern * Dominated by **genes regulated by estrogen** * **Flat epithelial atypia** and **ADH** precursor lesions * _Two major molecular subtypes_ ⇒ differ in **proliferation rate** and **response to therapy** * **ER-⊕, HER2-⊖, low proliferation** (45-55%) * Majority of cancers in **older women** * Most common type detected by mammographic screening and in women on HRT * Gene expression dominated by **genes directly regulated by ER** * _Prognosis:_ * Often detected early, **low rate of recurrence** * If metastasize, do it after many years and go to **bone** * **Respond well to hormonal treatment**, * Long survival even with metastases * Chemotherapy doesn’t add much therapeutic value * **ER-⊕, HER2-⊖, high proliferation** (10%) * Most common type ass. w/ **BRCA2 germline mutation** * mRNA like other ER-⊕ cancers but **higher expression of genes related to proliferation** * **More chromosomal aberrations** than low-grade * **10% show complete response to chemo**

Answer 6

* **10-20%** of Breast CA * 2^nd most common molecular subtype of invasive breast CA * Seen more in **young and non-white women** * _Most common subtype_ in pts with **germline TP53 mutation** (Li-Fraumeni) * **Can be ER-⊕ or ER-⊖** * **Atypical Apocrine Adenosis** ⇒ suspected precursor * **Complex chromosomal translocations** * Arise via pathway strongly ass. w/ **high-level amplification of HER2 on chromosome 17q** * **Mostly poorly differentiated**, no specific pattern * 50% of apocrine CA and 40% of micropapillary are in this group * Often show **extensive DCIS** * _Assay_: **HER2 protein overexpression** or **HER2 gene amplification** * Tumor can **metastasize early** and **when small** → _viscera and brain_ * Before HER-2 targeted tx, these were bad * **Trastuzumab (Herceptin)** * ≥ ⅓ respond completely to Ab that block HER2 activity * Now have excellent prognosis * Some are non-responders and some become resistant

Answer 7

* **10-20%** of Breast CA * **Young premenopausal women, AA, Hispanic** * _Characteristics:_ * **Palpable mass, circumscribed pushing borders** * **Poorly differentiated**, **high proliferation fraction, rapid growth** * **Central** **fibrotic** or **necrotic center** * ± Medullary features * ± Spindle, squamous, etc. * Not much DCIS * Least understood pathway * **No precursor lesion described** * Most common type w/ **germline BRCA1 mutations** * ↑ Frequency in African Americans * **Basal-like pattern of mRNA expression** * Includes many genes expressed in normal myoepithelial cells * Has some similarities to serous ovarian CA * **Can metastasize when still small** * **30% completely respond to chemo** * **Recur in first 5 years**

Answer 8

* **Estrogen promotes breast CA** * Stimulates breast growth * Proliferate during menstrual cycle * More cycles = more risk * _↑ Estrogen exposure_ _⇒_ _↑ risk_ * **Menopausal HRT**, esp. if estrogen and progestin for many yrs * **Early menarche, late menopause** * **Nulliparity or first birth after age 35** * _↓ Estrogen exposure_ _⇒_ _↓ risk_ * **Oophorectomy** ⇒ ↓ endogenous estrogen * ↓ Breast CA risk by up to 75% * **Tamoxifen** (⊗ estrogenic effects) and **Aromatase inhibitors** (⊗ formation of estrogen) * ↓ Risk of **ER-⊕** breast CA * **Full term pregnancy before 20 halves risk**

Answer 9

* **12%** of breast CA * **Autosomal dominant** * Inherit _defective copy of tumor suppressor gene_ * Sporadic mutation in remaining nl allele ⇒ lose tumor suppressor function ⇒ **initiating driver mutation** * Creates a **‘mutator’ phenotype** * ↑ Propensity to genetic damage * Speeds cancer development * Major known susceptibility genes are **BRCA1, BRCA2, TP53, CHEK2** * All tumor suppressor genes w/ roles in DNA repair and maintenance of genomic integrity

Answer 10

* **BRCA1 and BRCA2** ⇒ 80-90% of single gene familial breast CA (3% of all breast CA) * Penetrance varies 30-90% * Involved in homologous recombination for repair of DS DNA breaks * _BRCA1_ ⇒ **Chromosome 17q21** * 20-40% ↑ risk of ovarian CA * _BRCA2_ ⇒ **Chromosome 13q12.3** * 10-20% ↑ risk for ovarian CA * Restrict genetic testing to pts w/ strong FHx and certain groups * **Ashkenazi Jews** * 1/40 carry 1 of 3 specific mutations * Once carriers ID’d ⇒ surveillance, mastectomy, BSO * _\< 10% of familial breast CA_ * **TP53** (Li-Fraumeni syndrome) [3%) * **CHEK2** = 8% of single gene breast CA [5%] * _\< 1% of familial breast CA_ * **PTEN** (Cowden Syndrome) * **STK11** (Peutz-Jeghers) * **ATM** (ataxia-telangiectasia)

Answer 11

* Tumors present w/ **breast swelling, erythema and skin thickening** * **± Palpable mass**, can be confused w/ infection * **Very poor prognosis** * 3-year survival rate 3-10% * Most pts have **distant metastases** at presentation * **Dermal lymphatics filled w/ metastatic carcinoma** ⇒ blocks lymphatic drainage * **Edematous skin** tethered to the breast by **Cooper ligaments** * Skin surface mimics surface of an orange peel ⇒ ***peau d’orange*** * **60% ER-⊖** * **40-50% overexpress HER2**

Answer 12

* Presents w/ **excoriated nipple lesion** * May need to biopsy to differentiate from skin lesion * **Large, pale Paget cells** * Extend from _DCIS in ductal system_ → _nipple skin_ via lactiferous sinuses w/o crossing BM * Tumor cells **disrupt normal epithelial barrier** ⇒ ECF seeps out onto nipple surface * Causes **eruption w/ a scale crust** * 50-60% w/ Paget have _palpable mass_ * **Almost all of these pts have underlying invasive CA** * Usu. poorly differentiated, **ER-⊖, HER2-⊕** * Paget _w/o palpable mass_ usually have **DCIS**

Answer 13

* Most important is **angiosarcoma** * \< 0.05% of breast malignancies * Can be **sporadic** or arise as a **complication of therapy** * _Sporadic_ * **Young women** (mean age 35) * **High grade** * **Poor prognosis** * _Treatment related_ * Arise secondary to **radiation or edema** * After radiation therapy, ~0.3% of women develop angiosarcomas in breast skin * Most cases are **dx 5-10 years after tx**

Answer 14

* **Enlargement of male breast** d/t _hypertrophy and hyperplasia of both glandular and stromal components_ * Most cases related to relative **↑ estrogenic activity**; **↓ in androgenic activity**, or **both** * Many are idiopathic

Answer 15

Rare \< 1% of all breast CA in the U.S. population