- 2nd M/C cancer in women
- 2nd M/C cause of cancer deaths in women (after lung cancer)
- 5-year survival: 88% in women
- In situ carcinoma (25% cases)
- Invasive/infiltrative carcinoma (M/C, 75% cases)
- Luminal-like (M/C):
- Luminal-A like: ER and/or PR, no HER2 & low proliferation
- Luminal-B like: ER and/or PR, no HER2 & high proliferation
- Triple-negative: No ER, no PR, no HER2
- HER +: Luminal like/non-luminal like
In situ carcinoma:Pre/non-invasive: limited by basement membrane
- Ductal carcinoma in situ (DCIS) (80% in situ cancers)
- Spreads through ducts & distorts duct architecture
- Can progress to invasive form
- Paget disease of Nipple
- Cancer cells migrate along lactiferous duct, through pore, onto skin → Mobility factor (helps break and settle b/w squamous epithelial cells) → Inflammation → Extracellular fluid leaks through skin breaks → Dries & forms crust
- Lobular carcinoma in situ (LCIS)
- Clusters of tumour cells grow within lobules (don’t invade ducts) → Lobules enlarge
- Doesn’t distort ductal architecture.
- Risk factor rather than precursor
- Can be bilateral
- Invasive ductal carcinoma (IDC) (80% of invasive breast cancers)
- Develops from DCIS
- Fibrous response to produce mass
- Metastasize via lymphatics & blood
- Invasive lobular carcinoma (ILC)
- Minimal fibrous response
- Female sex (8x higher risk)
- Previous history of breast, endometrial or ovarian cancer.
- Family history
- ↓ Phyto-oestrogen diet
- High alcohol intake (increase the amount of circulating estrogen, possibly by decreasing hepatic metabolism, increasing aromatase activity, or increasing adrenal sex hormone production)
- Obesity (risk factor for postmenopausal women, likely due to adipose tissue production of estrogen via aromatase)
Hormonal factors:Risk increases with lifetime oestrogen exposure.
- Early menarche, late-onset menopause
- Late pregnancy (> 35 years) & nulliparity
- Lack of breastfeeding
- Hormone replacement therapy (HRT) ↑ risk
- OCP does not increase risk
- Decrease risk:
- Early (& longer) breastfeeding
- Early pregnancy
Hereditary cancers (5-10% cases):
- BRCA1 & BRCA2 mutations (5-10% cases):
- Also increase risk of ovarian cancer
- Hereditary breast and ovarian cancer (HBOC) syndrome (caused by mutations in two genes, BRCA1 and BRCA2)
- Li-Fraumeni syndrome (p53 mutation): Characterized by early-onset breast cancers, sarcomas, brain tumors, adrenal cortical tumors and acute leukemias
- Lifetime risk= 90%
- Cowden syndrome (PTEN gene): Characterized by high rate of breast cancer and mucocutaneous findings, thyroid disorders and endometrial carcinomas.
- Lifetime risk = 50%
- Human epidermal growth factor receptor 2 (ERBB2/HER2)
Hormone receptor (HR) mutations:
- Oestrogen receptor (ER)
- Progesterone receptor (PR)
Tumorigenic effects of oestrogen:
- Genotoxic effects of estrogen metabolites via generation of radicals (initiator) and
- Hormonal properties of estrogen inducing proliferation of cancers as well as premalignant cells (promoter).
BRCA 1 & BRCA 2 (tumour suppressor genes) mutations:Cells lacking BRCA1/2 are much more sensitive to ionizing radiation, suggesting a role for BRCA1/2 in DNA damage response (DDR), specifically in repairing double-strand breaks (DSB), which is the major lesion inflicted by ionizing radiation.
- BRCA1&2 are involved in homologous DNA repair.
Human Epidermal Growth Factor Receptor 2 (HER2) (protooncogene):Mechanism of carcinogenesis largely unknown, but overexpression associated with:
- Rapid tumor growth
- Shortened survival
- Increased risk of recurrence after surgery
- Poor response to conventional chemotherapeutic agents
- Hard, painless lump/swelling in breast
- Upper & outer quadrant (M/C)
- Armpits (if spread to axillary LN)
- Breast immobile & fixed (cancer infiltrating pectoral muscles)
- Skin dimpling (involvement of skin)
- Breast retraction (fibrosis of lactiferous ducts & suspensory ligaments)
- Paget’s disease:
- Itching, redness
- Crusting & discharge
- Local inflammation ↑→ Damage to suspensory ligaments & lactiferous ducts → Fibrosis
- Enter & block lymphatic drainage → Breast unable to stretch d/t suspensory ligaments → Peau d’orange appearance
Metastasis:Spreads easily in males as underlying breast tissue is thin. Accounts for 90% breast cancer mortality.
- Local invasion: Pectoral muscle & skin
- Blood: Spine, brain, bone
- Lymph → Axillary lymph nodes → Other breast
Metastatic organotropism:Distribution of distant metastases to certain organs is a non-random process, regulated by multiple factors such as subtypes of cancer, molecular features of cancer cells, host immune microenvironment, and cross-talk and interactions with local cells.
- Fixed mass (eps, if attached to chest wall)
- Overlying skin changes:
- Orange peeling (peau d’orange)
- Nipple retraction
- Axillary lymphadenopathy
- X-ray chest
- CT liver
- Bone scan
Histopathology (tissue biopsy)
- Fine needle aspiration biopsy
- Core biopsy
- Surgical biopsy
Immunohistochemistry (IHC):M/C, convenient and cost-effective initial test for HER2 protein expression
- 1+ | HER2 negative
- 3+ | HER2 positive: Strong circumferential membrane staining in >10% cells)
- 2+ | Equivocal: Moderately strong circumferential staining in >10 % of cells
- FISH necessary for diagnosis
Fluorescence in situ hybridization (FISH):All cases showing IHC 2+ (equivocal) should be subjected to FISH to determine gene amplification status. If the FISH results are positive then they are labelled as Her-2 positive.
- Breast-conserving surgery (BSC): Lumpectomy or wide local excision
- BSC involves resection of the tumor along with a margin of tissue while conserving the cosmetic appearance of the breast.
- Most breast surgeries are of this type because:
- Most tumours are locally invasive
- Large primary tumours can be reduced in size by neoadjuvant chemotherapy prior to conservative surgery.
- Mastectomy: Surgical removal of the entire breast, including the fascia over the pectoralis muscles. Surgeons may preserve some skin and the nipple/areola for reconstruction.
- Indication for mastectomy:
- Multicentric invasive carcinoma
- Inflammatory carcinoma
- Extensive intraductal carcinomas
- Indication for mastectomy:
- Axillary lymph node dissection: Removal of the lymph nodes draining the breast tissue for lymph node micrometastasis. Done at the same time as BSC/mastectomy.
- Adjuvant therapy: Cytotoxic chemotherapy, endocrine therapy, or radiation therapy may be used postsurgery to prevent relapse.
- Whole/partial breast irradiation.
- Adjuvant radiation therapy applied post-BCS/mastectomy to prevent recurrence.
- Since most recurrence of early-stage breast cancer occurs locally, there are mortality benefits but an increased risk of local and axillary recurrence with partial irradiation.
Hormone therapy:Breast cancer is a hormone-sensitive cancer. Most breast cancer cells are ER-positive, and thus will respond to reduction of circulating estrogens. Hormone receptor-negative (HR-negative) breast cancers will not respond to endocrine therapy.
- Adjuvant therapy for early-stage hormone-sensitive breast cancer
- First-line therapy for metastatic hormone-sensitive breast cancer.
- Antiestrogens (e.g. tamoxifen)
- Aromatase inhibitors: Aromatase (estrogen synthase), is an enzyme responsible for estrogen synthesis.
- Steroidal type (type I) (e.g. exemestane): Androgen analogue that binds permanently with the aromatase enzyme, leading to long-term and specific inhibition of the enzyme.
- Non-steroidal type (type II) (e.g. anastrozole and letrozole): Originates from an anti-epileptic drug that reversibly binds and inhibits the cytochrome P450 unit in aromatase.
- Ovarian ablation: induction of artificial menopause by ovariectomy significantly reduces breast cancer risk.
- Adrenalectomy: Eliminates a source of androgens in females, which is the precursor to aromatase-derived estrogens.
- Ovarian suppression:
- LHRH (GnRH) agonist (e.g. goserelin and leuprorelin): Reversibly suppress LH/FSH release and thus estrogen release.
- Cytotoxic drugs: Cyclophosphamide, methotrexate, doxorubicin, and paclitaxel
- Hormone receptor-negative
HER2/neu oncogene +
- Trastuzumab (Herceptin)
Non-invasive breast cancer:
- Lumpectomy ± radiotherapy (breast conservation)
- Modified radical mastectomy (MRM)
- LCIS: Prophylactic bilateral mastectomy can be considered
Invasive breast cancer:
- Lumpectomy + sentinel node biopsy + radiotherapy
- Modified radical mastectomy (MRM)
- If invasion of pectoralis major: Radical mastectomy
- CHEMOTHERAPY (if nodal metastasis):
- CAF/CAMF: Cyclophosphamide + Adriamycin/Methotrexate + 5-FU
- HORMONE THERAPY (if tumour ER/PR+):
- Oestrogen inhibitors (Tamoxifen, Raloxifene)