Breast carcinoma

Breast cancer refers to several types of neoplasm arising from breast tissue, the most common being adenocarcinoma of the cells lining the terminal duct lobular unit.

• 2nd M/C cancer in women
• 2nd M/C cause of cancer deaths in women (after lung cancer)

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Epidemiology

• 5-year survival: 88% in women

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Classification

Histological classification:

• In situ carcinoma (25% cases)
• Invasive/infiltrative carcinoma (M/C, 75% cases)

Molecular subtypes:

• 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
  • Unliateral
  • 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/infiltrative carcinoma:

• 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

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Etiology

Risk factors:

• Age
• 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)
• Radiation

Hormonal factors:

Risk increases with lifetime oestrogen exposure.

• Nulliparity
• 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)

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Pathophysiology

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

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Presentation

• 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

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Complications

• 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.

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Diagnosis

Clinical examination:

• Fixed mass (eps, if attached to chest wall)
• Overlying skin changes:
  • Orange peeling (peau d’orange)
  • Dimpling
  • Erythema
• Nipple retraction
• Axillary lymphadenopathy
• Breast

Imaging:

• Mammography
• X-ray chest
• CT liver
• Bone scan

https://www.youtube.com/watch?v=zQTw_PVzdOQ

Histopathology (tissue biopsy)

• Techniques:
  • 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.

Staging:

https://www.youtube.com/watch?v=l2lRZuEK4Y0

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Management

Surgical management:

• 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
• 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.

https://www.youtube.com/watch?v=tFpVkTaav_I

Radiation therapy:

• 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.

• Indications:
  1. Adjuvant therapy for early-stage hormone-sensitive breast cancer
  2. 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.
  • Subtypes:
    1. 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.
    2. 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. 

Chemotherapy:

• Cytotoxic drugs: Cyclophosphamide, methotrexate, doxorubicin, and paclitaxel
• Indications:
  • Hormone receptor-negative
  • HER2-positive

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:

• SURGERY:
  • 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)
  • Anastrazole

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