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Female Reproductive System

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.

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)
Mutations In Two. (2019) Breast cancer | McMaster Pathophysiology Review. Retrieved December 31, 2019, from http://www.pathophys.org/breast-cancer/

Epidemiology

  • 5-year survival: 88% in women

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
Mutations In Two. (2019) Breast cancer | McMaster Pathophysiology Review. Retrieved December 31, 2019, from http://www.pathophys.org/breast-cancer/

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

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)
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Pathophysiology

Stages of breast cancer development. Tumour cell initiation and expansion within the mammary ducts characterises atypical ductal hyperplasia (ADH). This progresses to ductal carcinoma in situ (DCIS), which is identified as a complete filling of the mammary duct with tumour cells. Once the myoepithelium is breached and tumour cells escape beyond the mammary duct confinement, the cancer is classified as an invasive ductal carcinoma | Tower, H., Ruppert, M., & Britt, K. (2019). The Immune Microenvironment of Breast Cancer Progression. Cancers . https://doi.org/10.3390/cancers11091375

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

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
Clinical features in breast carcinoma | Mutations In Two. (2019) Breast cancer | McMaster Pathophysiology Review. Retrieved December 31, 2019, from http://www.pathophys.org/breast-cancer/
The Calgary Guide | http://calgaryguide.ucalgary.ca/

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.
Summary of breast cancer organotropic metastases. The site-specific organotropic metastasis is regulated by the breast cancer subtypes, different gene signatures and signaling pathways of metastatic tumor cells. Bone is the most common site of metastatic breast cancer patients, with the second most common site is brain, and liver and lungs are the next | Chen, W., Hoffmann, A. D., Liu, H., & Liu, X. (2018). Organotropism: new insights into molecular mechanisms of breast cancer metastasis. Npj Precision Oncology, 2(1), 4. https://doi.org/10.1038/s41698-018-0047-0

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

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.
(a) Fluorescence in situ hybridization image showing positive results for HER2/neu gene amplification: red signals in clusters of 8–10 and 2 green signals per nucleus. (b) Fluorescence in situ hybridization image showing negative results for HER2/neu gene amplification: 2–3 red signals and 2 green signals per nucleus. (c) Fluorescence in situ hybridization image showing equivocal results for HER2/neu gene amplification: 2–5 red signals and 2 green signals per nucleus | Patil Okaly, G., Panwar, D., Lingappa, K., Kumari, P., Anand, A., Kumar, P., … Kumar, R. (2019). FISH and HER2/neu equivocal immunohistochemistry in breast carcinoma. Indian Journal of Cancer, 56(2), 119–123. https://doi.org/10.4103/ijc.IJC_333_18

Staging:


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.

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)
  • LCISProphylactic bilateral mastectomy can be considered

Invasive breast cancer:

  • SURGERY:
    • Lumpectomy + sentinel node biopsy + radiotherapy
    • Modified radical mastectomy (MRM)
    • If invasion of pectoralis majorRadical mastectomy
  • CHEMOTHERAPY (if nodal metastasis):
    • CAF/CAMF: Cyclophosphamide + Adriamycin/Methotrexate + 5-FU
  • HORMONE THERAPY (if tumour ER/PR+):
    • Oestrogen inhibitors (Tamoxifen, Raloxifene)
    • Anastrazole
The adjuvant therapy options according to the intrinsic subtypes. | Nounou, M. I., ElAmrawy, F., Ahmed, N., Abdelraouf, K., Goda, S., & Syed-Sha-Qhattal, H. (2015). Breast Cancer: Conventional Diagnosis and Treatment Modalities and Recent Patents and Technologies. Breast Cancer : Basic and Clinical Research, 9(Suppl 2), 17–34. https://doi.org/10.4137/BCBCR.S29420

Harbeck, N., Penault-Llorca, F., Cortes, J., Gnant, M., Houssami, N., Poortmans, P., … Cardoso, F. (2019). Breast cancer. Nature Reviews Disease Primers, 5(1), 66. https://doi.org/10.1038/s41572-019-0111-2

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