Makindo Medical Notes

Introduction

• It is the most common malignancy among women worldwide.
• It arises from the uncontrolled growth of epithelial cells in the ducts or lobules.
• Early detection improves survival rate.

Epidemiology: affects women of all ages but is more prevalent in older age groups:

• Incidence: Approximately 2.3 million new cases diagnosed globally in 2020.
• Mortality: Responsible for over 680,000 deaths worldwide annually.
• Age: Risk increases with age, particularly after 50 years old; most cases occur in women over 70.
• Gender: While predominantly a female disease, male breast cancer accounts for about 1% of all cases.
• Geographic Variation: Higher incidence in developed countries due to lifestyle factors and screening practices.

Risk Factors

Risk Factor	Description	Effect on Breast Cancer Risk
Age	Risk increases with age, especially after 50.	Increases risk
Gender	Significantly more common in women.	Increases risk
Family History	First-degree relatives with breast cancer increase risk.	Increases risk
Genetic Mutations	BRCA1 and BRCA2 mutations markedly elevate risk.	Increases risk
Personal History	Previous breast cancer or certain benign breast conditions.	Increases risk
Reproductive History	Early menarche (<12 years), late menopause (>55 years), nulliparity, or first pregnancy after 30.	Increases risk
Hormone Replacement Therapy (HRT)	Long-term use of combined oestrogen-progestin therapy.	Increases risk
Obesity	Higher body fat increases oestrogen levels post-menopause.	Increases risk
Alcohol Consumption	Regular intake correlates with higher risk.	Increases risk
Radiation Exposure	Prior chest radiation therapy, especially during adolescence.	Increases risk
Physical Activity	Regular exercise helps maintain healthy weight and hormone balance.	Decreases risk
Breastfeeding	Extended breastfeeding reduces risk.	Decreases risk
Diet	Diet rich in fruits, vegetables, and whole grains.	Decreases risk
Avoiding Tobacco	Non-smoking reduces risk of various cancers.	Decreases risk

Pathophysiology: arises from genetic mutations leading to uncontrolled proliferation of epithelial cells in the ducts or lobules:

• Hormonal Influence:
  • Oestrogen and progesterone promote cell division in breast tissue.
  • Overexposure increases the likelihood of mutations during cell replication.
• Genetic Mutations:
  • BRCA1 and BRCA2: Tumour suppressor genes; mutations impair DNA repair mechanisms.
  • p53, PTEN, and others: Additional genes implicated in breast carcinogenesis.
• HER2 Overexpression:
  • HER2 (Human Epidermal growth factor Receptor 2) is a transmembrane receptor tyrosine kinase.
  • Overexpression leads to increased cell proliferation and tumour aggressiveness.
• Environmental Factors:
  • Lifestyle choices and exposures contribute to cumulative risk.

Clinical Presentation: Early-stage breast cancer may be asymptomatic and detected through screening.

• Painless Lump: Most common presenting symptom; may be hard, irregular, and fixed.
• Skin Changes:
  • Dimpling or puckering of the skin (peau d'orange).
  • Redness, scaling, or thickening of the nipple or breast skin.
• Nipple Changes:
  • Inversion or retraction of the nipple.
  • Nipple discharge, possibly bloody or serous.
• Axillary Lymphadenopathy: Swelling or lumps in the underarm area.
• Breast Pain: Less common; pain is usually not a symptom of breast cancer.
• Advanced Disease Symptoms:
  • Bone pain due to metastasis.
  • Shortness of breath from lung involvement.
  • Jaundice indicating liver metastasis.
  • Neurological symptoms if the brain is affected.

Differential Diagnosis

• Fibroadenoma: Benign, mobile, firm lumps common in younger women.
• Fibrocystic Changes: Lumpy or rope-like breast tissue, often cyclical with menstrual cycle.
• Breast Cysts: Fluid-filled sacs; can be tender and fluctuate with hormonal changes.
• Breast Infection (Mastitis) or Abscess: Painful, swollen areas with possible redness and warmth; more common during breastfeeding.
• Fat Necrosis: Firm lumps resulting from injury to fatty breast tissue.
• Intraductal Papilloma: Small benign tumours within the milk ducts causing discharge.

Diagnostic Evaluation: A thorough workup is essential for accurate diagnosis and staging.

Imaging Studies

• Mammography:
  • Primary screening tool for women over 40 or earlier in high-risk individuals.
  • Detects calcifications, masses, and architectural distortions.
• Ultrasound:
  • Useful in evaluating palpable masses, especially in women under 30 with dense breast tissue.
  • Distinguishes cystic from solid lesions.
• Magnetic Resonance Imaging (MRI):
  • Highly sensitive; used for high-risk screening, assessing implant integrity, and evaluating extent of disease.
  • Beneficial in cases of lobular carcinoma or when mammography is inconclusive.

Tissue Sampling: Histopathological confirmation is essential:

• Core Needle Biopsy:
  • Preferred method; provides sufficient tissue for histologic and receptor analysis.
• Fine Needle Aspiration (FNA):
  • Less invasive but provides cytology only; may be inadequate for definitive diagnosis.
• Excisional Biopsy: Complete removal of the lesion; used when needle biopsy is inconclusive.
• Sentinel Lymph Node Biopsy:
  • Assesses regional lymph node involvement.

Histopathological Analysis

Determines the type, grade, and receptor status:

• Types of Breast Cancer:
  • Invasive Ductal Carcinoma (IDC): Accounts for 70-80% of cases; originates in milk ducts.
  • Invasive Lobular Carcinoma (ILC): Represents 10-15% of cases; originates in lobules.
  • Ductal Carcinoma In Situ (DCIS): Non-invasive precursor to invasive cancer.
  • Other Types: Includes inflammatory breast cancer, Paget's disease of the nipple.
• Grade: Assessed based on tubule formation, nuclear pleomorphism, and mitotic rate (Nottingham grading system).
• Receptor Status:
  • Oestrogen Receptor (ER) and Progesterone Receptor (PR): Hormone receptor-positive cancers respond to endocrine therapy.
  • HER2 Status: Overexpression indicates potential benefit from HER2-targeted therapies.
  • Triple-Negative Breast Cancer (TNBC): Lacks ER, PR, and HER2 expression; often more aggressive with limited targeted therapy options.

Staging: guides treatment decisions and prognostication:

• Tumour-Node-Metastasis (TNM) System:
  • T (Tumour Size): Size and extent of the primary tumour.
  • N (Node Involvement): Regional lymph node involvement.
  • M (Metastasis): Presence of distant metastasis.
• Stage Grouping: Stages I to IV based on TNM classifications.
• Additional Investigations for Staging:
  • Blood Tests: Complete blood count (CBC), liver and renal function tests.
  • Imaging: Chest X-ray, liver ultrasound, bone scan, PET/CT scans if metastasis is suspected.

Treatment: involves surgery, radiation therapy, systemic therapies, and supportive care.

Surgical Management

• Breast-Conserving Surgery (Lumpectomy):
  • Removal of the tumour with clear margins.
  • Usually followed by radiation therapy.
• Mastectomy:
  • Total removal of breast tissue.
  • Options include skin-sparing and nipple-sparing mastectomy.
  • May be preferred for larger tumours, multicentric disease, or patient choice.
• Axillary Surgery:
  • Sentinel Lymph Node Biopsy: Minimally invasive; assesses first draining lymph nodes.
  • Axillary Lymph Node Dissection: Removal of multiple lymph nodes; higher risk of lymphedema.
• Reconstructive Surgery:
  • Can be immediate or delayed.
  • Options include implants or autologous tissue reconstruction.

Radiation Therapy: eliminate residual cancer cells post-surgery and reduce recurrence risk:

• Indicated after breast-conserving surgery.
• May be used after mastectomy in cases with large tumours or lymph node involvement.
• Techniques include external beam radiation and brachytherapy.

Systemic Therapy: Systemic treatments target cancer cells throughout the body:

Chemotherapy

• Recommended for:
  • High-risk early-stage cancers (large tumour size, positive nodes).
  • Triple-negative breast cancer.
  • HER2-positive cancers (in combination with targeted therapy).
• Common regimens include anthracyclines, taxanes, and cyclophosphamide.

Hormone (Endocrine) Therapy

• For ER and/or PR-positive cancers.
• Options include:
  • Selective Oestrogen Receptor Modulators (SERMs): Tamoxifen; used in pre- and postmenopausal women.
  • Aromatase Inhibitors (AIs): Anastrozole, letrozole, exemestane; used primarily in postmenopausal women.
  • Ovarian Suppression: Gonadotropin-releasing hormone (GnRH) analogues or oophorectomy in premenopausal women.
• Typically administered for 5-10 years depending on risk factors.

Targeted Therapy

• For HER2-positive cancers.
• Agents include:
  • Trastuzumab (Herceptin): Monoclonal antibody targeting HER2 receptors.
  • Pertuzumab: Used in combination with trastuzumab and chemotherapy.
  • Adotrastuzumab Emtansine (T-DM1): Antibody-drug conjugate for metastatic disease.
  • Lapatinib: Tyrosine kinase inhibitor used in advanced cases.
• Cardiac monitoring is essential due to potential cardiotoxicity.

Immunotherapy

• Emerging role in triple-negative breast cancer.
• Immune Checkpoint Inhibitors: Pembrolizumab in combination with chemotherapy.

Prognosis: depends on stage at diagnosis, tumour biology, and response to treatment:

• Early-Stage Disease: 5-year survival rates exceed 90% when detected early.
• Advanced Disease: Prognosis is poorer; median survival for metastatic breast cancer is about 2-3 years, but varies widely.
• Factors Influencing Prognosis:
  • Tumour size and grade.
  • Lymph node involvement.
  • Receptor status (ER, PR, HER2).
  • Proliferation indices (e.g., Ki-67).
  • Patient's overall health and comorbidities.

Follow-Up and Survivorship

• Regular Clinical Evaluations: Every 3-6 months for the first 2-3 years, then annually.
• Imaging Studies: Annual mammography of the preserved breast or contralateral breast if mastectomy performed.
• Management of Treatment Effects:
  • Lymphedema prevention and management.
  • Cardiac monitoring for those who received cardiotoxic agents.
  • Bone health evaluation, especially with aromatase inhibitors.
• Psychosocial Support: Counselling, support groups, and resources for coping with cancer survivorship.
• Lifestyle Modifications: Encouragement of healthy diet, regular exercise, and smoking cessation.

Prevention and Screening

• Mammography Screening: Recommended every 1-2 years for women aged 40-74, depending on guidelines and risk factors.
• Breast Awareness: Educating women on normal breast appearance and feel to facilitate early recognition of changes.
• Genetic Counselling and Testing: For those with family history suggestive of hereditary breast cancer syndromes.
• Risk-Reducing Strategies:
  • Prophylactic mastectomy or oophorectomy in high-risk individuals.
  • Chemoprevention with SERMs or AIs in select populations.

Conclusion

• Breast cancer management requires a comprehensive, multidisciplinary approach tailored to individual patient needs.
• Advances in early detection, molecular characterization, and targeted therapies have significantly improved patient outcomes.
• Ongoing research continues to refine treatment strategies and explore novel therapeutic options.

References

• American Cancer Society. Cancer Facts & Figures 2021. American Cancer Society; 2021.
• National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2021.
• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
• Gradishar WJ, Anderson BO, Abraham J, et al. Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(4):452-478.
• Harbeck N, Penault-Llorca F, Cortes J, et al. Breast cancer. Nat Rev Dis Primers. 2019;5(1):66.
• Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(8):1194-1220.