8. Introduction to Breast Cancer

Introduction to Breast Cancer

• Breast cancer is the most common cancer in women.
• In 2020, there were 2.3 million new cases globally.
• 685,000 deaths were globally.
• Epidemiological significance in 2021: 280,000 invasive, 49,000 non-invasive.
• In the USA, estimated deaths in 2021: 44,000.
• 3.8 million women in the USA have a history of breast cancer.

Learning Outcomes

• Understand the epidemiological significance.
• Recognize anatomical and pathophysiological aspects of breast cancer.
• Evaluate the risk factors.
• Discuss the importance of screening tools and diagnostic procedures for early detection.
• Analyze genetic/molecular profiling in predicting treatment responses.

Overview

• Introduction
• Anatomy and Pathophysiology of Breast Cancer
• Disease Progression and Metastasis
• Risk Factors and Protective Factors of Breast Cancer
• Screening and Diagnosis
• Prognostic and Predictive Factors
• Genetic and Molecular Profiling
• Posttherapy Considerations
• Case Studies and Clinical Applications
• Future Directions and Research Implications

Anatomy and Pathophysiology of Breast Cancer

• Anatomy of the Breast: Composed of glandular tissue, ducts, connective tissue, blood vessels, and lymphatics. Located anterior to the pectoral muscles, extending from the second to sixth rib, and from the sternum to the mid-axillary line.
• Key Structures in the Breast:
  • Glandular tissue: Lobes, lobules, and milk ducts that produce and transport milk.
  • Lymph nodes: Axillary lymph nodes (armpit) drain lymphatic fluid from the breast.
  • Cooper's ligaments: Connective tissue strands providing structural support.
• Breast Cancer Development: Originates in cells lining milk ducts or lobules. Abnormal cells lead to tumour development. Over time, cancer cells invade surrounding tissues and potentially spread via lymphatic or blood vessels.
• Types of Breast Cancer:
  • Ductal Carcinoma (most common), originating in milk duct cells.
  • Lobular Carcinoma, arising from lobules.
  • Other types: Inflammatory breast cancer, Paget's disease.
• Pathophysiology of Breast Cancer:
  • Genetic Mutations: Changes in genes like BRCA1 and BRCA2 increase breast cancer risk.
  • Hormonal Factors: Oestrogen and progesterone receptors play a role in cell growth.
  • HER2/neu Gene: Amplification/overexpression associated with aggressive breast cancers.
• Disease Progression and Metastasis:
  • Breast cancer progresses through stages (localized to regional to metastatic).
  • Metastasis: Cancer cells spread to distant organs (bones, liver, lungs, brain).
  • Process involves invasion of blood vessels or lymphatics, followed by dissemination.
• Inflammatory Breast Cancer (IBC): Rare, aggressive form. Presents with redness, swelling, and warmth of the breast. Characterized by cancer cells blocking lymph vessels.

Disease Progression and Metastasis of Breast Cancer

• Disease Progression: Local, regional, and metastatic breast cancer.
• Metastasis: Spread of cancer cells to distant organs (bones, liver, lung, brain).
• Mechanisms of Metastasis:
  • Invasion: Cancer cells break through the extracellular matrix and basement membrane.
  • Intravasation: Cancer cells enter blood vessels/lymphatics.
  • Circulation: Cancer cells travel through the bloodstream/lymphatic system.
  • Extravasation: Exit the circulation and invade surrounding tissues at metastatic sites.
  • Formation of metastatic tumours: Tumour cell proliferation in distant organs.
• Clinical Implications of Metastasis: Metastatic breast cancer is generally more challenging to treat, often associated with a poorer prognosis. Systemic treatment (chemotherapy, targeted therapy, hormone therapy) may be required.

Risk Factors and Protective Factors of Breast Cancer

• Risk Factors:
  • Genetic Factors: Inherited gene mutations (BRCA1 and BRCA2).
  • Age and Gender: Risk increases with age and is primarily seen in women.
  • Family History: Close relatives with breast cancer.
  • Personal History: Previous breast cancer diagnosis or non-cancerous breast conditions.
  • Hormonal Factors: Prolonged exposure to oestrogen and progesterone, early menstruation, late menopause, hormone replacement therapy (HRT).
  • Lifestyle Factors: Obesity, sedentary lifestyle, alcohol consumption, and tobacco.
  • BRCA1/2 Mutation: BRCA1 estimated lifetime risk 55-72%, BRCA2 45-69%. Germline mutations account for 5-10% of breast cancer cases.
• Genetic Susceptibility: Inherited gene mutations (BRCA1 and BRCA2) significantly increase breast cancer risk. Genetic testing to identify mutations for targeted surveillance and prevention. Other genes (TP53 and PTEN) also contribute to risk.
• Hormonal Influences: Oestrogen and progesterone play critical roles in development. Early menarche and late menopause increase cumulative exposure. HRT after menopause may elevate risk.
• Lifestyle Factors: Obesity, inactivity, alcohol consumption, and smoking may increase breast cancer risk.
• Protective Factors::
  • Early age at first childbirth, longer duration of breastfeeding, and use of oral contraceptives can be protective. Healthy weight and regular physical activity reduce risk. Early first childbirth, multiple pregnancies, and earlier menopause can lower risk.
• Protective Interventions:
  • Chemoprevention: Medications (SERMs, aromatase inhibitors) can reduce risk in high-risk individuals.
  • Lifestyle Modifications: Healthy lifestyle (weight, exercise, alcohol/tobacco) can mitigate risk.

Screening and Diagnosis

• Early Detection: Key to successful treatment.
• Mammography/Ultrasonography: Screening tools.
• Diagnostic Procedures:
  • Biopsy: Gold standard to confirm breast cancer. (Core needle, vacuum-assisted, surgical biopsy).
  • Magnetic Resonance Imaging (MRI): Assess breast cancer extent, lymph involvement, and screen high-risk individuals.
  • Staging: Determines the extent & spread (TNM system).
• Multidisciplinary Approach: Radiologists, pathologists, surgeons, medical oncologists, and radiation oncologists contribute to accurate diagnosis & treatment planning.

Prognostic and Predictive Factors

• Prognostic Factors: Provide info on disease likelihood (recurrence, progression, survival). Includes clinical factors (age, tumour size, lymph node involvement, histological grade) and pathological factors (hormone receptor status, HER2/neu status, lymphovascular invasion).
• Hormone Receptor Status: Oestrogen and progesterone receptors (essential prognostic factors). Hormone receptor-positive breast cancers may benefit from hormone therapies.
• HER2/neu Status: Amplification/overexpression (associated with aggressive disease). Patients with HER2-positive breast cancer may benefit from targeted therapies (e.g., trastuzumab, pertuzumab).
• Histological Grade: Reflects degree of tumour differentiation and aggressiveness (high-grade associated with poorer prognosis compared to low-grade).
• Lymphovascular Invasion: Refers to tumour cell presence within lymphatic or blood vessels (indicates higher risk of metastasis).
• Predictive Factors: Help assess likelihood of response to specific treatments. Molecular profiling and gene expression assays provide valuable information (e.g., Oncotype DX, MammaPrint, Prosigna, Breast Cancer Index, PAM50).
• Treatment Response Prediction: Molecular profiling/gene expression assays predict response to treatments. (e.g., Oncotype DX to guide chemotherapy use for hormone receptor-positive, HER2-negative breast cancers).
• Precision Medicine: Integration of prognostic/predictive factors allows for precision medicine approaches in cancer care. Tailoring treatments improves outcomes.

Genetic and Molecular Profiling

• Genetic Testing: Crucial for identifying inherited mutations (e.g., BRCA1 and BRCA2) that increase breast cancer risk.
• BRCA1 and BRCA2 Mutations: The most well-known genetic mutations; associated with significantly elevated lifetime breast and ovarian cancer risks.
• Implications of BRCA1 and BRCA2 Mutations: Can guide decisions for surgical interventions, targeted therapies, and counselling for family members and use as part of personalized treatment plans.
• Molecular Profiling: Analyzing specific genes and molecular pathways aids in understanding tumour behavior, response to treatment, and prognosis. Examples include Oncotype DX, MammaPrint, Prosigna.
• Gene Expression Assays: Measure gene activity levels in tumour samples to predict recurrence risk and guide treatment decisions. Examples include Breast Cancer Index and PAM50.
• Treatment Decision-Making: Molecular profiling helps determine treatment approach.

Posttherapy Considerations

• Breast Cancer Treatment & Hormonal Changes: Surgery, chemotherapy, and endocrine therapy can lead to hormonal changes, menopausal symptoms, and difficulties.
• Hormone Replacement Therapy (HRT): Can be contraindicated for breast cancer survivors due to concerns of cancer recurrence and risks. (Decisions need individualization).
• Evolving Perspectives on HRT: Decisions to use HRT become individualized according to factors including breast cancer type, patient age, treatment history, and overall health.
• Patient-Centred Care: Emphasize open communication, shared decision-making, tailoring interventions to individual needs/preferences, assessing menopausal symptoms and impact on quality of life, cancer recurrence risk, and overall health status. Personalized interventions are tailored to individual patient needs and preferences.
• Shared Decision-Making & Multidisciplinary Approach: Important for patients undergoing therapies. Collaborations involving multidisciplinary teams (experts such as radiologists, pathologists, surgeons, oncologists, and radiation oncologists) allows for precision medicine.
• Survivorship Programs: Support programs for long-term survivors.

Case Studies and Clinical Applications

• Case Study 1: Genetic Profiling and Targeted Therapy - advanced breast cancer, genetic profiling, targeted therapy selection.
• Case Study 2: BRCA1/BRCA2 Mutation and Risk Management - family history, genetic testing, risk-reducing strategies, heightened surveillance.
• Case Study 3: Molecular Profiling and Treatment Selection - early-stage breast cancer, molecular profile test (MammaPrint or Oncotype DX), influencing treatment decisions.
• Case Study 4: Personalized Treatment Approach - unique characteristics, comprehensive understanding of patient's molecular profile, tailoring therapies.
• Case Study 5: Long-Term Survivorship Care - ongoing genetic and molecular profiling for monitoring disease, optimizing follow-up care (personalized survivorship), and early detection of recurrence

Future Directions and Research Implications

• Precision Medicine in Breast Cancer: Tailoring medical treatments based on factors such as genetic makeup, molecular profiles, and lifestyle factors. Optimizing therapy selection, prediction of treatment response, and personalized survivorship care are priorities.
• Genomic and Molecular Profiling, Liquid Biopsies and ctDNA, Immunotherapy and Targeted Therapies, Artificial Intelligence (AI), Long-Term Survivorship Care, Clinical Trials and Collaborative Research, Ethical Considerations and Patient Empowerment. These are areas of promising investigation in breast cancer research.