What is the pathophysiology and management of cancer?

Pathophysiology and Management of Cancer

Cancer is characterized by uncontrolled proliferation of cells that have evaded normal endogenous control mechanisms through sequential acquisition of genetic mutations, resulting in altered cell growth, differentiation, and survival mechanisms that must be targeted through multimodal therapy approaches. 1, 2

Cancer Pathophysiology

Genetic Basis

Cancer is fundamentally a genetic disease where normal cells undergo progressive transformation to malignancy through sequential acquisition of mutations. These mutations affect two main classes of growth-regulatory genes:

1. Oncogenes: Function as positive growth regulators that become hyperactivated
2. Tumor suppressor genes: Function as negative growth regulators that become inactivated 3

The accumulation of these genetic alterations leads to:

• Irregular cell differentiation
• Excessive proliferation
• Uncontrolled growth
• Invasion of nearby tissues
• Spread to distant organs (metastasis) 4

Molecular Mechanisms of Cancer Development

Cancer cells develop through several key processes:

• Genetic alterations: Mutations arise from:

  • Endogenous processes (DNA replication errors, chemical instability of DNA bases)
  • Exogenous agents (radiation, chemical carcinogens) 2

• Cellular transformation: Involves:

  • Epigenetic and proliferative changes
  • Development of new blood vessels (angiogenesis)
  • Vascular invasion 5

• Metastatic process: For brain metastases, involves:

  • Traversing the blood-brain barrier
  • Adhesion to brain endothelia through upregulation of specific genes
  • Interaction with brain cells to promote tumor cell survival
  • Formation of tumor-astrocyte gap junctions 5

Hallmarks of Cancer Progression

The progression from normal cell to malignant cell requires:

1. Activation of genes stimulating proliferation (oncogenes)
2. Inactivation of genes inhibiting proliferation (tumor suppressor genes)
3. Overcoming replicative senescence (becoming immortal)
4. Obtaining adequate nutrient and oxygen supply 2

Cancer Management

Cancer management requires a comprehensive approach targeting the disease at multiple levels:

1. Diagnostic Evaluation

• Pathologic assessment: Critical for determining:

  • Disease extent and biologic features
  • Tumor histology and grade
  • Biomarkers (e.g., hormone receptors, HER2 status in breast cancer)
  • Lymphovascular invasion
  • Surgical margins
  • Lymph node status 5

• Molecular profiling: Increasingly important for:

  • Determining molecular characteristics
  • Identifying targetable mutations
  • Guiding precision medicine approaches 5

2. Treatment Modalities

Surgery

• Primary treatment for localized disease
• Goals include:
  • Complete tumor removal with clear margins
  • Staging through lymph node assessment
  • Reducing tumor burden 5

Radiation Therapy

• Used in approximately 50% of all cancer patients
• Contributes to 40% of curative cancer treatments
• Primary goal: Deprive cancer cells of their multiplication potential
• Can be used:
  • As primary treatment
  • Adjuvantly after surgery
  • For palliation of symptoms 6

Systemic Therapy

A. Chemotherapy

• Mechanism: Interferes with rapidly proliferating malignant cells
• Example: Cyclophosphamide
  • Acts through cross-linking tumor cell DNA
  • Biotransformed in liver to active alkylating metabolites
  • Used in multiple malignancies including lymphomas, leukemias, breast cancer 7

B. Endocrine Therapy

• Particularly important in hormone-dependent cancers (e.g., breast cancer)
• Based on hormone receptor status (ER/PR) 5

C. Targeted Therapy

• Directed at specific molecular alterations
• Examples:
  • HER2-targeted therapy in breast cancer
  • EGFR inhibitors in lung cancer 5

D. Immunotherapy

• Enhances the body's immune response against cancer cells 6

3. Supportive Care

Management of Cancer Cachexia

• A complex metabolic syndrome characterized by weight loss, reduced muscle mass
• Staged as precachexia, cachexia, and refractory cachexia
• Interventions include:
  • Nutritional support
  • Pharmacologic interventions
  • Exercise programs 5

4. Treatment Selection Considerations

Treatment decisions should be based on:

• Tumor characteristics (histology, stage, molecular features)
• Patient factors (performance status, comorbidities)
• Prognostic indices (e.g., DS-GPA for brain metastases) 5

Special Considerations in Specific Cancers

Breast Cancer

• 85-90% of invasive carcinomas are ductal in origin
• Treatment includes local therapy (surgery, radiation) and systemic therapy
• Critical to determine ER, PR, and HER2 status for treatment planning
• Treatment selection based on disease stage, biomarkers, and patient factors 5

Lung Cancer

• Molecular profiling increasingly important (e.g., EGFR, ALK alterations)
• "Oncogene addiction" concept guides targeted therapy approaches
• Synoptic reporting of pathologic features recommended 5

Future Directions

The rapid technological advances in molecular biology are enabling:

• More precise diagnostics
• More effective and less toxic therapies
• Personalized treatment approaches based on individual tumor characteristics
• Development of engineered therapeutic approaches 1, 4

Cancer management continues to evolve toward precision medicine, with treatment increasingly tailored to the specific molecular characteristics of each patient's tumor, aiming to improve survival and quality of life while reducing treatment side effects.