Outline of disease process

Question 1

Describe the principles of ‘staging’ in cancer.

Answer 1

Staging in cancer refers to the process of determining the extent of the spread of cancer in the body. It helps guide treatment decisions, predict outcomes, and assess prognosis. The stage of cancer is typically determined by evaluating the size of the tumor, how deeply it has invaded surrounding tissues, whether it has spread to nearby lymph nodes, and whether it has metastasized to distant organs.

The main principles of staging include:

1. Tumor Size and Local Invasion (T)
   T stands for the primary tumor. It describes the size of the tumor and how far it has grown into surrounding tissues. This is usually broken down into categories like:
   T1: Small tumor, limited in size.
   T2: Larger tumor, but still confined to the primary site.
   T3: Tumor has grown into surrounding tissues but not distant organs.
   T4: Tumor has grown deeply into surrounding structures or organs.
2. Lymph Node Involvement (N)
   N refers to the regional lymph nodes, which are groups of immune cells that filter lymph fluid and can harbor cancer cells.
   The stage is based on whether and how many lymph nodes are affected:
   N0: No regional lymph node involvement.
   N1–N3: Increasing extent of regional lymph node involvement (e.g., number and/or size of affected nodes).
3. Metastasis (M)
   M refers to the presence or absence of distant metastasis, meaning whether cancer has spread to other organs or parts of the body, far from the original tumor site.
   M0: No distant metastasis.
   M1: Cancer has spread to distant organs or tissues (e.g., liver, lungs, bones).
4. The TNM System
   The most commonly used cancer staging system is the TNM system, where:

T: Tumor size and extent.
N: Lymph node involvement.
M: Distant metastasis.
Each of these components is given a numerical value or descriptor (e.g., T1, T2, N0, N1, M0) to create a stage for the cancer, which is usually categorized into 0-4:

Stage 0: In situ (localized, no spread).
Stage I: Early stage, limited to the organ of origin.
Stage II: Larger tumor or regional lymph node involvement but no distant spread.
Stage III: More extensive regional spread, often to lymph nodes.
Stage IV: Distant metastasis (advanced stage).
5. Other Factors
Histological Grade: How abnormal the cancer cells look under a microscope; this gives an idea of how aggressive the cancer might be.
Biomarkers: Some cancers are staged more precisely by evaluating specific genetic or molecular markers.
6. Staging Systems for Specific Cancer Types
Different cancers may have variations in the way staging is defined, especially in regard to unique characteristics of the cancer’s spread or location. For example, staging in breast cancer often includes hormone receptor status, HER2 status, and other factors beyond just tumor size or lymph node involvement.
In addition to TNM, there are specialized staging systems used for certain cancers (e.g., the Ann Arbor staging system for lymphoma).

Why Staging Matters
Treatment Planning: The stage helps doctors decide on treatment options (e.g., surgery, chemotherapy, radiation).
Prognosis: Knowing the stage helps predict how likely the cancer is to respond to treatment or recur.
Clinical Trials: Staging is crucial for determining eligibility for clinical trials or experimental treatments.

Question 2

Explain the importance of genetic changes in cancer.

Answer 2

1. Mutations Drive Cancer Development
   Cancer is primarily caused by genetic mutations that affect the normal processes that regulate cell growth and division. These mutations can occur in oncogenes, tumor suppressor genes, and DNA repair genes, each of which plays a crucial role in maintaining cellular homeostasis.

Oncogenes: These are genes that, when mutated or overexpressed, can drive the uncontrolled growth of cells. In their normal state, oncogenes promote cell division and survival, but mutations can turn them into “drivers” of cancer.
Example: The HER2 gene in some breast cancers, or the RAS gene in various cancers like lung and colon cancer.
Tumor Suppressor Genes: These genes act as the body’s “brakes” for cell growth, repair damaged DNA, and ensure normal cell function. When tumor suppressor genes are mutated or inactivated, cells can grow uncontrollably and accumulate additional mutations.
Example: TP53 (the p53 gene) is a critical tumor suppressor, often called the “guardian of the genome.” Mutations in TP53 are found in over half of all human cancers.
DNA Repair Genes: These genes are responsible for fixing errors that occur in the DNA during cell division. If DNA repair mechanisms are defective, genetic mutations accumulate at an accelerated rate, contributing to cancer development.
Example: Mutations in the BRCA1 and BRCA2 genes, which impair DNA repair, are associated with an increased risk of breast and ovarian cancers.
2. Genetic Mutations and Cancer Types
The genetic changes driving cancer vary across different types of cancer, and they can be somatic (acquired mutations) or germline (inherited mutations).

Somatic Mutations: These mutations occur during a person’s lifetime and are not inherited. They accumulate in specific cells due to environmental factors (e.g., smoking, UV radiation, exposure to carcinogens) or random errors in DNA replication. Most cancers are driven by somatic mutations.

Example: A KRAS mutation in lung or colorectal cancer can arise due to environmental exposures, such as smoking.
Germline Mutations: These are inherited genetic mutations present in the egg or sperm and are passed down from parents to offspring. Germline mutations predispose individuals to certain cancers, and people with these mutations are at a higher risk of developing cancer over their lifetime.

Example: Inherited mutations in BRCA1 or BRCA2 genes increase the risk of breast and ovarian cancers.
3. Genetic Heterogeneity and Tumor Evolution
Cancer is genetically heterogeneous, meaning that different cells within the same tumor can have different mutations. This genetic diversity within a tumor complicates treatment, as some cancer cells may be resistant to therapy due to the presence of specific mutations.

Over time, tumors can evolve as cancer cells accumulate more mutations, enabling them to adapt to changing environments (such as resistance to treatment or the immune system). This process of clonal evolution can make cancer more aggressive and harder to treat.

Example: In lung cancer, a mutation in the EGFR gene may initially make the tumor responsive to targeted therapy, but over time, the tumor can acquire additional mutations (like T790M) that confer resistance to the drug.
4. Targeted Therapies Based on Genetic Changes
Understanding the genetic changes in a cancer can lead to more personalized treatment approaches. Targeted therapies are drugs designed to specifically target the molecular abnormalities found in cancer cells, with the aim of treating the cancer while minimizing damage to normal cells.

Targeted therapies exploit specific mutations that drive cancer growth. For instance, in cancers with mutations in EGFR (e.g., non-small cell lung cancer), drugs like erlotinib or gefitinib can specifically inhibit the mutant EGFR protein.
Immunotherapies also benefit from genetic knowledge. Tumors that express high levels of specific genetic markers like PD-L1 can be treated with checkpoint inhibitors (e.g., pembrolizumab), which block the tumor’s ability to evade the immune system.
5. Genetic Testing and Cancer Risk
Genetic testing can help identify individuals at high risk of developing certain cancers due to inherited mutations. This is particularly important for hereditary cancer syndromes, where families may share genetic mutations that significantly increase cancer risk.

For example, people with hereditary breast and ovarian cancer syndrome due to mutations in the BRCA1 or BRCA2 genes can be monitored more closely, and preventive measures (like prophylactic surgery or increased screening) can be recommended.
6. Genomic Medicine and Cancer Research
The field of genomics has revolutionized cancer research and treatment. Comprehensive genomic profiling of tumors allows doctors to identify specific genetic mutations driving an individual’s cancer. This can:

Help predict how a cancer will behave (e.g., how aggressive it is, whether it is likely to metastasize).
Provide insights into potential drug targets and biomarkers for treatment.
Enable clinical trials to be tailored to specific genetic alterations, accelerating the development of new therapies.
Next-generation sequencing (NGS) technologies have made it possible to sequence large numbers of genes and identify mutations in a patient’s tumor in a relatively quick and cost-effective way.

7. Epigenetics and Cancer
   In addition to changes in the DNA sequence itself (mutations), epigenetic changes can also play a crucial role in cancer. Epigenetics refers to modifications to DNA or histones that affect gene expression without altering the underlying DNA sequence. These changes can silence tumor suppressor genes or activate oncogenes, contributing to cancer development.

DNA methylation and histone modification are two common forms of epigenetic regulation. Abnormal epigenetic changes can lead to the activation of oncogenes or the silencing of tumor suppressor genes, facilitating the growth and spread of cancer.
Conclusion
Genetic changes are central to the pathogenesis of cancer. They can drive the initiation, progression, and spread of cancer by disrupting normal cell function, and they shape the response to treatment. Understanding these genetic changes not only helps in diagnosing and classifying cancer but also provides opportunities for personalized treatments, better risk assessment, and more effective prevention strategies. As research advances, the hope is that genetic insights will continue to lead to innovative therapies that are more effective and less toxic than traditional treatments.

Question 3

Describe modalities of therapy currently available.

Answer 3

1. Surgery
   Description: Surgery involves the physical removal of a tumor or cancerous tissue. It is often the first-line treatment for cancers that are localized and accessible for surgical removal.
   Purpose: To remove the tumor, potentially cure the cancer (if it is localized and hasn’t spread), or reduce tumor burden to make other therapies more effective.
   Types:
   Curative surgery: Removes the entire tumor in early-stage cancers.
   Debulking surgery: Removes part of the tumor to alleviate symptoms or make other treatments more effective.
   Palliative surgery: Used to relieve symptoms in advanced cancers, such as obstruction or bleeding, but does not cure the disease.
   Example: Removal of a breast tumor (lumpectomy) in early-stage breast cancer or removing a colon tumor in colorectal cancer.
2. Radiation Therapy (Radiotherapy)
   Description: Radiation therapy uses high-energy rays (like X-rays) or particles (like protons) to damage the DNA inside cancer cells, causing them to die or stop dividing.
   Purpose: To kill or shrink tumors, control local disease, and manage symptoms such as bleeding, pain, or obstruction in advanced cancer.
   Types:
   External beam radiation: Focused radiation delivered from outside the body to the tumor.
   Internal radiation (Brachytherapy): Radioactive material is placed directly inside or near the tumor.
   Systemic radiation: Radioactive substances are injected into the body, and they target cancer cells throughout the body (e.g., radioisotopes).
   Example: Radiation to treat prostate cancer, brain tumors, or to shrink a tumor before surgery.
3. Chemotherapy
   Description: Chemotherapy uses cytotoxic drugs to kill or inhibit the growth of cancer cells. These drugs typically target fast-growing cells, which includes both cancerous and some normal cells.
   Purpose: To destroy cancer cells, shrink tumors, prevent metastasis, or make other therapies (e.g., surgery or radiation) more effective.
   Mechanism: Chemotherapy can kill cancer cells by interfering with their ability to divide or by damaging their DNA, leading to cell death.
   Administration: Can be administered orally (pills), intravenously (IV), or directly into the tumor.
   Example: Common chemotherapy drugs include cisplatin, paclitaxel, and methotrexate. They are used in cancers like breast, lung, colon, and ovarian cancer.
4. Targeted Therapy
   Description: Targeted therapies are designed to specifically target molecular changes (mutations, overexpressed proteins) that are driving the growth of cancer cells. These therapies are more selective than chemotherapy and aim to minimize damage to healthy cells.
   Purpose: To block specific pathways that cancer cells need to grow and survive, leading to their death or inhibiting their growth.
   Mechanism: Targeted therapies can act on specific proteins, genes, or tumor vasculature.
   Types:
   Monoclonal antibodies: Lab-created antibodies that target specific antigens on cancer cells or blood vessels supplying tumors.
   Small molecule inhibitors: Drugs that block the activity of proteins involved in cancer cell growth (e.g., kinase inhibitors).
   Cancer vaccines: Designed to stimulate the immune system to recognize and attack cancer cells.
   Example:
   Herceptin (trastuzumab) for HER2-positive breast cancer.
   Imatinib (Gleevec) for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs).
   Targeted immunotherapies like bevacizumab (Avastin), which targets blood vessel growth in tumors.
5. Immunotherapy
   Description: Immunotherapy aims to harness the body’s own immune system to recognize and attack cancer cells. It works by boosting the immune response or by targeting immune checkpoints that allow cancer cells to evade immune detection.
   Types:
   Checkpoint inhibitors: Block checkpoints (like PD-1/PD-L1 or CTLA-4) that prevent immune cells from attacking cancer cells.
   Monoclonal antibodies: Can be used to either stimulate the immune system or directly target cancer cells for destruction.
   Cancer vaccines: Stimulate the immune system to recognize and target cancer-specific antigens.
   Adoptive cell transfer (ACT): Involves modifying a patient’s immune cells (e.g., T-cells) to better target cancer.
   Cytokine therapy: Uses substances like interleukins or interferons to boost the immune response.
   Example:
   Pembrolizumab (Keytruda) and nivolumab (Opdivo), PD-1 inhibitors used in melanoma, lung cancer, and others.
   CAR-T cell therapy (e.g., Kymriah) for certain leukemias and lymphomas.
   BCG vaccine for bladder cancer, which stimulates an immune response.
6. Hormone Therapy
   Description: Hormone therapy blocks or lowers the levels of hormones (like estrogen or testosterone) that fuel certain cancers, especially those of the breast, prostate, or endometrium.
   Purpose: To treat hormone-sensitive cancers by preventing the hormone from binding to its receptor on cancer cells or by lowering hormone production.
   Types:
   Anti-estrogens (e.g., tamoxifen) block estrogen from binding to its receptor in breast cancer.
   Aromatase inhibitors (e.g., letrozole) reduce estrogen production.
   Androgen deprivation therapy (ADT): Lowers testosterone levels in prostate cancer (e.g., leuprolide).
   Selective estrogen receptor degraders (SERDs) and anti-androgens for targeted action on hormone receptors.
   Example: Tamoxifen and aromatase inhibitors in breast cancer; leuprolide and bicalutamide in prostate cancer.
7. Stem Cell Transplantation
   Description: Stem cell transplant (also known as bone marrow transplant) is used to replace damaged or destroyed bone marrow with healthy stem cells. It is typically used after high-dose chemotherapy or radiation therapy that destroys bone marrow.
   Purpose: To restore the body’s ability to produce healthy blood cells after intensive cancer treatment, especially in cancers like leukemia, lymphoma, and multiple myeloma.
   Types:
   Autologous transplant: Uses the patient’s own stem cells.
   Allogeneic transplant: Uses stem cells from a donor, which may involve a sibling, unrelated donor, or cord blood.
   Example: Used in leukemias, lymphomas, and myeloma.
8. Precision Medicine and Genomic-Based Therapy
   Description: Precision medicine involves tailoring treatments based on the genetic profile of an individual’s tumor or the specific mutations driving the cancer.
   Purpose: To provide more personalized treatments that target the molecular abnormalities specific to the patient’s cancer, enhancing efficacy and minimizing side effects.
   Example:
   Next-generation sequencing (NGS) to identify actionable mutations (e.g., EGFR mutations in lung cancer, BRAF mutations in melanoma).
   Therapies targeting genetic mutations, such as EGFR inhibitors (erlotinib, osimertinib) in non-small cell lung cancer or PARP inhibitors (e.g., olaparib) in BRCA-mutant cancers.
9. Palliative Care
   Description: Palliative care is a comprehensive approach to improve the quality of life for patients with advanced cancer, focusing on symptom management and emotional support.
   Purpose: To manage pain, nausea, fatigue, and other symptoms related to cancer or its treatment, and to help patients cope with the psychological and social impact of cancer.
   Example: Use of painkillers, anti-nausea medications, and counseling for emotional support.