Precision Medicine Notes

Precision Medicine (Personalized Cancer Therapy)

Traditional Cancer Treatment: "One-Size-Fits-All"

• Concept: A single treatment is used to treat multiple types of cancer.

• Example: Patients with breast cancer all receive the same treatment.

Cancer Heterogeneity

• Each patient's tumor has unique genetic and molecular features.

• Example: Breast cancer subtypes include:

  • Estrogen Receptor positive (ER+): 6 in 10 cases.

  • HER2 positive (HER2+): 2 in 10 cases.

  • Triple-Negative Breast Cancer (TNBC): 2 in 10 cases.

• Genetic distinctions:

  • ER+ may have BRCA1 mutation (10-20%).

  • TNBC: BRCA1 mutation is most common.

• Treatments vary based on subtypes:

  • Hormonal therapy for ER+.

  • HER2 targeting therapy.

  • PARP inhibitors for BRCA1 mutated cancers.

Limitations of "One-Size-Fits-All" Cancer Therapy

• Ineffective due to cancer heterogeneity.

• Ignores genetic and molecular diversity of tumors.

• Leads to acquired drug resistance.

• Causes unnecessary side effects.

• Example illustrating resistance:

  • Primary TNBC tumors exhibit intrinsic resistance to chemotherapy.

  • Treatment cycles lead to dead cancer cells, but also drug-tolerant persister cells and cancer stem cells, causing acquired resistance.

Traditional Treatment vs. Precision Medicine

• Traditional:

  • Patients with breast cancer receive the same treatment.

• Precision Medicine:

  • DNA analysis leads to individualized treatment.

Precision Medicine: Next Generation Cancer Therapy

• Goal: Select the most effective treatment by analyzing an individual's unique genetic and molecular characteristics.

• This patient-centered approach:

  • Profiles the DNA of cancer cells to identify genetic mutations driving tumor's growth, delivering personalized therapy.

  • Addresses cancer heterogeneity and drug resistance.

Components of Precision Medicine

• Precision diagnosis considers genetics and family history.

• Precise understanding facilitates precise therapy.

• Advancement of clinical genomics:

  • Profiling entire genetic sequence.

  • Innovations in analyzing genetic information.

  • New tools (e.g., AI) to predict cancer risk and tailor treatments.

Precision Medicine in Action - Genomics

• Case Study: Anna, a 60-year-old with Triple-Negative Breast Cancer (TNBC).

• Genomic testing identified BRCA1 gene mutation.

• BRCA1:

  • A tumor suppressor that helps repair damaged DNA.

  • Mutation inhibits the ability of cells to repair DNA damage, leading to rapid cell growth and tumor formation.

• Mechanism:

  • In healthy cells, BRCA1, PALB2, BRCA2, and RAD51 form a complex to repair DNA double-strand breaks (DSB).

  • With BRCA1 mutation (or loss), this repair mechanism is inhibited.

PARP inhibitors

• PARP inhibitors are FDA-approved for treating cancers with BRCA mutations.

• Mechanism:

  • Normal cells use PARP1 to repair single-strand DNA breaks.

  • PARP inhibitors block this repair pathway.

  • In cells with BRCA1/2 mutations (HR-Deficiency), double-strand DNA break repair is disrupted, leading to cell death.

Personalized Treatment Plan for Anna

• Surgery, followed by chemotherapy + PARP inhibitor (targeted therapy).

Precision Medicine in Action - Family History

• Breast cancer can be inherited (5-10% of cases).

• Key inherited genes involved in DNA damage repair:

  • BRCA1 and BRCA2.

  • TP53.

  • PTEN.

• Inherited genetic mutations are passed down from parents in an autosomal dominant manner.

• Examples of Hereditary Cancers:

  • Hereditary Breast/Ovarian syndrome (BRCA1, BRCA2) linked to breast, ovarian, prostate, and pancreatic cancers.

  • Lynch Syndrome (DNA mismatch repair genes) linked to colorectal cancer.

  • Familial adenomatous polyposis (FAP) (APC gene) linked to colorectal cancer.

  • Li-Fraumeni syndrome (TP53) linked to breast cancer.

Genomic Testing vs. Hereditary Testing

• Genomic tumor testing:

  • Analyzes genetic changes in cancer cells to guide treatment options.

• Hereditary genetic testing:

  • Identifies inherited mutations that increase cancer risk.

Key Differences Between Genomic and Hereditary Testing

• Genomic tumor testing:

  • Focuses on acquired mutations isolated to the tumor cell.

  • Mutations are due to exposures (UV, chemicals).

  • Cannot be passed on.

• Hereditary genetic testing:

  • Focuses on inherited mutations present in every cell of the body (blood cell or saliva).

  • Can be passed on from parent to child.

  • Example: Tumor suppressor BRCA: increased cancer risk, reduced defense against external exposures.

Anna's Hereditary Genetic Testing Results

• Germline BRCA2 mutation.

• Implications:

  • Anna has a possible risk of developing another cancer.

  • Anna's daughter or other family members could be at an increased risk of developing cancer.

Genomics as a Key Technology Driving Precision Medicine

• Genomic tumor testing:

  • Identifies mutations in a tumor.

  • Provides evidence for the design of targeted therapy.

• Hereditary genetic testing:

  • Identifies mutations in every cell inherited from parents.

  • Identifies individuals at high risk of cancer.

  • Provides evidence for screening and prevention.

Summary

1. Cancer heterogeneity is a main reason for developing precision medicine, which replaces the traditional "one-size-fits all".

2. Precision medicine is transforming cancer therapy by providing targeted solutions to complex challenges:

   • Cancer heterogeneity: Tailoring treatments to the unique genetic makeup of each tumor.

   • Drug resistance: Identifying specific mutations and adapting treatments accordingly.

3. Precision medicine utilizes genomic profiling of a tumor to identify targetable mutations and select appropriate therapies; and uses genetic testing to identify inherited mutations that may increase an individual's inherited risk to certain cancers.

   • By combining these two approaches, precision medicine aims to provide a more comprehensive and personalized strategy for cancer prevention, diagnosis, and treatment.