What are the key cancer molecules to know for step 1 in understanding cancer therapy, including those targeted by drugs like trastuzumab (Herceptin) (trastuzumab), erlotinib (Tarceva) (erlotinib), vemurafenib (Zelboraf) (vemurafenib), and pembrolizumab (Keytruda) (pembrolizumab)?

Key Cancer Molecules for Step 1 Understanding

The most important cancer molecules to know for Step 1 are HER2, EGFR, BRAF V600E, PD-1/PD-L1, and MSI-H/dMMR, as these are targeted by FDA-approved therapies that significantly improve patient survival.

Key Molecular Targets and Associated Therapies

1. HER2 (Human Epidermal Growth Factor Receptor 2)

• Mechanism: Tyrosine kinase receptor that regulates cell growth and repair 1
• Cancer association: Overexpressed in ~25% of breast cancers and some gastric cancers 1
• Targeted therapy: Trastuzumab (Herceptin)
• Clinical significance:
  • Reduces recurrence by 50% and mortality by 33% in HER2+ breast cancer 1
  • Cardiotoxicity risk: 1.7-4.1% HF when used alone; up to 27% when combined with anthracyclines 1
  • Testing method: IHC or FISH (preferred for accuracy) 1

2. EGFR (Epidermal Growth Factor Receptor)

• Mechanism: Tyrosine kinase receptor overexpressed in 40-80% of NSCLC 1
• Cancer association: Activating mutations in exons 18-21 of tyrosine kinase domain 1
• Targeted therapy: Erlotinib (Tarceva)
• Clinical significance:
  • Response rates ~70% in EGFR mutant lung adenocarcinoma 1
  • More common in Asian populations (20-40%) than whites (5-20%) 1
  • Mutations in exon 20 (T790M) confer resistance to EGFR TKIs 1

3. BRAF V600E

• Mechanism: Constitutively activated BRAF protein causing cell proliferation without growth factors 2
• Cancer association: Common in melanoma
• Targeted therapy: Vemurafenib (Zelboraf)
• Clinical significance:
  • Low molecular weight inhibitor of mutated BRAF serine-threonine kinase 2
  • Also inhibits CRAF, ARAF, wild-type BRAF, and other kinases 2
  • Can cause QTc prolongation (concentration-dependent) 2

4. PD-1/PD-L1 (Programmed Death-1 and its Ligand)

• Mechanism: Immune checkpoint proteins that suppress T-cell activity
• Cancer association: Expression in multiple cancer types
• Targeted therapy: Pembrolizumab (Keytruda)
• Clinical significance:
  • FDA-approved for multiple cancers including melanoma, NSCLC, HNSCC, and MSI-H tumors 3
  • Testing method: IHC with Combined Positive Score (CPS) ≥1 considered positive 1
  • Often combined with other targeted therapies (e.g., with trastuzumab in HER2+ gastric cancer) 4, 5

5. MSI-H/dMMR (Microsatellite Instability-High/Deficient Mismatch Repair)

• Mechanism: Defects in DNA mismatch repair leading to genomic instability
• Cancer association: Various solid tumors, especially colorectal cancer
• Targeted therapy: Pembrolizumab/nivolumab
• Clinical significance:
  • FDA-approved for unresectable or metastatic MSI-H/dMMR solid tumors 3
  • Testing methods: PCR/NGS for MSI or IHC for MMR proteins 1
  • Universal testing recommended for newly diagnosed patients 1

Additional Important Molecular Targets

6. ALK (Anaplastic Lymphoma Kinase)

• Mechanism: Chromosomal translocation creating fusion proteins
• Cancer association: 3-5% of NSCLC, mutually exclusive with EGFR and KRAS mutations 1
• Clinical significance: Tumors negative for EGFR and KRAS should be screened for ALK rearrangements 1

7. KRAS

• Mechanism: GTPase involved in signal transduction
• Cancer association: Present in ~30% of lung adenocarcinomas 1
• Clinical significance:
  • KRAS mutations confer resistance to EGFR TKIs 1
  • Mutations confined to three codons, making testing relatively simple 1

8. NTRK Gene Fusions

• Mechanism: Fusion proteins involving neurotrophic tropomyosin-related kinase
• Cancer association: Various solid tumors
• Targeted therapy: Entrectinib/larotrectinib
• Clinical significance: FDA-approved for NTRK gene fusion-positive solid tumors 1

Testing Approaches and Considerations

Biomarker Testing Methods

• IHC (Immunohistochemistry): For protein expression (HER2, PD-L1, MMR proteins)
• FISH (Fluorescence In Situ Hybridization): For gene amplification (HER2, ALK)
• PCR/NGS (Next-Generation Sequencing): For mutations and MSI status 1
• Liquid biopsy (ctDNA): For patients unable to undergo traditional biopsy 1

Clinical Pearls

1. Mutual exclusivity: Key lung cancer mutations (EGFR, KRAS, ALK) are typically mutually exclusive 1
2. Combination approaches: Targeted therapies are increasingly used in combination (e.g., pembrolizumab + trastuzumab) 4
3. Resistance mechanisms: Understanding acquired resistance (e.g., T790M mutation in EGFR) is critical 1
4. Tumor Mutation Burden (TMB): High TMB is a biomarker for immunotherapy response 1

Remember that these molecular targets represent the foundation of precision oncology, where treatment is tailored to the specific molecular alterations in a patient's tumor, leading to improved survival outcomes while potentially reducing toxicity compared to traditional chemotherapy 6, 7.