Resistance to Methotrexate develops due to?

Increased production of dihydrofolate reductase (DHFR)

Rapid proliferation of cancer cells

Thymidylate synthetase deficiency

A 55-year-old woman with non-small cell lung cancer is found to have an ALK gene rearrangement. How should this finding influence her treatment?

Switch to crizotinib, a targeted ALK inhibitor

Refer for surgical resection, if appropriate

Consider radiation therapy, if indicated

Continue standard chemotherapy, if appropriate for the patient's condition

All are true regarding Sunitinib except which of the following?

It is excreted primarily in urine

It inhibits tyrosine kinase receptors

It is used for the treatment of GIST

It is used for renal cell carcinoma

Pharmacogenomics in Oncology for FMGE: High-Yield Pharmacology Lessons

Intro to PGx in Oncology - Cancer Code Crackers

Pharmacogenomics (PGx) in oncology aims to personalize cancer treatment by analyzing an individual's genetic makeup. It deciphers how genetic variations in both the patient (germline) and the tumor (somatic) influence drug efficacy and toxicity.

Primary Goals:
- Maximize therapeutic benefit.
- Minimize adverse drug reactions (ADRs).
Key Genetic Variations:
- Germline (Patient's DNA): Inherited variants affecting drug metabolism, transport, or targets.
  - Crucial for predicting systemic drug toxicity.
  - Examples: DPYD (5-Fluorouracil), UGT1A1 (Irinotecan), TPMT (Thiopurines).
- Somatic (Tumor DNA): Acquired mutations within the tumor driving cancer growth or conferring drug resistance/sensitivity.
  - Essential for selecting targeted therapies.
  - Examples: EGFR, ALK, BRAF, KRAS.

⭐ Identifying specific somatic mutations (e.g., EGFR T790M) can predict resistance to certain targeted therapies and guide subsequent treatment choices.

Key Gene-Drug Pairs - Target Titans

Gene	Drug(s)	Cancer(s)	Key Implication
TPMT	Azathioprine, 6-MP, Thioguanine	ALL	Low activity → ↑ myelosuppression. Test & dose adjust.
UGT1A1	Irinotecan	Colorectal	*UGT1A128** → ↓ SN-38 metabolism → ↑ toxicity (neutropenia, diarrhea). Reduce dose.
DPYD	5-FU, Capecitabine	Colorectal, Breast	Deficiency → ↓ 5-FU clearance → ↑ severe toxicity. Test, avoid/reduce dose.
EGFR	Gefitinib (TKI); Cetuximab (MAb)	NSCLC, CRC	NSCLC: Activating muts (Ex19del, L858R) → TKI sensitive. T790M → Osimertinib. CRC: WT KRAS/NRAS for MAb.
HER2	Trastuzumab, T-DM1	Breast, Gastric	Amplification/Overexpression → predicts anti-HER2 benefit.
KRAS	(Resistance to Cetuximab, Panitumumab)	CRC, NSCLC	Mutations (codons 12, 13, 61) → anti-EGFR MAb resistance in CRC.
BRAF	Vemurafenib (BRAFi); Trametinib (MEKi)	Melanoma, NSCLC	V600E/K muts → BRAFi ± MEKi response.
BCR-ABL1	Imatinib, Ponatinib (TKIs)	CML, Ph+ ALL	Philadelphia t(9;22) → TKI target. T315I mut → Ponatinib.
ALK	Crizotinib, Alectinib (ALKi)	NSCLC	Rearrangements (EML4-ALK) → ALKi sensitivity.
ROS1	Crizotinib, Entrectinib (ROS1i)	NSCLC	Rearrangements → ROS1i sensitivity.

Clinical Implementation & Challenges - Bedside & Barriers

Bedside Application:
- PGx Testing:
  - Germline (Blood/Saliva): Inherited variants (e.g., DPYD, UGT1A1) for predicting toxicity.
  - Somatic (Tumor Tissue): Acquired mutations (e.g., EGFR, BRAF) for guiding targeted therapy selection.
  - Methods: Next-Generation Sequencing (NGS), Polymerase Chain Reaction (PCR), Microarrays.
- Clinical Decision Support (CDS):
  - Electronic Health Record (EHR) integration for real-time alerts & guidance.
  - Guidelines: CPIC, ESMO, NCCN.
- Patient Journey:
  - Pre-test: Informed consent, discussion of Ethical, Legal, and Social Implications (ELSI).
  - Post-test: Result interpretation, potential family implications, counseling.
Significant Barriers:
- Tumor Heterogeneity:
  - Intra- & inter-tumoral variations; clonal evolution can impact therapeutic efficacy.
- Interpretation Complexity:
  - Variants of Unknown Significance (VUS) pose challenges.
  - Complex polygenic and environmental interactions influence drug response.
- Systemic Hurdles:
  - Cost-effectiveness, insurance reimbursement issues, test Turn-Around Time (TAT).
  - Gap in clinician education and awareness.
- Ethical Dilemmas:
  - Management of incidental findings, data privacy concerns, risk of genetic discrimination.

⭐ Somatic tumor testing (e.g., KRAS in colorectal cancer, HER2 in breast cancer) is more established in guiding oncology treatment selection than germline testing for Adverse Drug Reactions (ADRs), though DPYD testing for 5-Fluorouracil (5-FU) toxicity is a key germline example gaining traction.

Pharmacogenomics in Polypharmacy Workflow

High‑Yield Points - ⚡ Biggest Takeaways

TPMT variants predict thiopurine (azathioprine, 6-MP) toxicity.

UGT1A1*28 polymorphism increases irinotecan toxicity.

DPYD deficiency causes severe 5-FU/capecitabine toxicity.

KRAS mutations predict resistance to EGFR inhibitors (cetuximab) in colorectal cancer.

BRAF V600E mutation guides use of BRAF inhibitors (vemurafenib) in melanoma.

HER2/neu amplification is crucial for trastuzumab efficacy in breast cancer.

EGFR mutations (exon 19 del, L858R) in NSCLC predict response to EGFR TKIs; T790M indicates resistance to early TKIs but sensitivity to osimertinib.

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