Genetic Testing in Breast Cancer

Genetic testing in Breast Cancer

Breast Cancer Overview

• Breast cancer is the most frequently diagnosed cancer worldwide.
• It remains a leading cause of cancer-related mortality.
• A complex and heterogeneous disease with strong genetic influences.

The Role of Next-Generation Sequencing (NGS)

• Enhances understanding of breast cancer at the molecular level.
• Identifies pathogenic genetic variants (mutations) associated with disease predisposition.
• Enables targeted therapy for improved treatment outcomes.

Genetic testing in breast cancer helps in both risk assessment and personalised treatment strategies.

Somatic vs. Germline Genetic Testing

Somatic Genetic Testing

• Identifies mutations found within the tumour itself (not inherited).
• Mutations arise from environmental or lifestyle factors (e.g., smoking, radiation).
• Performed on tumour tissue or circulating tumour DNA (liquid biopsy).
• Provides information on:
  • Recurrence risk.
  • Prognosis.
  • Targeted therapy options.

Germline Genetic Testing

• Identifies inherited mutations present in all cells from birth.
• Performed on a blood sample (EDTA).
• Used for risk evaluation in individuals with or without cancer.
• Facilitates:
  • Early detection strategies.
  • Preventative medical or surgical interventions.
  • Family risk assessment and genetic counselling.

Both somatic and germline genetic testing play crucial roles in breast cancer management.

BRCA1/BRCA2 Tumour Testing and Germline Confirmation

What If a BRCA1/BRCA2 Variant is Identified in Tumour Tissue?

• Tumour-based BRCA1/BRCA2 testing cannot distinguish between inherited (germline) and acquired (somatic) mutations.
• If the variant frequency in the tumour is high (~50%), germline confirmatory testing is recommended.
• If the variant frequency is low, it is likely a somatic variant, requiring no further testing.

Confirmatory germline testing ensures appropriate genetic counselling and risk assessment for relatives.

Genetic Testing Panels for Breast Cancer

Germline Testing Panels

Comprehensive Breast Cancer Panel (Mnemonic: BREAST)

• Includes genes: BRCA1, BRCA2, PTEN, TP53, CDH1, PALB2, RAD51C, RAD51D, STK11.
• Indications:
  • Hereditary breast/ovarian cancer syndrome.
  • Cowden syndrome.
  • Li-Fraumeni syndrome (TP53-related).
  • CDH1-associated cancers.
  • PALB2-associated breast cancer.
  • Peutz-Jeghers syndrome.
• Specimen: EDTA blood (5 mL).

Full BRCA1/BRCA2 Panel (Mnemonic: ONCOBRCA)

• Includes copy number variant analysis (MLPA).
• Indications:
  • Hereditary breast/ovarian cancer syndrome.
  • Somatic BRCA testing on tumour tissue.
• Specimen: EDTA blood (5 mL) or FFPE tissue (4–6 slides).

Targeted BRCA Testing for Afrikaner/Ashkenazi Jewish Ancestry (Mnemonic: BRCAFDR)

• Tests for common BRCA1/BRCA2 variants found in these populations.
• Specimen: EDTA blood (5 mL).

ATM-Related Cancer Testing (Mnemonic: ATMNGS)

• Indications:
  • ATM mutations associated with breast, prostate, and pancreatic cancer.
  • Ataxia-telangiectasia (autosomal recessive inheritance).
• Specimen: EDTA blood (5 mL).

Specific Familial Variant Testing (Mnemonic: DNAMUT)

• Used for previously identified familial pathogenic variants.
• Requires submission of a copy of the original genetic report.
• Specimen: EDTA blood (5 mL).

Pharmacogenomics Panel for Tamoxifen Metabolism (Mnemonic: PHARMA)

• Includes CYP2D6 gene (affects tamoxifen metabolism).
• Genetic variations impact enzyme activity, influencing drug efficacy.
• Specimen: EDTA blood (5 mL).

Germline testing enables early cancer risk assessment, family screening, and risk-reduction strategies.

Somatic (Tumour) Testing for Targeted Therapy

Actionable Genomic Alterations in Breast Cancer

HER2 (ERBB2) Amplification

• Tests:
  • Oncomine™ Precision Assay (Mnemonic: OPANGS).
  • HER2 Fluorescence in Situ Hybridisation (FISH) (Mnemonic: HER2 FISH).
• Approved therapies:
  • Trastuzumab, Pertuzumab, Lapatinib, Neratinib.

BRCA1/BRCA2 Mutations

• Test: BRCA1/BRCA2 gene sequencing (Mnemonic: ONCOBRCA).
• Approved therapy: Olaparib.

PIK3CA Mutations

• Tests:
  • PIK3CA NGS (Mnemonic: EGFRASSEQ).
  • Oncomine™ Precision Assay (Mnemonic: OPANGS).
• Approved therapy: Alpelisib.‍

NTRK Fusions

• Test: Oncomine™ Precision Assay (Mnemonic: OPANGS).
• Approved therapies: Larotrectinib, Entrectinib.

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Somatic genetic testing identifies treatment targets, enabling precision oncology.

Contact Information

For Genetic Testing Queries

• Ampath NGS Laboratory: 012 678 0645
• Email: ngs@ampath.co.za

For Genetic Counselling

• Email: geneticsclinic@ampath.co.za

Genetic testing in breast cancer enhances early detection, personalised treatment, and risk management strategies for patients and their families.