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BRCA1/BRCA2 Mutation-Associated Markers (ctDNA)

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A Quick Guide for Patients

  • What are BRCA genes? BRCA1 and BRCA2 are your body's "DNA repair" genes. When they have a harmful mutation (an error), they can't fix DNA damage properly, which greatly increases the risk of developing certain cancers, like breast, ovarian, prostate, and pancreatic cancer.
  • What is a liquid biopsy? It's a simple blood test that looks for tiny pieces of DNA shed by tumors into the bloodstream (called ctDNA). This test can find BRCA mutations in the tumor without needing a surgical biopsy.
  • Why is finding a BRCA mutation important? It opens the door to powerful targeted drugs called PARP inhibitors. These drugs are highly effective against cancers with a faulty BRCA gene.
  • How is this test used? A liquid biopsy can help determine if you are eligible for a PARP inhibitor, monitor how well the treatment is working, and give an early warning if the cancer is becoming resistant or returning.

BRCA1/BRCA2 Mutation-Associated Markers (ctDNA) Overview

BRCA1 and BRCA2 are tumor suppressor genes critical for DNA repair via homologous recombination (HR). Germline mutations in these genes confer high lifetime risks of breast (up to 72% for BRCA1, 69% for BRCA2) and ovarian cancer (up to 44% for BRCA1, 17% for BRCA2), and increase susceptibility to prostate and pancreatic cancers. Somatic mutations also occur in these cancers.

Circulating tumor DNA (ctDNA) refers to tumor-derived cell-free DNA fragments in the bloodstream, enabling non-invasive liquid biopsy for detecting BRCA1/2 mutations. ctDNA analysis complements tissue genotyping, particularly for monitoring treatment response, detecting minimal residual disease (MRD), and identifying resistance mechanisms like BRCA reversion mutations.

Tumour markers serve as indispensable tools in the realm of cancer detection and diagnosis, offering valuable insights into disease progression and treatment response.

Indications for ctDNA Testing in BRCA1/2 Contexts

ctDNA testing for BRCA1/2 mutations is indicated for:

  1. Genotyping: Identifying somatic/germline BRCA alterations in metastatic breast, ovarian, prostate, or pancreatic cancers when tissue is unavailable.
  2. PARP Inhibitor Eligibility: Confirming BRCA mutations for olaparib or other PARP inhibitors (PARPi) in advanced ovarian, breast, prostate cancers.
  3. MRD Detection: Post-treatment monitoring in early-stage BRCA-associated cancers to detect recurrence earlier than imaging/CA-125.
  4. Resistance Monitoring: Detecting BRCA reversion mutations during PARPi or platinum therapy, guiding treatment switches.
  5. Prognostic Assessment: In triple-negative breast cancer (TNBC) or high-grade serous ovarian cancer (HGSOC), where TP53/BRCA ctDNA positivity predicts poor recurrence-free survival.

Biology of BRCA1/2 and ctDNA

BRCA1/2 proteins maintain genomic stability by repairing double-strand breaks. Pathogenic mutations (e.g., frameshifts, nonsense) lead to HR deficiency (HRD), synthetic lethality with PARPi, and genomic scarring (e.g., loss of heterozygosity). ctDNA originates from apoptotic/necrotic tumor cells, comprising 0.1–10% of total cell-free DNA in advanced disease, carrying tumor-specific mutations including BRCA1/2 variants.

Germline mutations appear at ~50% variant allele frequency (VAF) in ctDNA; somatic at lower VAFs. Reversion mutations restore BRCA function, conferring resistance.

Detection of BRCA1/2 Mutations in ctDNA

Next-generation sequencing (NGS) panels (e.g., AVENIO ctDNA Kit targeting BRCA1/2, TP53) detect mutations at >70,000x depth. Concordance with tissue is high (90–94% for BRCA alterations). In ovarian cancer, ctDNA detects 24.8% BRCA1/2 variants (mostly germline). In prostate cancer (PROfound trial), ctDNA identified BRCA/ATM alterations in 82% of tissue-positive cases.

Liquid biopsy enables serial sampling, unlike invasive tissue biopsy.

Frequently Asked Questions (FAQ)

What is the difference between a germline and a somatic BRCA mutation?

A germline mutation is inherited from a parent and is present in every cell in your body. It increases your lifetime risk of developing certain cancers. A somatic mutation is not inherited; it is acquired by the cancer cells themselves during a person's life. Finding a somatic BRCA mutation in a tumor can still make you eligible for targeted therapies like PARP inhibitors, even if you did not inherit the mutation.

What are PARP inhibitors and how do they work?

PARP inhibitors are a class of targeted therapy drugs. Think of it this way: cancer cells with a broken BRCA gene have a major weakness in their DNA repair system. PARP inhibitors work by taking out a *second*, different DNA repair pathway. When both pathways are blocked, the cancer cell can no longer fix its DNA damage and dies. This concept is called "synthetic lethality" and is highly effective in BRCA-mutated cancers.

If my ctDNA test for a BRCA mutation is negative, does that mean I don't have one?

Not necessarily. While ctDNA tests are very good, their sensitivity can be limited if the tumor isn't shedding much DNA into the bloodstream (common in early-stage or low-volume disease). A negative ctDNA result is not definitive. Guidelines often still recommend a traditional tissue biopsy or a germline (saliva or blood) test to be certain, as these are considered the gold standard.

ctDNA for Monitoring and Prognosis

In HGSOC, ctDNA detects MRD post-PARPi maintenance, predicting progression-free survival (PFS) with 100% positive predictive value. In TNBC, TP53/BRCA1 ctDNA positivity pre-treatment correlates with worse relapse-free survival.

During PARPi therapy, rising ctDNA signals resistance (e.g., BRCA2 reversion); declining levels indicate response. In metastatic breast cancer, ctDNA monitors somatic BRCA mutations for PARPi eligibility.

Interpreting ctDNA Results

Key metrics:

  • VAF: >30–40% suggests germline; lower indicates somatic.
  • ctDNA Fraction: >1% improves detection sensitivity.
  • Trends: Decreasing ctDNA post-therapy predicts better PFS; increasing signals progression.
  • Thresholds: BRCA1 VAF >32.4%, BRCA2 >28.5% predict germline confirmation.

Combine with HRD scores for comprehensive assessment.

Limitations and Challenges

ctDNA sensitivity varies by disease burden (low in early-stage); misses low-VAF variants. False negatives occur in low-shedding tumors. Standardization needed for assays; not yet routine for germline screening. Confounders: clonal hematopoiesis. NCCN/ESMO guidelines recommend ctDNA as adjunct, not replacement, for tissue testing.

ctDNA in Other BRCA-Associated Conditions

Beyond breast/ovarian, ctDNA detects BRCA mutations in prostate (mCRPC) for PARPi, pancreatic cancer for olaparib eligibility. In fallopian tube/peritoneal cancers (BRCA-linked), ctDNA monitors response. Emerging: population screening via ctDNA for germline carriers.

Your Partner in Precision Oncology

Liquid biopsy results provide powerful insights but require expert interpretation to guide your cancer care. It's essential to discuss your results with a medical oncologist to understand their implications for your treatment plan.

Request a Consultation with Our Specialists

References

  1. Chi KN, et al. (2021). Concordance of BRCA1/2 and ATM mutations in tumor tissue and ctDNA in mCRPC (PROfound). *J Clin Oncol*, 39(6_suppl), 26. https://doi.org/10.1200/JCO.2021.39.6_suppl.26
  2. Szulzewsky F, et al. (2017). Detection of BRCA1/2 mutations in ctDNA from ovarian cancer patients. *Oncotarget*, 8(65), 109004–109014. https://doi.org/10.18632/oncotarget.22628
  3. George A, et al. (2021). Clinical practice guidelines for BRCA1/2 testing. *Eur J Cancer*, 138, 202–212. https://doi.org/10.1016/j.ejca.2020.09.025
  4. Heo J, et al. (2024). Serial ctDNA analysis detects MRD in ovarian cancer. *Cancer Res*, 84(3), 468–478. https://doi.org/10.1158/0008-5472.CAN-23-1429
  5. Annunziata CM, et al. (2024). ctDNA as biomarker for PARPi in EOC. *OncLive*. Retrieved from https://www.onclive.com/view/ctdna-offers-potential-biomarker-for-parp-inhibitor-maintenance-therapy-in-epithelial-ovarian-cancer
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