This policy does not address the use of blood-based testing (liquid biopsy) to select targeted treatment for certain tumor types, including breast cancer, non-small cell lung cancer (NSCLC), melanoma/glioma, ovarian cancer, pancreatic cancer, and prostate cancer. It also excludes use of liquid biopsy to select immune checkpoint inhibitor therapy, tumor‑informed ctDNA testing for cancer management, comprehensive genomic profiling for selecting targeted cancer therapies, blood‑based testing for detection or risk assessment of prostate cancer, and AR‑V7 circulating tumor cell (CTC) testing for metastatic prostate cancer. Refer to the member's contract benefits at the time of service to determine coverage for these services.

Alternate listing: the policy specifically excludes liquid biopsy to select targeted therapies for breast, non‑small cell lung, melanoma/glioma, ovarian, pancreatic, and prostate cancers; selection of immune checkpoint inhibitor therapy based on blood testing; tumor‑informed ctDNA testing for management; comprehensive genomic profiling via blood; blood‑based prostate cancer detection/risk assessment; and AR‑V7 CTC testing for metastatic prostate cancer. Coverage determinations depend on the member's contract benefits.

Use of ctDNA or CTC assays for purposes other than monitoring for residual tumor or molecular relapse (for example, unrelated population screening) is not described as an intended use in this policy. When tissue biopsy is feasible, tissue‑based molecular characterization remains the expected comparator and individuals with negative liquid biopsy results should be reflexed to tumor biopsy testing if able to undergo tissue sampling.

Because assays, timing, and definitions of molecular response vary substantially across studies, heterogeneity and lack of standardized definitions reduce the ability to generalize results and may confound clinical validity. Assay variability and inconsistent timepoints limit comparability across tests and studies and should be considered when interpreting results or requesting coverage.

ASCO guidance states that, in early‑stage breast cancer (node‑negative or node‑positive ER‑positive, HER2‑positive, or triple‑negative disease), clinicians should not use ctDNA or circulating tumor cells to guide decisions about adjuvant endocrine therapy or adjuvant chemotherapy (evidence‑based recommendation; strength: strong).

Administrative note: this policy does not address use of liquid biopsy to select targeted treatments for the tumor types listed above, nor does it address tumor‑informed ctDNA testing or AR‑V7 CTC testing for metastatic prostate cancer; such uses are outside the scope of this policy and require review under the applicable tumor‑specific policy or the member's contract.

Coverage stance: circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) testing for indications not otherwise addressed in this policy or in separate, tumor‑specific policies is considered experimental/investigational and not medically necessary.

Currently available commercially marketed CTC assays lack independently established clinical validity for the management decisions reviewed here; therefore, using CTC test results to select or guide treatment is not supported by sufficient evidence of clinical utility.

Assay sensitivity is critical for clinical utility in the MRD/molecular relapse setting. Tests that cannot detect ultra‑low ctDNA concentrations risk high false‑negative rates and would not meet the necessary clinical validity for MRD surveillance or for informing early intervention decisions.

Performance limitation: clinical sensitivity of ctDNA assays for postoperative MRD detection is often suboptimal, with sensitivity shortly after completion of therapy frequently reported at or below 50% (≤50%), while clinical specificity is generally high (often ≥90%). Variable performance across assays and timepoints limits reliability for routine MRD use.

ASCO recommendation: clinicians should not use ctDNA or CTC to guide adjuvant endocrine or chemotherapy decisions in node‑negative or node‑positive ER‑positive, HER2‑positive, or triple‑negative early‑stage breast cancer (strong, evidence‑based recommendation).

All ctDNA and/or CTC testing indications that are not specifically addressed in other policy guidelines are considered experimental/investigational and not medically necessary, and claims for such testing may be denied unless coverage is established under a separate tumor‑specific policy or member contract.

Specific tests and contexts not addressed by this policy include tumor‑informed ctDNA testing for cancer management and AR‑V7 circulating tumor cell assays for metastatic prostate cancer; these uses lack established policy coverage within this document.

Tests that are unable to reliably detect ultra‑low ctDNA concentrations, or tests not used in the context of MRD/molecular relapse monitoring, lack demonstrated clinical utility for the uses evaluated in this policy.

Circulating tumor cell assays that lack independent demonstration of clinical validity are not established as clinically useful for guiding management decisions and therefore are considered not proven for treatment selection or monitoring.

ctDNA or CTC testing to guide adjuvant therapy decisions in early‑stage breast cancer is not supported; ASCO explicitly recommends against using these assays to guide adjuvant endocrine or chemotherapy in node‑negative or node‑positive early breast cancer subtypes.

Use of liquid biopsy to select targeted therapies, to select immune checkpoint inhibitor therapy, or tumor‑informed MRD approaches outside the specified indications are not covered under this policy and are treated as experimental/investigational.

Eligibility excerpts: when a tissue biopsy is feasible, tissue‑based molecular characterization is the standard comparator; liquid biopsy is generally considered when tissue is unavailable or biopsy is not feasible. Individuals with negative liquid biopsy results who can undergo tissue biopsy should be reflexed to tissue testing.

Eligibility excerpts: prior authorization for MRD surveillance should confirm the individual has received curative‑intent therapy and that the intended use is monitoring for molecular/minimal residual disease or molecular relapse using an assay capable of detecting ultra‑low ctDNA concentrations; documentation should include the specific assay and intended management action.

Eligibility excerpt (ASCO‑related): ordering clinicians should document the intended management action (for example, a plan to omit or administer adjuvant chemotherapy based on ctDNA results) and specify the assay/version used because trial results and recommendations are assay‑ and protocol‑specific; ASCO also notes cfDNA testing is most helpful when tissue results are unavailable.

Background: Liquid biopsy refers to analysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) from peripheral blood. ctDNA are small fragments of tumor‑derived cell‑free DNA used to quantify tumor DNA burden and assess treatment dynamics; CTCs are intact tumor cells shed into the circulation and are primarily used for prognostic enumeration or characterization. Detection is technically challenging because tumor‑derived material can be present at very low concentrations and requires sensitive targeted or broad genomic methods.