High concordance exists between liquid and tissue biopsies (~89%) for PIK3CA mutations. However, since each method can uniquely identify mutations in some cases, using both liquid and tissue offers the most comprehensive detection strategy to determine patient eligibility for PI3K inhibitors and avoid false negatives.

The CAPItello-281 trial shows the benefit of the AKT inhibitor capivasertib is on a spectrum. Patients with 100% PTEN protein loss by IHC derive a much greater benefit than those with partial loss, suggesting a quantitative biomarker may optimize patient selection.

Because PTEN loss is an early, truncal mutation in prostate cancer, clinicians should perform NGS testing on the first day a patient is seen. This proactive approach ensures that crucial biomarker information is not lost and is available to guide future treatment decisions, such as the use of an AKT inhibitor, should the disease progress.

While liquid biopsies (ctDNA) excel at detecting mutations, tissue biopsies are irreplaceable for assessing the fundamental biology of the most life-threatening metastatic sites. For instance, a direct liver biopsy is needed to confirm estrogen receptor expression, a critical factor that ctDNA cannot determine.

While Next-Gen Sequencing (NGS) provides genetic data, IHC directly measures the protein, is faster, cheaper, and requires less tissue. This makes it more scalable for routine clinical use, especially with small biopsy samples. High-level IHC loss correlates well with genetic loss seen on NGS.

Clinicians must recognize that liquid and solid biopsies show significant discordance. ESR1 mutations are more frequently detected in liquid assays, while PIK3CA mutations are more often found in solid tissue. This variability by gene directly impacts the optimal testing strategy for patients.

Unlike androgen receptor mutations which arise under treatment pressure, PTEN loss is an earlier event. Therefore, archival tissue from a primary biopsy is generally sufficient for determining PTEN status, even years later at metastatic relapse, avoiding a new invasive procedure.

Even with contemporaneously collected samples, biomarker concordance between solid tissue and liquid biopsies is not uniform. Data shows ESR1 mutations are consistently more likely to be discordant—often found only in liquid—than PIK3CA or AKT mutations, reinforcing the need for gene-specific testing strategies.

While Next-Gen Sequencing (NGS) can detect PTEN genetic loss, Immunohistochemistry (IHC) is often more practical for routine clinical use. IHC directly measures protein loss, requires less tissue, is faster, more affordable, and highly scalable.