Experts overwhelmingly favor tissue-based testing (IHC or NGS) to determine MSI status in localized colorectal cancer. They express concern that liquid biopsies (ctDNA) may produce false negatives because smaller, localized tumors might not shed enough DNA into the bloodstream for reliable detection.

While liquid biopsies are a valuable, less invasive tool, a negative result is inconclusive for ruling out actionable mutations in NSCLC. It may simply mean the tumor isn't shedding enough DNA. Therefore, a negative liquid biopsy should never be the final word; it must be followed by a tissue biopsy to ensure patients don't miss out on targeted therapies.

While ctDNA is a powerful tool, it is not interchangeable with tissue testing for PI3K pathway alterations. Analysis from Capitello-291 showed PTEN deletions were the most discordant, with 11% of pathway alterations found only in tissue. This highlights the need for a complementary strategy, using both methods to ensure all eligible patients are identified for targeted therapy.

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 patients increasingly ask about ctDNA, clinicians are hesitant to use it for treatment decisions in ovarian cancer management. A rising ctDNA level may prompt more vigilant surveillance but does not yet trigger treatment initiation, as its correlation with survival outcomes is unproven.

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.

Despite the promise of liquid biopsies for monitoring, the SERENA-6 trial revealed a significant challenge: fewer than 10% of screened patients developed a detectable ESR1 mutation. This low yield questions the efficiency and broad applicability of this serial screening strategy to guide treatment changes.

Unlike many cancers, younger patients (in their 20s-30s) with low-grade serous ovarian cancer have a worse prognosis than older patients. This is because they are less likely to carry a KRAS mutation, making them less responsive to highly effective targeted therapies.

The TRACK-ER study reveals a critical weakness of tumor-informed ctDNA monitoring: a 16% failure rate. This occurs when there's insufficient tumor tissue or too few personalized variants to track. This technical barrier poses a significant obstacle to widespread clinical implementation, highlighting the need for more robust or alternative assay technologies for all patients to benefit.