There's a growing recognition that the molecular profile of a primary tumor can differ significantly from its metastases. To guide treatment more accurately, the preferred practice is to biopsy an accessible metastatic lesion when possible, as this better reflects the biology of the active disease being treated.

In neoadjuvant settings, ctDNA monitoring allows for real-time therapy adjustment. Data from the iSpy platform shows 80% of hormone-positive patients clear ctDNA with half the chemotherapy, enabling de-escalation, while the remaining 20% can be identified for escalated treatment.

The treatment landscape for platinum-resistant ovarian cancer has rapidly evolved into a biomarker-driven paradigm. Clinicians must now test for and choose between therapies targeting distinct markers like folate receptor alpha (mirvetuximab), HER2 (T-DXd), and PD-L1 (pembrolizumab), requiring a sophisticated sequencing strategy.

Clinicians should view HRD scores as a spectrum rather than a simple positive/negative result. For a patient with a score near the arbitrary cutoff and an excellent clinical response to platinum, oncologists may advocate for insurance coverage of PARP inhibitors.

To maximize the chances of successful biomarker identification from a liquid biopsy, especially when tissue is scant, the blood sample must be drawn before initiating any chemotherapy. This pre-treatment timing is critical for improving the diagnostic yield of blood-based next-generation sequencing (NGS) testing.

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.

For HRD-positive ovarian cancer, a strong initial response to platinum chemotherapy may justify using a PARP inhibitor alone for maintenance. A weaker response, however, suggests adding bevacizumab for a potentially greater benefit, using clinical response as a key decision-making tool.

When an HRD test is inconclusive due to insufficient tumor tissue after neoadjuvant chemotherapy, it can paradoxically indicate a very strong response to treatment and high platinum sensitivity, as there is little to no residual tumor to analyze.

While retreating with a PARP inhibitor after a long progression-free interval is a viable strategy for patients with BRCA mutations, experts express caution and hesitancy in applying the same approach to patients who are HRD-deficient but BRCA wild-type, partly due to changing FDA labels.