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.

HER2 positivity is a strong negative prognostic marker even in early-stage (Stage 1) uterine cancer, associated with a 50% recurrence rate versus 17% in HER2-negative cases, despite most patients receiving chemotherapy.

HER2 expression in cervical cancer can be heterogeneous and may emerge in metastatic sites even if the primary tumor was negative. Given the availability of effective HER2-targeting drugs, re-biopsying a metastatic focus is crucial to unlock previously unavailable treatment options for patients with recurrent disease.

Retesting for biomarkers with liquid biopsy in the third-line setting is crucial. It can uncover new, actionable mutations that have emerged during treatment or confirm the absence of resistance mutations, potentially allowing patients to benefit from re-challenging with a previously used 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 re-biopsying at disease progression is the "by-the-book" standard to confirm biomarkers like HER2, clinicians acknowledge it is often skipped. The difficulty of obtaining tissue and the desire to provide patients with potential treatment options create a gap between guidelines and clinical reality.

The RAS/MAP kinase pathway is an "underrecognized" and "underutilized" therapeutic target in endometrial cancers. Despite up to a quarter of these cancers having mutations in pathway genes, clinical focus has often been elsewhere. This highlights a significant, overlooked opportunity for applying RAS-targeted therapies to a broader patient population.

Despite the risk of missing mutations, oncologists predominantly use convenient, less-invasive liquid biopsies to test for biomarkers at disease progression. A more invasive tissue biopsy is generally reserved for situations where the cancer behaves unexpectedly, such as a sudden shift from bone-only to visceral disease, which might suggest a missed biological driver.

Due to selective pressure from first-line treatment, 30-40% of HER2-positive gastroesophageal cancers lose HER2 expression by the time of progression. It is crucial to re-test these patients, either via tissue biopsy or ctDNA, to confirm continued HER2 positivity before initiating second-line HER2-targeted therapy like TDXD.