Relying solely on Next-Generation Sequencing (NGS) is insufficient for HER2 testing in biliary tract cancers. Data shows NGS misses up to 15% of patients with HER2 overexpression detected by immunohistochemistry (IHC). Performing both tests is essential to avoid denying patients effective targeted therapies.

A dramatic epidemiological shift has occurred in HER2+ breast cancer. Due to highly effective adjuvant therapies preventing recurrence, the majority of new metastatic cases (two-thirds) are now de novo, a complete reversal from 15 years ago when relapsed disease dominated.

Clinicians should consider re-biopsying tumors at recurrence, not upfront. Endometrial cancer can evolve, and a metastatic site may develop new targetable markers, like HER2, that were not present in the primary tumor, opening up new treatment avenues.

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.

Hormone receptor-positive (HR+) HER2+ breast cancers often show lower rates of pathologic complete response (pCR) to pre-surgical therapy. This is due to their slower-growing biology, not treatment ineffectiveness. Clinicians should recognize this nuance and not assume a worse prognosis based on pCR alone in this subtype.

Unlike in breast cancer, where HER2 IHC 2+ requires FISH confirmation, in gynecologic cancers an IHC 2+ result is often considered directly actionable for prescribing HER2-targeted ADCs like T-DXD. This reflects a different, less stringent clinical standard for biomarker-guided therapy in this setting.

Contrary to the belief that HR+ breast cancer primarily carries a late recurrence risk, data shows high-risk, node-positive patients can be extremely aggressive early on. With recurrence rates up to 29.1% within five years, this subgroup can perform as poorly, or even worse, than triple-negative breast cancer, highlighting the need for intensive adjuvant therapy.

A negative liquid biopsy (ctDNA) result for HER2 amplification does not prove a patient is HER2-negative. The test's sensitivity is limited by tumor fraction in the blood. While a positive ctDNA result is highly specific and trustworthy, a negative result is simply 'not detected' and requires a tissue biopsy to definitively determine HER2 status for treatment decisions.

Experts question if HER2 status truly predicts ADC efficacy in urothelial cancer. The benefit seen across low-expression levels suggests HER2's main role may be simply to target the chemo payload to cancer cells, rather than indicating a specific biological dependency.