Concordance between local and central HER2 testing for ovarian cancer is poor. However, early data suggests the T-DXd antibody-drug conjugate is effective regardless of this variability, meaning any positive signal could be clinically actionable for this difficult-to-treat cancer.

Driven by T-DXd's high efficacy and the known variability of IHC testing, oncologists are pragmatically retesting HER2-negative tumors and treating HER2-low (1+) patients. This blurs official indications to maximize patient access to a transformative drug.

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.

For HER2+ metastatic colorectal cancer, experts choose HER2-targeted therapies like TDXD or tucatinib/trastuzumab over standard second-line chemotherapy (FOLFIRI/BEV), despite label constraints. The rationale is the significantly higher response rate from targeting the oncogenic driver directly.

Clinicians face a strategic dilemma where using an ADC off-label for a patient with a low-expressing biomarker (e.g., TDXD for HER2 1+) could provide benefit but also render that patient ineligible for a future clinical trial of a potentially more effective ADC. This highlights a tension between immediate access and optimizing long-term treatment sequencing.

Although HER2 expression is rare in cervical cancer, it is a crucial biomarker to test for. In these uncommon cases, patients who have progressed on standard immunotherapy can achieve "wonderful responses" with trastuzumab deruxtecan (T-DXd), highlighting a powerful, targeted option for a population with high unmet need.

Physicians face a dilemma: using an ADC off-label for a patient with a weak biomarker (e.g., HER2 1+), as permitted by NCCN compendium listings, may provide some benefit. However, this prior exposure can disqualify the patient from future clinical trials for potentially more effective ADCs.

The standard HER2 tests were developed to identify HER2-positive tumors, not to precisely quantify low levels of expression. This creates a diagnostic challenge for identifying patients eligible for HER2-low targeted ADCs, requiring closer collaboration with pathology to interpret results that may be near the threshold, such as HER2-zero but with some minimal staining.

Clinicians are pushing back against simple "negative" HER2 pathology reports, demanding detailed Immunohistochemistry (IHC) scores (0, 1+, 2+, 3+) and the criteria used. This granular data is crucial for determining eligibility for modern treatments like antibody-drug conjugates (ADCs), where even low protein expression can be clinically relevant and actionable for patient care.