Next Investigation: HER2 and Hormone Receptor Testing of Metastatic Lesions
The next critical investigation is to perform a biopsy of an accessible metastatic site (preferably the liver lesion or mediastinal lymph node) with comprehensive immunohistochemical and molecular testing, specifically evaluating HER2 status, hormone receptor status (ER/PR), and confirming the origin of the adenocarcinoma to determine if this represents metastatic breast cancer versus a new primary lung cancer. 1
Rationale for Metastatic Site Biopsy
The lung biopsy has already confirmed adenocarcinoma, but the critical question is whether this represents:
- Metastatic HER2-positive breast cancer
- A new HER2-negative breast cancer metastasis (due to clonal evolution)
- A new primary lung adenocarcinoma
HER2 status can change between primary and metastatic sites in up to 20-30% of cases due to tumor heterogeneity and clonal dynamics. 1 The 2025 expert consensus emphasizes that evaluating HER2 status at metastatic sites increases the likelihood of patients receiving suitable treatment based on their latest disease profile. 1
Specific Testing Panel Required
The biopsy specimen should undergo:
HER2 testing via both IHC and FISH/ISH to definitively establish current HER2 status, as recommended by ASCO/CAP guidelines requiring testing from a CAP-accredited laboratory with 95% concordance standards 1
Estrogen receptor (ER) and progesterone receptor (PR) testing to determine hormone receptor status, which may have also changed from the primary tumor 1
Immunohistochemical markers to distinguish breast origin (GATA3, mammaglobin, GCDFP-15) from primary lung adenocarcinoma (TTF-1, napsin A) 1
Clinical Decision Algorithm Based on Results
If HER2-Positive Metastatic Breast Cancer Confirmed:
- Initiate first-line HER2-targeted therapy for metastatic disease with trastuzumab, pertuzumab, and taxane-based chemotherapy 1
- This represents progression on adjuvant therapy, requiring escalation to metastatic treatment protocols 1
If HER2-Negative Metastatic Breast Cancer:
- Treatment decisions become complex and controversial. 1 The 2025 expert recommendations note that many clinicians would treat according to the most recent biopsy when there is discordance between primary and metastatic sites 1
- Some experts may continue HER2-targeted therapy despite loss of HER2 positivity, particularly if the primary tumor was not resected (though this patient had mastectomy) 1
- Alternative approach: switch to chemotherapy appropriate for HER2-negative disease 1
If Primary Lung Adenocarcinoma:
- Pursue lung cancer staging and molecular testing (EGFR, ALK, ROS1, PD-L1) rather than breast cancer treatment protocols
- The liver lesion and mediastinal nodes would represent lung cancer metastases
Critical Pitfalls to Avoid
Do not assume the lung adenocarcinoma represents metastatic breast cancer without tissue confirmation of breast origin and current HER2 status. 1 The ASCO/CAP guidelines specifically recommend HER2 testing on metastatic sites, especially for patients who previously tested HER2-positive in primary tumors and present with disease recurrence. 1
Do not initiate HER2-targeted therapy without confirming current HER2 status, as tumor biology may have evolved during the disease-free interval. 1 The expert consensus emphasizes that subsequent biopsies should be performed at time of progression due to tumor heterogeneity. 1
Avoid routine brain MRI screening at this time unless neurologic symptoms develop, as ASCO guidelines recommend against routine surveillance imaging but maintain a low threshold for diagnostic brain MRI with any neurologic symptoms given the high incidence of brain metastases in HER2-positive disease. 1
Additional Staging Considerations
While awaiting biopsy results, complete metastatic staging should include:
- PET-CT scan to fully characterize extent of disease and identify the most accessible biopsy site
- Brain MRI only if any neurologic symptoms are present, given the 50% lifetime risk of brain metastases in HER2-positive breast cancer 1