Can a patient with a history of Human Epidermal growth factor Receptor 2 positive (HER2+) breast cancer in remission experience a relapse in the form of adenocarcinoma of the lung and pleural space?

HER2+ Breast Cancer Relapse as Lung and Pleural Adenocarcinoma

Yes, HER2+ breast cancer in remission can relapse as metastatic adenocarcinoma involving the lung and pleural space—this represents metastatic breast cancer, not a new primary lung cancer, and requires HER2-targeted therapy rather than lung cancer treatment protocols. 1

Understanding Metastatic Patterns in HER2+ Breast Cancer

HER2-enriched breast cancers have a documented propensity to metastasize to the liver and lung, distinguishing them from hormone receptor-positive tumors that preferentially spread to bone. 1 The molecular subtype of breast cancer directly influences both the pattern and timing of metastatic spread:

• HER2-enriched cancers demonstrate higher rates of recurrence in the first 4 years compared to luminal subtypes, with lung being a common metastatic site (14% of all breast cancer metastases historically involve lung). 1
• Pleural involvement occurs in approximately 16% of breast cancer metastases, often accompanied by malignant pleural effusion. 1, 2
• The lung and pleural space are anatomically proximate targets for breast adenocarcinoma cells, which can invade these sites through direct extension or hematogenous spread. 2

Critical Diagnostic Distinction

The key clinical challenge is distinguishing metastatic breast adenocarcinoma from a new primary lung adenocarcinoma—this distinction fundamentally changes treatment approach and prognosis. 3

Essential Diagnostic Steps:

• Biopsy of the lung/pleural lesion is mandatory to confirm the diagnosis and reassess HER2 status, as receptor expression can change over time. 1
• Comprehensive molecular profiling should be performed to determine whether the adenocarcinoma represents metastatic breast cancer or a second primary malignancy. 3
• HER2 status must be retested on the metastatic tissue, as up to 10-15% of cases show discordance between primary and metastatic sites due to clonal selection under treatment pressure. 1

Treatment Implications for Confirmed Metastatic HER2+ Breast Cancer

If the lung/pleural adenocarcinoma is confirmed as metastatic HER2+ breast cancer, immediate initiation of HER2-targeted therapy is essential, as delaying treatment eliminates the survival advantages demonstrated in pivotal trials. 3

First-Line Treatment Approach:

• Trastuzumab plus pertuzumab plus a taxane (paclitaxel or docetaxel) represents the standard first-line regimen for patients with adequate performance status, regardless of hormone receptor status. 1, 3
• Median overall survival with optimal first-line dual HER2 blockade plus chemotherapy is approximately 57 months, with 8-year survival rates reaching 37%. 3
• Mandatory cardiac monitoring is required given trastuzumab's cardiotoxicity risk, particularly in elderly patients or those with cardiovascular comorbidities. 4

Subsequent Treatment Lines:

• Trastuzumab deruxtecan (T-DXd) is the preferred second-line therapy following progression on trastuzumab, pertuzumab, and taxane, with median overall survival of 22.7 months. 1, 3
• Third-line treatment with tucatinib plus trastuzumab plus capecitabine achieves median overall survival of 24.7 months and provides CNS penetration. 3

Brain Metastasis Surveillance

Baseline brain MRI and serial imaging every 2-4 months is recommended, as up to 50% of patients with HER2+ metastatic breast cancer develop brain metastases over time. 1, 3 This is particularly critical given:

• HER2 positivity is a known risk factor for CNS involvement, with brain metastases occurring in a continuous fashion even years after initial metastatic diagnosis. 1
• Even patients with multiple brain metastases and extracranial disease can achieve median survival of approximately 3 years with modern HER2-targeted therapies and appropriate local CNS treatment. 1, 3

Common Pitfalls to Avoid

Do not assume a lung adenocarcinoma in a patient with prior breast cancer is automatically a new primary lung cancer—this error leads to inappropriate treatment with lung cancer protocols rather than HER2-targeted breast cancer therapy. 3

Do not rely solely on the original primary tumor's HER2 status—tumor heterogeneity and clonal evolution under treatment pressure can result in HER2 status changes, requiring rebiopsy of metastatic sites. 1

Do not delay systemic therapy while pursuing extensive local treatments for oligometastatic disease—while selected patients with isolated metastases may benefit from aggressive local approaches, systemic HER2-targeted therapy remains the foundation of treatment. 1, 3

Special Considerations for Hormone Receptor-Positive Disease

If the metastatic disease is both HER2+ and hormone receptor-positive, maintenance therapy following chemotherapy should consist of trastuzumab, pertuzumab, and endocrine therapy to address both oncogenic drivers. 1 This combination approach:

• Provides dual pathway inhibition targeting both HER2 and estrogen receptor signaling. 1
• Allows for prolonged disease control with lower toxicity compared to continuous chemotherapy. 1
• Should be continued indefinitely until disease progression or unacceptable toxicity, as there is no evidence supporting planned treatment discontinuation in responding patients. 1