In the latest Case Record of the Massachusetts General Hospital, a 32-year-old woman noted a crease in her right breast. Imaging studies showed a suspicious mass, and a biopsy specimen revealed infiltrating ductal carcinoma, positive for HER2. Staging showed liver lesions consistent with metastases. Management decisions were made.
HER2, a proto-oncogene encoding the HER2 tyrosine kinase receptor, is amplified in 15 to 20% of patients with breast cancer, resulting in HER2-receptor overexpression and an aggressive clinical phenotype associated with high metastatic potential and shortened survival.
• What is the current recommendation for treatment in a patient with HER2-positive metastatic breast cancer?
The outcome of patients with HER2-positive breast cancer has markedly improved with the advent of molecular targeting of the HER2 receptor with the humanized monoclonal antibody trastuzumab (Herceptin, Genentech). In patients with metastatic HER2-positive breast cancer, although single-agent trastuzumab is clinically active, the highest clinical benefit is observed when trastuzumab is given in combination with chemotherapy. Multiple agents in combination with trastuzumab have shown clinical activity. However, the only randomized trials that have shown improved survival are those involving the use of taxanes.
• Is there any role for surgical resection of the primary tumor in a patient with metastatic HER2-positive breast cancer?
Although surgical resection of the primary tumor has traditionally been reserved for symptom palliation, retrospective series suggest a survival benefit associated with removal of the primary tumor in metastatic disease, and a case-matched series suggests clinical benefit from local therapy in carefully selected patients with metastatic disease.
Morning Report Questions
Q: What is the prognosis in HER2-positive metastatic breast cancer?
A: Although an overall response of HER2-positive metastatic disease to first-line therapy occurs in up to 70% of patients, complete remissions are seen in only 7 to 8% of patients. Nonetheless, the remissions can be long-lasting; some patients who participated in the initial clinical trials with trastuzumab are still in remission more than 15 years later. Median survival is shorter in patients who have visceral metastases than in those who have bone-only metastases. Although the disease may recur in multiple sites, trastuzumab-treated populations have an especially high risk of central nervous system metastasis — more than 30% of the patients in some series. The high rate of metastatic disease to the brain is probably due to the high invasive and metastatic potential of HER2-positive breast cancer, together with the limited penetration of trastuzumab across the blood-brain barrier.
Q: How does trastuzumab enhance the cardiotoxic effects of anthracyclines?
A: The heart depends on HER2 signaling to recover from a number of insults, including the cardiotoxic effects induced by anthracyclines. Therapy with trastuzumab prevents HER2 from signaling appropriately in the heart and may be responsible for the enhanced cardiac toxic effects observed when anthracyclines are given in combination with trastuzumab.