Benefits for patients with hormone-receptor-positive and HER2-positive metastatic breast cancer.

About 70% of breast tumors are hormone receptor (HR) positive.  Besides, 10% of these tumors overexpress the human epidermal growth factor receptor 2 (HER2). Trastuzumab is effective for HER2-positive patients, regardless of the patient’s HR status.  The concomitant inhibition of both pathways (HER2/ER) should be more effective than the estrogen receptor inhibition alone. In a phase II study, the combination of trastuzumab and letrozole was effective and well-tolerated.

The TAnDEM study randomly assessed the effectiveness of the trastuzumab (loading dose: 4 mg/kg, followed by 2 mg/kg/wk) and anastrozole (1 mg) combination versus hormone therapy alone as first-line treatment in 207 patients with hormone-receptor-positive and HER2-positive metastatic breast cancer. The primary end point was the progression-free survival (PFS).  Time to progression (TTP), overall survival (OS), objective response (OR), response duration and toxicity were also assessed as a secondary analysis. 

Patient characteristics across the two arms of the study were balanced.  HR positivity was confirmed by means of a central review. Results are shown in the table.

Table. Results of the TAnDEM study.

PFS = progression-free survival; TTP = time to progression; OS = overall survival; OR= objective response.

This study is the first randomized phase III study assessing the combination of a hormone agent and trastuzumab, without chemotherapy, as first-line treatment in patients with HER2-positive and HR-positive breast cancer. The trial shows that the addition of the antibody to the hormone treatment significantly improves PFS, OR and TTP, in comparison with hormone therapy alone. Although 3-4-grade toxicity was higher in the trastuzumab arm, the adverse effects were reversible and not life-threatening.   Likewise, treatment duration was also greater for this arm.

The primary end point (PFS) data were subject to a blinded central review way by an independent oncologist in order to guarantee the certainty of the results.

However, PFS was lower than expected in both arms. This result may be explained by the aggressive behavior of the HER2-positive and HR-positive tumors in comparison with HER2-negative and HR-positive tumors.

The small difference in OS may be explained by the fact that patients receiving anastrozole could change to the combination arm in the event of progression.
When hormone therapy or chemotherapy should be used in combination with trastuzumab for patients with HER2-positive and HR-positive metastatic breast cancer is still a topic for discussion. In these cases, chemotherapy plus anti-HER2 therapy should generally be the choice, but in patients with fragility symptoms or with a less aggressive disease, the use of hormone therapy plus trastuzumab may be considered.

Kaufman B, Mackey J, Clemens M. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2 positive, hormone receptor positive metastatic breast cancer: Results from the randomized phase III TAnDEM study. J Clin Oncol 2009; 27:5529-37.