ER ER ER ER - Endocrine Reviews

efficacy of a small molecule inhibitor of HER2 in patients resistant to therapy with
trastuzumab. A phase II trial of lapatinib has been completed in heavily pretreated
patients with advanced breast cancer that progressed on prior trastuzumab-containing
regimens. A recent analysis of the first 41 patients confirmed clinical activity for
lapatinib in breast cancer, with partial response in 7% of patients and/or stable disease in
24% of patients after 16 weeks of therapy (174).
Based on the preclinical and clinical evidence suggesting benefit, several phase II/III
trials have been initiated with TKIs or monoclonal antibodies in combination with
tamoxifen, fulvestrant, or aromatase inhibitors (Table 2). Some of these trials are in the
second-line setting, including patients whose tumors were progressing on tamoxifen, and
then adding lapatinib to tamoxifen to see whether clinical responses could be observed
and resistance reversed. The majority, however, are randomized phase II studies with
only 100-200 patients, and in some studies the primary efficacy endpoint is objective
response rate rather than time to progression. Such studies are asking whether the
combination may provide greater initial anti-neoplastic activity than endocrine therapy
alone, expecting to enhance or restore the response in tumors with de novo endocrine
resistance. However, given the preclinical data, prolongation of time to progression (i.e.,
delaying resistance onset) rather than response rate might be a better endpoint for these
trials.
The first safety and efficacy data for the combination of an aromatase inhibitor (letrozole)
with trastuzumab for the treatment of ER and/or PgR-positive and HER2-positive
32