Phase II Trial of the Combination of Letrozole 2.5 mg Daily and Trastuzumab 2 mg/kg Weekly in ErbB2 Positive and Estrogen Receptor and/or Progesterone Receptor Positive Metastatic Breast Cancer
Since ER function is regulated by peptide growth factor signaling, the phenotype of ER
positive tumors may be influenced by the expression of growth factors and growth factor
receptors. A potential interaction between ErbB2 (HER2/neu) expression and the success of
endocrine therapy has been examined. ErbB2 expression was shown to correlate with
resistance to hormone therapy.
An inverse relationship between endocrine therapy responsiveness and ErbB2 expression has
not been observed in all studies. This may be due to discordant ER status between the
primary tumor and metastatic sites. ER status can be discordant in approximately 20% of
cases, with a tendency for metastatic disease to become ER negative with time. Data
concerning ErbB2 is more limited, but there may be similar lack of concordance between
primary tumor and metastases.
Inhibition of ErbB2 signaling may slow the development of resistance to estrogen deprivation
therapy by inhibiting a pathway that promotes estrogen independent growth. The ErbB2 signal
transduction pathway bypasses the requirement for estrogen for breast epithelial cell
growth. When ErbB2 is activated in ER positive breast cancer cells in vitro, ER becomes
phosphorylated and capable of stimulating transcription without estrogen. Chronic
activation with heregulin, a ligand for the ErbB family of receptors, leads to ER
down-regulation and the acquisition of an ER negative phenotype.
Estrogen deprivation therapy with selective aromatase inhibitors (SAIs) has become the
standard of care for postmenopausal women with tamoxifen-resistant advanced breast cancer.
About 1/3 of patients benefit from this therapy. There is interest in treating endocrine
therapy refractory breast cancer with the recombinant DNA-derived humanized monoclonal
antibody trastuzumab. When given alone, trastuzumab has an endocrine therapy-like risk
benefit ratio. Trastuzumab targets ErbB2 (HER2/neu). Some breast cancers may coexpress ER
Letrozole (Femara™) is a highly selective oral non-steroidal aromatase inhibitor. According
to in vitro data, letrozole is 170-fold more potent in inhibiting aromatase than
aminoglutethimide (AG) and 19-fold more active than anastrozole. Letrozole effectively
inhibits intratumoral aromatase according to in vitro and in vivo data. It is indicated for
the treatment of advanced breast carcinoma in post-menopausal women who have failed prior
anti-estrogen therapy. Final FDA approval was granted in 1997. In two randomized phase
IIb/III studies in patients previously treated with an antiestrogen, 19.5% and 23.6% of
patients achieved an objective response with letrozole 2.5 mg/day compared with 12.4%
receiving AG and 16.4% of patients receiving megace. Median overall survival was increased
in the letrozole 2.5 mg/day group by 8 months compared to AG and by 3 months compared to
megace. The lower 0.5 mg/day dose of letrozole was associated with poorer response rates
and overall survival in both studies.
Trastuzumab (Herceptin®) was approved in 1998. A trial of trastuzumab as a single agent for
first line treatment of advanced disease has been reported. Response rate in the first 62
patients was 24%.
The primary objective of this trial is to determine the proportion of patients with ER
and/or PR positive, ErbB2 positive tamoxifen resistant metastatic breast cancer who achieve
complete remission or partial remission or no significant change in lesion size for > 24
weeks from a combination of letrozole and trastuzumab. The study will also determine
duration of response and median time to progression, evaluate toxicity, generate a tumor and
serum bank, and analyze ErbB2 expression on circulating malignant cells during treatment.
The study will enroll 35 patients
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the proportion of patients with ER and/or PR positive, ErbB2 positive tamoxifen resistant metastatic breast cancer who achieve complete remission (CR)
Paul K Marcom, MD
United States: Institutional Review Board
|Duke University Medical Center||Durham, North Carolina 27710|
|Dana Farber Cancer Institute||Boston, Massachusetts 02115|
|Lombardi Cancer Institute, Georgetown University Medical Center||Washington, District of Columbia 20007|
|Siteman Cancer Center, Washington University||St. Louis, Missouri 63110|