This was the first clinical trial initiated to explore the hypothesis that activation of the HER pathway during tamoxifen treatment in ER-positive tumors contributes to acquired resistance. It was further hypothesized that simultaneous blockade of HER receptors and ER may delay this resistance even in tumors with low initial levels of EGFR/HER2 because expression of these proteins can increase when ER is blocked. The EGFR inhibitor gefitinib was chosen since it inhibits signaling from EGFR homo- and heterodimers and since it was effective in preclinical studies in which upregulation of EGFR was a dominant characteristic of tamoxifen-resistant tumors (16
This randomized Phase II trial was not designed to show a statistically significant advantage for the addition of gefitinib to tamoxifen, but rather to determine if the addition of gefitinib resulted in a numerical advantage compared with placebo of sufficient interest to warrant further study. This proof-of-concept trial included two different studies that differ with regards to the patient population, primary endpoints, and sample size. In Stratum 1, patients receiving tamoxifen plus gefitinib did have a numerical advantage compared with placebo in PFS; this numerical advantage was greater than the predefined criterion (≥ 5% advantage predefined as being the minimum to warrant further investigation of this strategy). Stratum 1 patients also had a slight numerical advantage for gefitinib in CBR (10%). Although there was a greater numerical PFS advantage for gefitinib in patients whose initial primary tumor was HER2-expressing (Allred score ≥ 3), this did not explain the entire PFS advantage of gefitinib seen in this stratum since a small minority of the patients were HER2 positive. Furthermore, the HR for the subset with Allred scores ≥ 6 which correlates with gene amplification was 0.82, very similar to that for the entire group in Stratum 1. This suggests that patients whose tumors were initially low/negative for HER2 and EGFR may also have received some benefit compatible with the clinical and preclinical observations that EGFR and HER2 levels can increase during tamoxifen treatment in some tumors (13
The retrospective analysis by previous endocrine therapy provided further insight into which groups of patients in Stratum 1 may obtain the greatest benefit from gefitinib and tamoxifen combination therapy. Numerically prolonged PFS was observed in endocrine therapy-naïve patients compared to a numerical disadvantage in patients who had received prior endocrine therapy, although the interaction test did not reach statistical significance at the conventional 5% level. ORRs were not numerically superior with gefitinib in either the endocrine therapy-naïve or those with prior endocrine therapy. Similar findings have also been reported in a subset analysis of a second placebo-controlled trial evaluating gefitinib plus anastrozole v
anastrozole alone (NCT00077025) in postmenopausal women with newly-diagnosed hormone receptor-positive metastatic breast cancer (27
). PFS was prolonged in the endocrine therapy-naïve patient subgroup when gefitinib was combined with anastrozole compared with anastrozole alone (median PFS 20.2 months versus 8.4 months [HR 0.39; 95% CI 0.16, 0.97]); while in the prior endocrine therapy subgroup there appeared to be less benefit from adding gefitinib (median PFS 11.2 vs 7.1 months [HR 0.65; 95% CI 0.32, 1.33]).
The results for Stratum 2 (patients progressing after AI treatment) demonstrated no objective responses in either arm of this stratum, but in the placebo arm slightly more patients had SD and there was also a slight advantage in PFS compared with the gefitinib arm. This result suggests that tamoxifen plus gefitinib given after resistance to an AI is not effective.
It could be argued that the 5% improvement in PFS with gefitinib established before the study began was too low to provide a meaningful indicator that this strategy was worth additional study. However, because of difficulties inherent in biopsying metastatic breast cancer just before treatment to assess EGFR/HER2 status and not knowing how often EGFR/HER2 would increase over time with treatment, a relatively low bar was set so as not to miss a hint of activity that might be important for a small subset of patients. Furthermore, the response rate of gefitinib in prior studies in unselected patients with metastatic disease was very low (28
Both regimens were reasonably well tolerated, although there were more AEs in the gefitinib arm that led to a higher withdrawal rate. The AEs reported in this study are consistent with the established safety profile of gefitinib and the clinical characteristics of the patients did not suggest any difference in safety between the two strata.
The results in Stratum 1 lend support to the idea that signaling through the EGFR/HER2 pathway may contribute to acquired resistance to tamoxifen in some patients. ER-positive patients rarely express detectable levels of EGFR, and only overexpress HER2 in about 12% of cases. The 18% reported in this study may be due to the definition used (Allred score ≥ 3). It is possible that tumors with initially low expression of EGFR and HER2 may upregulate the expression of these receptors when the patient is treated with tamoxifen or other ER-targeted therapies. ER signaling is known to downregulate the expression of EGFR and HER2, and, therefore, it is not surprising that ER blockade might therefore increase expression of these receptors (29
). More clinical biomarker data are needed to determine how frequently this occurs in patients, although three small studies evaluating HER2 reported increasing levels in 12-35% of patients treated with endocrine therapy (13
). It will also be important to determine if molecular profiling of the primary tumor can predict which tumors are likely to increase the expression of EGFR/HER2 when treated with ER-targeted therapy. Our biomarker studies of EGFR, p-ERK, p-Akt, and p-27 were disappointing in this regard. Perhaps the results are not surprising since these biomarkers were determined on the primary tumor before any treatment and would not necessarily predict the pathway driving tumor growth when the tumor recurs sometimes years later or after intervening treatment. The correlation between low ER determined by a sensitive fluorescence method and benefit with gefitinib should be interpreted with great caution and could be due to chance alone. However, tumors with active growth factor receptor signaling or high PI3K activity tend to have lower ER expression, and it is interesting to speculate that such tumors may be those most likely to upregulate EGFR and then be inhibited by EGFR blockade (30
). Furthermore the correlation between lower ER and benefit from the addition of lapatinib to letrozole was recently reported lending support to this possibility (31
). The results also suggest that to more accurately select patients for this kind of targeted therapy, a tumor biopsy taken just before the start of treatment is likely to be more informative. Preliminary results from a small recently reported study showing an advantage for anastrozole plus gefitinib compared with anastrozole alone and an exploratory analysis of HER2-negative patients in a very large recent randomized trial of letrozole with or without lapatinib lend support to our hypothesis and suggest that the HER pathway may also be important for acquired resistance to AIs (27
The small numerical disadvantage with gefitinib in patients resistant to AIs in Stratum 2 is difficult to explain and may reflect low patient accrual. The results for Stratum 2 (patients progressing after AI treatment) demonstrated no objective responses in either arm of this stratum. The marginally greater number of patients who had SD and the slight advantage in PFS in the placebo arm represented a numerical disadvantage for gefitinib when given to patients who have developed resistance to an AI and indicates that further investigation in this group of patients is not warranted. Perhaps blocking EGFR led to enhanced signaling from other HER receptor dimers that generate more potent survival stimuli in some tumors.
A problem that complicates virtually all metastatic breast cancer studies is that expression levels of biomarkers are usually measured on the primary tumor but are not reassessed in metastatic disease that is not easily biopsiable prior to starting protocol therapy. Although 98% of the primary tumors from patients on this study were ER-positive, some would have been expected to lose ER at the time of recurrence when they entered the study (33
), and others might have increased levels of EGFR or HER2 due to prior endocrine therapy. In this era of targeted therapy serial tissue biopsies will be necessary to accurately determine optimal therapy at any timepoint in individual patients. Nevertheless, this study together with others showing similar results lends support to the hypothesis that the EGFR/HER2 pathway may contribute to the development of tamoxifen resistance in some patients and that further investigation of this approach is warranted.