Our results document activity of combination anastrozole plus gefitinib and of fulvestrant and gefitinib. The phase II nature of this trial does not allow the assessment of the antitumor activity provided by gefitinib alone, endocrine therapy alone, or the combination of gefitinib plus endocrine therapy. There was a 35% frequency of Grade 3–4 toxicity in this trial, therefore the safety profile of the combinations was less favourable than that expected with any of the agents alone.”
Two randomized studies have compared fulvestrant to anastrozole as second-line endocrine therapy in postmenopausal women with endocrine sensitive advanced breast cancer. A combined analysis of these studies documented a clinical benefit rate with fulvestrant of 43.5% and with anastrozole of 40.9%.[16
] As the clinical benefit rate is highly dependent upon patient population, direct comparison of these clinical benefit rates with those experienced in our patient population is difficult and is impacted by differences in patient population, sites of disease, and measurement of effect. However, comparison of these published data with those obtained in the present study suggests no improvement in overall rates of response with the addition of gefitinib to endocrine therapy with fulvestrant or anastrozole.
A recent multi-institutional, double-blind randomized clinical trial compared fulvestrant 500 mg monthly (plus a loading dose) versus 250 mg monthly in postmenopausal women with ER and/or PgR positive or ER and PgR unknown metastatic breast cancer previously untreated with endocrine therapy. [17
] This trial demonstrated a statistically significant improvement in progression free survival (hazard ratio 0.80; 95% confidence interval 0.68 – 0.94; P
= 0.006) with no statistically significant difference in objective response rate, clinical benefit rate, or overall survival. As our trial utilized a dose of fulvestrant 250 mg, it is possible that a high dose would have been associated with an improvement in outcome.
A randomized phase II trial of neoadjuvant anastrozole or anastrozole plus gefitinib in postmenopausal women with hormone receptor positive breast cancer, demonstrated that the addition of gefitinib to anastrozole was not superior to anastrozole alone, with objective rates or response of 48% and 61%, respectively.[18
] In another study, 93 postmenopausal women with hormone receptor-positive disease who had not received prior endocrine therapy for metastatic disease were enrolled and randomized on a phase II trial of anastrozole in combination with either gefitinib or placebo.[19
] The clinical benefit rate for anastrozole plus gefitinib was 49% compared with 34% with anastrozole plus placebo. Progression free survival also favored anastrozole plus gefitinib (hazard ratio 0.55; 95% confidence interval 0.32 – 0.94; median progression-free survival 14.7 vs. 8.4 months).
In this study, the clinical benefit rates are 44% (95% confidence interval 33%–57%) with anastrozole plus gefitinib and 41% (95% confidence interval 29%–53%) with fulvestrant plus gefitinib. While our study did not include a gefitinib alone or endocrine therapy alone cohort, these clinical benefit rates are not clearly superior to those with endocrine therapy alone,[20
] and are similar to that of gefitinib alone in tamoxifen resistant disease.[8
] The limited benefit of adding gefitinib may be related to multiple mechanisms. Only approximately 30% of ER/PgR positive breast cancers over-express EGFR, and those that do tend to be more aggressive and resistant to endocrine therapy. Our subjects were not selected for levels of EGFR expression, and it is possible that the impact of even a highly active endocrine therapy might be missed because of a high proportion of tumors not expressing high levels of EGFR. We do not have information regarding the degree of EGFR inhibition at the dose of 250 mg of gefitinib, and it is possible that more selective and complete inhibition of tumoral EGFR would be more effective. There is also evidence that HER2 expression is associated with endocrine resistance, and gefitinib does not suppress HER2-related signaling.[1
] Tumor blocks were collected as a part of the current clinical trial, and biomarker assessment is in process to address some of these important questions. Multiple additional questions exist regarding the importance of facilitating or inhibiting various combinations of multiple regulators of signaling pathways including EGFR, HER2, mTOR, ER, PgR and others, and how they interact with each other in clinical outcomes.
Areas for further investigation include the performance of a prospective randomized trial of endocrine therapy alone versus endocrine therapy plus EGFR inhibition using either targeted EFGR inhibition or an inhibitor of multiple growth factor receptors. Important design considerations in such a trial would include determination and stratification of initial EGFR status and outcomes. It could be argued that subjects with an initially increased expression of EGFR would be those most likely to benefit from EFGR inhibition, although it could also be argued that the prevention of acquired endocrine resistance in those with low initial EGFR expression is at least as important. Only prospective clinical trials with assessment of biomarker expression including quantitative ER, PgR, EFGR, and HER2 measurements is likely to further clarify these important considerations.
Based upon the results of this randomized phase II trial, the antitumor activity of anastrozole plus gefitinib and fulvestrant plus gefitinib appears modest, and these combinations have a less favorable safety profile compared to endocrine monotherapy Further trials of these combinations do not appear warranted.