[P3-14-16] Can Resistance to Trastuzumab Be Reversed by Endocrine Therapy? Results from a Proof-of-Principle Trial in Postmenopausal Patients with Hormonal Receptor (HR) Positive, HER-2 Positive Advanced Breast Cancer (SAKK 23/03).
Koeberle D, Ruhstaller T, Jost L, Pagani O, Zaman K, von Moos R, Crowe S, Thuerlimann B, on Behalf of the Swiss Group for Clinical Cancer Research (SAKK). Kantonsspital St. Gallen, St. Gallen, Switzerland; Bruderholz Hospital, Basel, Switzerland; Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland; University Hospital CHUV, Lausanne, Switzerland; Kantonsspital Chur, Chur, Switzerland; Statistics Unit, SAKK Coordination Center, Berne, Switzerland
Introduction: Trastuzumab (T) is a cornerstone in the treatment of patients with HER2-overexpressing advanced breast cancer and development of resistance to T is a major therapeutic problem. HER-2 is part of a highly interactive signaling network that may impair efficacy of endocrine therapy. A sequential treatment design was chosen in this trial to ensure complete resistance to single agent therapy before receiving both a non-steroidal aromatase inhibitor (AI) and T. Any kind of clinical activity with combined treatment of AI and T after progression of single agent treatments could indicate restoration of sensitivity as a consequence of cross-talking and networking between both pathways.
Methods: Key eligibility criteria included postmenopausal patients (pts.) with advanced, measurable, HER-2 positive (assessed by FISH, ratio (≥2)), HR positive disease and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in an adjuvant or advanced setting. Pts. received standard dose T monotherapy either weekly or three-weekly in step 1 and upon disease progression, continued T in combination with letrozole in step 2. The primary endpoint was clinical benefit response (CBR: CR, PR or SD for at least 24 weeks (+/- 1 week) according to RECIST) in step 2.
Results: Thirteen pts. were enrolled in five centers in Switzerland. In step 1, six pts. (46%) achieved CBR. Median time to progression (TTP) was 161 days (Range: 50 - 627). Based on data collected until the end of May 2010, CBR was observed in seven out of the eleven evaluable pts. (64%) in step 2, including one pt. with partial response. Four of the seven pts. within step 2 that achieved CBR also had CBR in step 1. Seven out of eleven pts. have documented tumor progression during step 2 treatment. Median TTP for all eleven pts. was 184 days (range 61 - 471). Mean time on study treatment (TTP in step 1 plus TTP in step 2) for pts. reaching step 2 was 380 days (range 174 - 864). Adverse events were generally mild.
Conclusion: Results of this proof-of-principle trial suggest that complete resistance to both AI and T can be overcome in a proportion of pts. by combined treatment of AI and T, as all pts. served as their own control. Our results appear promising for a new treatment strategy which offers a chemotherapy-free and well-tolerated option for at least a subset of the pts. with HR positive, HER-2 positive breast cancer. Further trials will need to corroborate this finding.
Friday, December 10, 2010 5:30 PM
Poster Session 3: Treatment - Therapeutic Strategies: HER2-Targeted Therapy (5:30 PM-7:30 PM)