A phase II trial of letrozole and trastuzumab for ER and/or PgR and HER2 positive metastatic breast cancer: Final results

Abstract

596 Background: About 50% of HER2+ breast cancers exhibit ER coexpression and HER2 signaling may impair responses to endocrine treatment. A Phase II trial was therefore conducted to examine trastuzumab (TRAS) with letrozole (LET) in patients with ER and HER2 positive advanced disease. Methods: Postmenopausal women with ER and/or PR+, HER2 IHC 2–3+ or FISH+, measurable (WHO) metastatic breast cancer, ECOG 0–2 and LVEF greater than 50%. Loading dose TRAS within 28 days of initiating aromatase inhibitor (AI). Patients who had been started on other AI were switched to LET. The exclusion criteria were prior AI > 28 days, prior TRAS, cumulative anthracycline > 360 mg/m2, brain metastases, visceral crisis, prior radiation to only evaluable lesion, severe comorbidity or other malignancies and > 1 prior chemotherapy for metastatic disease. All responses at 3 months were confirmed with a second CT scan at six months. Results: 32 patients were accrued. The majority had visceral metastases (72%). Twenty tumors were either HER2 3+ and/or FISH+, the rest were either 2+ to 3+ or 2+. 30 were ER+ and 2 ER-, PgR+. Twenty-six had received prior tamoxifen the remaining six were endocrine-therapy naïve. Of 27 patients evaluable for response at the time of this report, there were 2 CR, 5 PR, 7 SD (at 24 weeks) and 13 PD giving an objective RR of 25% and clinical benefit rate (response or stable disease) of 52%. Median duration of response was 73 weeks (range 47 to 180+). The median overall TTP was 32 weeks (range 6 to 180+ weeks). Of the remaining 5 patients, 2 have been followed for less than 24 weeks, 1 came off study early for toxicity and 2 withdrew consent before response could be assessed. 7 patients are still on therapy. The toxicities were mainly grade 1 to 2. The only serious complication was cardiomyopathy in a patient with prior doxorubicin and left chest wall irradiation. Conclusions: TRAS with LET was well-tolerated and active with durable responses in about 1 in 4 patients. However, despite dual targeting, early progression occurred in 1 in 2 patients suggesting TRAS and AI have common resistance pathways. A final update and a central HER2 FISH analysis will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Genentech, Novartis Genentech, Novartis