Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with estrogen receptor-positive, HER-2-positive advanced breast cancer: a proof-of-concept trial (SAKK 23/03)

Abstract

A sequential treatment design was chosen in this trial to ensure complete resistance to singleagent non-steroidal aromatase inhibitor (AI) and trastuzumab both given as monotherapy before receiving the combination of a non-steroidal AI and trastuzumab. Key eligibility criteria included postmenopausal patients with advanced, measurable, human epidermal growth factor receptor-2 (HER-2)-positive disease (assessed by FISH, ratio (R2)), hormone receptor (HR)-positive disease, and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in the adjuvant or in the advanced setting. Patients received standard dose trastuzumab monotherapy in step 1 and upon disease progression continued trastuzumab in combination with letrozole in step 2. The primary endpoint was clinical benefit rate (CBR) in step 2. Totally, 13 patients were enrolled. In step 1, six patients (46%) achieved CBR. Median time to progression (TTP) was 161 days (95% confidence interval (CI): 82-281). In step 2, CBR was observed in eight out of the 11 evaluable patients (73%), including one patient with partial response. Median TTP for all the 11 patients was 188 days (95% CI: 77-not reached). Results of this proof-of-concept trial suggest that complete resistance to both AI and trastuzumab can be overcome in a proportion of patients by combined treatment of AI and trastuzumab, as all patients served as their own control. Our results appear promising for a new treatment strategy that offers a chemotherapy-free option for at least a subset of patients with HR-positive, HER-2-positive breast cancer over a clinically relevant time period.

Endocrine resistance in breast cancer – An overview and update

“…Overexpression of EGFR or HER2 generally downregulates ERα expression in experimental models [132], and HER2 overexpression is often associated with a clinically meaningful but less robust response to endocrine therapies [133]. Studies in the subgroup of ERα+/HER2+ breast cancers, comprising approximately 10% of all ERα+ breast cancers, suggest a modest potential benefit in combining endocrine therapies with inhibition of HER2 or its signaling for these patients [134–136]. Whether strategies that combine EGFR and endocrine interventions will have an advantage in the chemopreventive setting also remains unclear [137].…”

Meeting the needs of breast cancer: A nucleolin’s perspective

“…The overexpression of HER2 in luminal tumors have also been associated with increased relapse rate in patients treated with endocrine therapy, compared with HER2 negative tumours 57 . Moreover, in those patients with HER2-overexpressing tumors, the combination of endocrine and anti-HER2 therapy revealed a significant therapeutic benefit (Table 1.3) 21,35,36,58,59 , and recent evidence further suggested that complete resistance to both Anastrozole and Trastuzumab sequential monotherapies can be overcome in a proportion of patients, through the combined treatment with these compounds 60 .…”

Models and mechanisms of acquired antihormone resistance in breast cancer: significant clinical progress despite limitations

“…Fulvestrant (to destroy the ER) plus an aromatase inhibitor is superior to either strategy alone [86] and trastuzumab reverses letrozole resistance and amplifies the sensitivity of breast cancer cells to estrogen [161]. Each of these strategies have been addressed in clinical trials [162–164] recruiting patients with ER-positive tumors in late-stage breast cancer, but it will be in the adjuvant setting that most gains may occur for patient survivorship. Osborne’s group [155,165] has independently pioneered the strategy of using multiple inhibitors of the growth factor receptor family in combination with either estrogen deprivation or tamoxifen therapy and these strategies are moving into clinical trial.…”