Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study

Abstract

Background HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines. Methods The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models. Results We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively). Conclusions Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.

Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer

“…Comparing three autopsy cases with multiple tumor lesions available for analysis, we find an association between absence of TROP2 expression and a lack of clinical response to SG. In general, reduced expression of an ADC target antigen could impact both binding of the antibody as well as intracellular uptake and payload release (15,16). In the pivotal EMILIA trial, which led to approval of the HER2-directed ADC trastuzumab emtansine (T-DM1) for metastatic HER2+ breast cancer, the survival benefit with T-DM1 compared to control arm was greater in patients whose tumors had high HER2 mRNA levels (Hazard Ratio = 0.53; median OS, 34.1 vs. 26.5 months), compared to lower HER2 mRNA levels (Hazard Ratio, 0.80; median OS, 24.8 vs. 23.7 months) (17).…”

Imaging-Guided Therapy Simultaneously Targeting HER2 and EpCAM with Trastuzumab and EpCAM-Directed Toxin Provides Additive Effect in Ovarian Cancer Model

“…To overcome it, combination therapies have been investigated, such as the addition of pertuzumab, a mAb also targeting HER2, or the tyrosine kinase inhibitor lapatinib, or targeted delivery of a cytotoxic drug by the antibody-drug conjugate (ADC) trastuzumab emtansine (T-DM1) [14]. Mechanisms involved in resistance to treatment are shared between HER2-targeting agents [14] and cases with a reduced number of HER2 receptors on the cancer cell membrane due to exposure to trastuzumab have been reported [15]. The heterogeneity of HER2 expression within tumors in the same patient and between patients also creates issues for HER2-targeting therapy [16].…”

EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

“…Inhibition of apoptotic pathways[65,66], activation of bypass receptors (i.e., HER3, MET, AXL, ER)[67][68][69][70], activation of downstream signaling pathways[71,72], T798I mutation[73,74]. Expression of a truncated form of HER2 (p95HER2)[75], decreased mAb binding to the receptor due to overexpression of Mucin 4 (epitope masking)[76], activation of downstream signaling pathways[77][78][79], activation of bypass receptors[80][81][82], impaired ADCC (FcγRIII 158 V/F or 158 F/F polymorphisms)[83], loss of HER2[84].…”