Abstract PD2-08: Neratinib + fulvestrant in <i>ERBB2</i>-mutant, HER2–non-amplified, estrogen receptor (ER)-positive, metastatic breast cancer (MBC): Preliminary analysis from the phase II SUMMIT trial

Hyman, D. M.; Piha-Paul, S. A.; Saura, Cristina; Arteaga, CL; Mayer, Ingrid; Shapiro, Geoffrey I.; Loi, Sherene; Lalani, AS; Xu, Fengrui; Cutler, Richard E.; Butturini, Anna; Bryce, RP; Meric‐Bernstam, Funda; Baselga, José; Solit, D.

doi:10.1158/1538-7445.sabcs16-pd2-08

Cited by 18 publications

(15 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet the majority of the patients with those HER2 mutations did not benefit from Nrb treatment alone. A recent preclinical study in ER+ MCF7 cells expressing HER2 kinase domain mutations (52), as well as early results from an additional clinical trial investigating the efficacy of Nrb + fulvestrant in ER+ metastatic breast cancer patients with HER2 mutations (SUMMIT, NCT01953926) (53), further support the notion that a simultaneous inhibition of ER (fulvestrant) and the mutant HER2 by irreversible TKIs is needed. However, a significant portion of patients did not benefit even with the combination of Nrb+fulvestrant while other patients developed acquired resistance.…”

Section: Discussionmentioning

confidence: 85%

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Angelis

Burke

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Resistance to anti-HER2 therapies in HER2+ breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2+ breast cancer can reactivate the HER network under potent HER2-targeted therapies. Experimental Design Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER+/HER2+ BT474 cell lines (AZ/ATCC). Two derivatives resistant to the L-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared to parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. In vitro and in vivo experiments were performed to test alternative therapies for mutant HER2 inhibition. Results Genomic analyses revealed that the HER2L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of HER2L755S induced acquired L resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. HER2L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2 irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by HER2L755S in vitro and in vivo. Conclusion HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to L-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors.

show abstract

Section: Discussionmentioning

confidence: 85%

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Angelis

Burke

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…We speculate these co-mutations resulted in increased dependence on the ERBB pathway and contributed to the tumor’s initial sensitivity to neratinib. Consistent with this speculation, preliminary results from the SUMMIT trial show that among 17 patients who exhibited clinical benefit from neratinib, 2 patients harbored ERBB3 missense mutations, whereas none of the 25 patients who did not benefit harbored ERBB3 alterations in their cancer (27). …”

Section: Discussionmentioning

confidence: 78%

An Acquired HER2 T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant–Driven Breast Cancer

et al. 2017

View full text Add to dashboard Cite

We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I. In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib.

show abstract

“…Studies have shown that tumours carrying these activating HER2 mutations respond to treatment with the irreversible pan-HER kinase inhibitor neratinib [219,220]. Preliminary results from the ongoing SUMMIT trial, exploring the efficacy of neratinib in patients carrying activating HER2 and HER3 mutations, have been encouraging [221,222], while other work continues to investigate how specific mutations may impact responsiveness to this and other inhibitors [223].…”

Section: Somatic Mutations In Her2 As Biomarkersmentioning

confidence: 99%

The evolving role of receptors as predictive biomarkers for metastatic breast cancer

Martínez-Pérez

Turnbull

Dixon

2018

Expert Review of Anticancer Therapy

View full text Add to dashboard Cite

Introduction:In breast cancer, oestrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) are essential biomarkers to predict response to endocrine and anti-HER2 therapies, respectively. In metastatic breast cancer, the use of these receptors and targeted therapies present additional challenges: temporal heterogeneity, together with limited sampling methodologies, hinders receptor status assessment and the constant evolution of the disease invariably leads to resistance to treatment. Areas covered:We summarise genomic abnormalities in ER and HER2, such as mutations, amplifications, translocations and alternative splicing, emerging as novel biomarkers that provide an insight into underlying mechanisms of resistance and hold potential predictive value to inform treatment selection. We also describe how liquid biopsies for sampling of circulating markers and ultrasensitive detection technologies have emerged which complement ongoing efforts for biomarker discovery and analysis. Expert commentary:While evidence suggests that genomic aberrations in ER and HER2 could contribute to meeting the pressing need for better predictive biomarkers, efforts need to be made to standardise assessment methods and better understand the resistance mechanisms these markers denote. Taking advantage of emerging technologies, research in upcoming years should include prospective trials incorporating these predictors into the study design to validate their potential clinical value.

show abstract

Abstract PD2-08: Neratinib + fulvestrant in ERBB2-mutant, HER2–non-amplified, estrogen receptor (ER)-positive, metastatic breast cancer (MBC): Preliminary analysis from the phase II SUMMIT trial

Cited by 18 publications

References 0 publications

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

An Acquired HER2 T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant–Driven Breast Cancer

The evolving role of receptors as predictive biomarkers for metastatic breast cancer

Contact Info

Product

Resources

About