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

Hanker, Ariella B.; Brewer, Monica Red; Sheehan, Jonathan H.; Koch, James P.; Sliwoski, Gregory; Nagy, Rebecca J.; Lanman, Richard B.; Berger, Michael F.; Hyman, David M.; Solit, David B.; He, Jie; Miller, Vincent A.; Cutler, Richard E.; Lalani, Alshad S.; Cross, Darren A.E.; Lovly, Christine M.; Meiler, Jens; Arteaga, Carlos L.

doi:10.1158/2159-8290.cd-16-1431

Cited by 90 publications

(72 citation statements)

References 39 publications

(42 reference statements)

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“…1). Consistent with this, another group separately reported identification of a gatekeeper HER2 T789I mutation in a HER2-mutant patient treated with neratinib (34). Another group recently reported a case series of patients with ER + breast cancer who developed emergence of HER2 mutations after exposure to various antiestrogen therapies (14).…”

Section: Discussionmentioning

confidence: 70%

Efficacy and Determinants of Response to HER Kinase Inhibition inHER2-Mutant Metastatic Breast Cancer

et al. 2020

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HER2 mutations defi ne a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversi ble pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER + patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2 -activating events , as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefi t from neratinib. Collectively, these data defi ne HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations defi ne a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modifi ed by the presence of concurrent activating genomic events in the pathway. These fi ndings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defi ned subset of breast cancer.

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Section: Discussionmentioning

confidence: 70%

Efficacy and Determinants of Response to HER Kinase Inhibition inHER2-Mutant Metastatic Breast Cancer

et al. 2020

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“…Further, 24% of those resistance-harboring samples (91/381) had >1 alteration associated with resistance to the same therapy, suggesting independent evolution in distinct tumor lesions (20) or sequential treatment with distinct therapies targeted to the same gene. For example, one NSCLC patient had an EML4-ALK fusion (VAF of 7.1%) and ALK SNVs reported to confer resistance to crizotinib (L1196M, 2.5%), crizotinib/alectinib (I1171T, 0.1%), and crizotinib/ceritinib/alectinib (G1202R, 5% relative to the original driver alteration and many were missed by single-metastatic-site tissue biopsy but confirmed by repeat biopsy or biopsy of multiple metastases at autopsy (21,22,25).…”

Section: The Landscape Of Actionable Resistance Alterations In Cfdnamentioning

confidence: 99%

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Zill

Banks

Fairclough

et al. 2018

Clinical Cancer Research

308

249

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Running title: Somatic genomic landscape of circulating tumor DNA Keywords: circulating tumor DNA, tumor heterogeneity, resistance, genomic landscape, cfDNA clonality Financial support: The study was funded by and conducted at Guardant Health, Inc. No additional grant support or administrative support was provided for the study. *Corresponding author:Stephen R. Fairclough Translational relevanceThis study describes genomic alterations from the largest cell-free circulating tumor DNA cohort to date, as derived from regular clinical practice. The high prevalence of resistance alterations found in advanced, treated cancer patients necessitated accurate methods for determining mutation clonality and driver/resistance status from plasma. We provide such methods, thereby extending the utility of cell-free DNA sequencing analysis. Our finding of an association between estimated circulating tumor DNA (ctDNA) levels and tumor mutational burden ascertained from plasma suggests that ctDNA level is likely an important variable to consider for immunotherapy applications of ctDNA analysis. Although cell-free DNA can provide a summary of tumor heterogeneity across multiple metastatic sites in a patient, our findings of high variability in ctDNA levels across patients, and its impact on variant detection, highlight the need for an improved understanding of factors influencing ctDNA levels and safe methods for maximizing them at the time of ctDNA testing. AbstractPurpose: Cell-free DNA (cfDNA) sequencing provides a non-invasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants.Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. To facilitate interpretation of the genomic complexity of circulating tumor DNA in advanced, treated cancer patients, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality.Results: Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (TCGA and COSMIC;, with the principle differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naïve tumors. Upon applying novel cfDNA clonality and copy-number driver identification methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations (FDR=5x10 -7 for EGFR and ERBB2), in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel ...

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“…However, there has been no large clinical trial of afatinib or osimertinib conducted for ERBB2 mutation-positive cancers. Moreover, recent studies have also reported the emergence of ERBB2 K753E or L755S mutation after trastuzumab treatment or of ERBB2 T798I mutation after neratinib treatment, suggesting that acquired secondary mutations may be a mechanism of resistance to ERBB2-targeted inhibitors (25,26).…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2

Nagano

Kohsaka

Ueno

et al. 2018

Clinical Cancer Research

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The advent of next-generation sequencing technologies has enabled the identification of several activating mutations of Erb-B2 receptor tyrosine kinase 2 (ERBB2) among various cancers. However, the significance of infrequent mutations has not been fully investigated. Herein, we comprehensively assessed the functional significance of the mutations in a high-throughput manner. We evaluated the transforming activities and drug sensitivities of 55 nonsynonymous mutations using the mixed-all-nominated-in-one (MANO) method. G776V, G778_S779insG, and L841V were newly revealed to be activating mutations. Although afatinib, neratinib, and osimertinib were shown to be effective against most of the mutations, only osimertinib demonstrated good efficacy against L755P and L755S mutations, the most common mutations in breast cancer. In contrast, afatinib and neratinib were predicted to be more effective than other inhibitors for the A775_776insYVMA mutation, the most frequent mutation in lung cancer. We surveyed the prevalence of concurrent mutation with gene amplification and found that approximately 30% of ERBB2-amplified urothelial carcinomas simultaneously carried mutations, altering their sensitivity to trastuzumab, an mAb against ERBB2. Furthermore, the MANO method was applied to evaluate the functional significance of 17 compound mutations within reported in the COSMIC database, revealing that compound mutations involving L755S were sensitive to osimertinib but insensitive to afatinib and neratinib. Several mutations showed varying sensitivities to ERBB2-targeted inhibitors. Our comprehensive assessment of mutations offers a fundamental database to help customize therapy for ERBB2-driven cancers.We identified several mutations as activating mutations related to tumorigenesis. In addition, our comprehensive evaluation revealed that several mutations showed varying sensitivities to ERBB2-targeted inhibitors, and thus, the functional significance of each variant should be interpreted precisely to design the best treatment for each patient. .

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

Cited by 90 publications

References 39 publications

Efficacy and Determinants of Response to HER Kinase Inhibition inHER2-Mutant Metastatic Breast Cancer

Efficacy and Determinants of Response to HER Kinase Inhibition inHER2-Mutant Metastatic Breast Cancer

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2

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