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New HER2-negative breast cancer subtype responsive to anti-HER2 therapy identified.

ABSTRACT: PURPOSE:HER2 signaling functional activity may be important to measure in addition to HER2 protein quantification when identifying patients eligible for HER2 therapies. A HER2 Signaling Function (CELx HSF) Test for HER2-negative patients uses patient's live tumor cells on a biosensor to identify patients with abnormally high HER2-related signaling (HSFs+) likely to respond to anti-HER2 therapies. METHODS:The CELx HSF test was employed to: (1) characterize the sensitivity and specificity of the test to detect abnormal levels of HER2 signaling; (2) evaluate the inhibitory effectiveness of five different anti-HER2 therapies; (3) assess the correlation between CELx HSF test detection of abnormal HER2 signaling and response to HER2 therapy using xenograft models; and (4) confirm the prevalence of abnormal HER2 signaling amongst HER2-negative breast cancer patients (HER2-/HSFs+). RESULTS:HER2-/HSFs+?breast cancer patient samples were identified and showed sensitivity to five approved anti-HER2 therapies. Xenograft studies using both HER2+?and HER2- cell lines confirmed that CELx HER2 signaling status better predicts HER2 inhibitor efficacy than HER2 receptor status. In a study of 114 HER2-negative breast tumor patient samples, 27 (23.7%; 95% CI?=?17-32%) had abnormal HER2 signaling (HSFs+). A ROC curve constructed with this dataset projects the CELx HSF Test would have greater than 90% sensitivity and specificity to detect the HER2-/HSFs+?patient population. CONCLUSIONS:The CELx HSF test is a well-characterized functional biomarker assay capable of identifying dynamic HER2-driven signaling dysfunction in tumor cells from HER2-negative breast cancer patients. This test has demonstrated efficacy of various HER2 targeted therapies in live tumor cells from the HSFs+?population and correlated the test result to HER2 drug response in mouse xenograft studies. The proportion of HER2-negative breast cancer patients found to have abnormal HER2 signaling in a 114 patient sample study, 20-25%, is significant. A clinical trial to evaluate the efficacy of anti-HER2 therapies in this patient population is warranted.

SUBMITTER: MacNeil IA

PROVIDER: S-EPMC7039866 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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New HER2-negative breast cancer subtype responsive to anti-HER2 therapy identified.

MacNeil Ian A IA Burns David J DJ Rich Benjamin E BE Soltani Sajjad M SM Kharbush Samantha S Osterhaus Nicole G NG Sullivan Brian F BF Hawkins Douglas M DM Pietruska Jodie R JR Laing Lance G LG

Journal of cancer research and clinical oncology 20200208 3

<h4>Purpose</h4>HER2 signaling functional activity may be important to measure in addition to HER2 protein quantification when identifying patients eligible for HER2 therapies. A HER2 Signaling Function (CELx HSF) Test for HER2-negative patients uses patient's live tumor cells on a biosensor to identify patients with abnormally high HER2-related signaling (HSFs+) likely to respond to anti-HER2 therapies.<h4>Methods</h4>The CELx HSF test was employed to: (1) characterize the sensitivity and speci ...[more]

PMID: 32036454

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Project description:PurposeThe 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline on HER2 testing in breast cancer permits reclassification of cases with HER2-equivocal results by FISH. The impact of such reclassification is unclear. We sought to determine the proportion of HER2-equivocal cases that are reclassified as HER2-negative and the impact of anti-HER2 therapy on survival in HER2-equivocal cases.MethodsWe reviewed medical records of breast cancer patients who had HER2 testing by fluorescence in stitu hybridization (FISH) and immunohistochemistry (IHC) performed or verified at The University of Texas MD Anderson Cancer Center during April 2014 through March 2018 and had equivocal results according to the 2013 ASCO/CAP guideline. The population was divided into 2 cohorts according to whether the biopsy specimen analyzed came from primary or from recurrent or metastatic disease. HER2 status was reclassified according to the 2018 ASCO/CAP guideline. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method, and the relationship between anti-HER2 therapy and clinical outcomes was assessed.ResultsWe identified 139 cases with HER2-equivocal results according to the 2013 ASCO/CAP guideline: 90 cases of primary disease and 49 cases of recurrent/metastatic disease. Per the 2018 ASCO/CAP guideline, these cases were classified as follows: overall, HER2-negative 112 cases (80%), HER2-positive 1 (1%), and unknown 26 (19%); primary cohort, HER2-negative 85 (94%), HER2-positive 1 (1%), unknown 4 (4%); and recurrent/metastatic, HER2-negative 27 (55%) and unknown 22 (45%). Five patients in the primary-disease cohort and 1 patient in the recurrent/metastatic-disease cohort received anti-HER2 therapy. There was no significant association between anti-HER2 therapy and OS or EFS in either cohort (primary disease: OS, p = 0.67; EFS, p = 0.49; recurrent/metastatic-disease, OS, p = 0.61; EFS, p = 0.78.ConclusionsThe majority of HER2-equivocal breast cancer cases were reclassified as HER2-negative per the 2018 ASCO/CAP guideline. No association between anti-HER2 therapy and OS or EFS was observed. HER2-equivocal cases seem to have clinical behavior similar to that of HER2-negative breast cancers.

Project description:Amplification of chromosome 17q23 is a frequent genomic event that occurs in ~ 11% of human breast cancers. The 17q23 amplification is enriched in HER2+ breast cancers, which is significantly correlated with poor clinical outcomes. Previous studies have identified the oncogenic phosphatase WIP1 gene in the amplicon, which functions as a master inhibitor in DNA damage response. While the possibility of any other protein-coding oncogenes in the WIP1-containing 17q23 amplicon was ruled out, our analysis of human breast cancer genomics uncovered an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing amplicons. Interestingly, DEAD-box helicase 5 (DDX5), co-amplified with WIP1 and MIR21 in the 17q23 amplicon, facilitates the essential processing of primary miR-21 transcripts. Accordingly, the 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 using small molecular inhibitor against WIP1 (GSK2830371) and anti-miR-21 oligonucleotides selectively inhibits the proliferation, survival and tumorigenic potential of HER2+ breast cancer cells harboring 17q23 amplification. However, the in vivo bioavailability of the two agents in their free form is poor. To overcome the resistance of trastuzumab-based therapies in vivo, we developed pH-sensitive nanoparticles for specific co-delivery of the two agents into breast tumors. The nanoparticles consist of four materials approved by the Food and Drug Administration (FDA) for medical use: Poly (d,l-lactide-co-glycolide) (PLGA), Pluronic F127 (PF127), chitosan, and 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC). Moreover, chitosan was modified with guanidine to form chitosan-guanidine (CG), which not only can improve the encapsulation efficiency of anti-miR-21 oligonucleotides but also effectively capture carbon dioxide (CO2) into the nanoparticle to achieve the ‘nano-bomb’ effect for triggered drug release under the reduced pH in tumors. The two agents (inhibitors of miR-21 and WIP1)-laden nanoparticles can be used to efficiently kill trastuzumab-resistant HER2+ breast cancer cells, leading to a profound reduction of the tumor growth in vivo. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the HER2+ breast cancers resistant to anti-HER2-based therapies.

Project description:To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSC) using radioresistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2(-/low) breast cancers.HER2-expressing BCSCs (HER2(+)/CD44(+)/CD24(-/low)) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radioresistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2(+)/CD44(+)/CD24(-/low) versus HER2(-)/CD44(+)/CD24(-/low) BCSCs was conducted with two-dimensional difference gel electrophoresis (2-D DIGE) and high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) analysis and HER2-mediated signaling network was generated by MetaCore program.Compared with HER2-negative BCSCs, HER2(+)/CD44(+)/CD24(-/low) cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by Matrigel invasion, tumor sphere formation, and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2(+)/CD44(+)/CD24(-/low) cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells coexpressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC/MS-MS of HER2(+)/CD44(+)/CD24(-/low) versus HER2(-)/CD44(+)/CD24(-/low) BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function, and DNA repair. A specific feature of HER2-STAT3 network was identified.This study provides the evidence that HER2-mediated prosurvival signaling network is responsible for the aggressive phenotype of BCSCs that could be targeted to control the therapy-resistant HER2(-/low) breast cancer.

Project description:Herceptin (trastuzumab) is used in patients with breast cancer who have HER2 (ErbB2)-positive tumours. However, its mechanisms of action and how acquired resistance to Herceptin occurs are still poorly understood. It was previously thought that the anti-HER2 monoclonal antibody Herceptin inhibits HER2 signalling, but recent studies have shown that Herceptin does not decrease HER2 phosphorylation. Its failure to abolish HER2 phosphorylation may be a key to why acquired resistance inevitably occurs for all responders if Herceptin is given as monotherapy. To date, no studies have explained why Herceptin does not abolish HER2 phosphorylation. The objective of this study was to investigate why Herceptin did not decrease HER2 phosphorylation despite being an anti-HER2 monoclonal antibody. We also investigated the effects of acute and chronic Herceptin treatment on HER3 and PKB phosphorylation in HER2-positive breast cancer cells. Using both Förster resonance energy transfer (FRET) methodology and conventional Western blot, we have found the molecular mechanisms whereby Herceptin fails to abolish HER2 phosphorylation. HER2 phosphorylation is maintained by ligand-mediated activation of EGFR, HER3, and HER4 receptors, resulting in their dimerisation with HER2. The release of HER ligands was mediated by ADAM17 through a PKB negative feedback loop. The feedback loop was activated because of the inhibition of PKB by Herceptin treatment since up-regulation of HER ligands and ADAM17 also occurred when PKB phosphorylation was inhibited by a PKB inhibitor (Akt inhibitor VIII, Akti-1/2). The combination of Herceptin with ADAM17 inhibitors or the panHER inhibitor JNJ-26483327 was able to abrogate the feedback loop and decrease HER2 phosphorylation. Furthermore, the combination of Herceptin with JNJ-26483327 was synergistic in tumour inhibition in a BT474 xenograft model. We have determined that a PKB negative feedback loop links ADAM17 and HER ligands in maintaining HER2 phosphorylation during Herceptin treatment. The activation of other HER receptors via ADAM17 may mediate acquired resistance to Herceptin in HER2-overexpressing breast cancer. This finding offers treatment opportunities for overcoming resistance in these patients. We propose that Herceptin should be combined with a panHER inhibitor or an ADAM inhibitor to overcome the acquired drug resistance for patients with HER2-positive breast cancer. Our results may also have implications for resistance to other therapies targeting HER receptors.

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New HER2-negative breast cancer subtype responsive to anti-HER2 therapy identified.

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New HER2-negative breast cancer subtype responsive to anti-HER2 therapy identified.

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