Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab

Loi, Sherene; Dafni, Urania; Karlis, Dimitris; Polydoropoulou, Varvara; Young, Brandon; Willis, Scooter; Long, Bradley; Azambuja, Evandro de; Sotiriou, Christos; Viale, Giuseppe; Rüschoff, Josef; Piccart, Martine; Dowsett, Mitchell; Michiels, Stefan; Leyland‐Jones, Brian

doi:10.1001/jamaoncol.2016.0339

Cited by 79 publications

(54 citation statements)

References 24 publications

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“…Another (N9831) trial conducted during March 2002 to April 2005 revealed that the benefit from trastuzumab mainly relies upon IHC or FISH HER2 testing, irrespective of the degree of amplification . However, in a secondary analysis of the HERA trial with a median follow‐up time of 8 years, ER‐positive patients with a low ISH ratio (≥2 to <5) derived significantly less benefit from adjuvant trastuzumab therapy . This indicates that a longer follow‐up time may be necessary to accurately assess the benefits from anti‐HER2 treatment in such a group.…”

Section: Discussionmentioning

confidence: 99%

“…15 However, in a secondary analysis of the HERA trial with a median follow-up time of 8 years, ER-positive patients with a low ISH ratio (≥2 to <5) derived significantly less benefit from adjuvant trastuzumab therapy. 7 This indicates that a longer follow-up time may be necessary to accurately assess the benefits from anti-HER2 treatment in such a group. In our hormone-receptorpositive subgroup, patients with a low ISH ratio tumour displayed a worse outcome (Table S5), which is consistent with the findings from the HERA trial.…”

Section: Discussionmentioning

confidence: 99%

“…As the protein expression of HER2 IHC 3+ is higher than that of HER2 IHC 2+, we predicted that patients with HER2 IHC 3+ tumours would have a better response to anti‐HER2 therapy, and their prognosis would be better than those with HER2 IHC 2+ tumours. Other prognostic factors that may have impacts on the survival of breast cancer patients, such as age, cancer stage, hormone receptor status, intermediate HER2 copy number (6–12), HER2 low ISH ratio (≥2 to <5) and dual blockade of anti‐HER2 therapy, are all included in the analysis.…”

Section: Introductionmentioning

confidence: 99%

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HER2 immunohistochemical scores provide prognostic information for patients with HER2‐type invasive breast cancer

et al. 2019

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Aims Invasive breast cancer patients with human epidermal growth factor receptor 2 (HER2) immunohistochemical (IHC) scores of 3+ or 2+ with reflex in‐situ hybridisation (ISH) positivity are suitable for anti‐HER2 therapies. The aim of this study is to investigate whether the prognoses between IHC 3+ patients and IHC 2+/ISH+ patients are different. Methods and results We analysed the clinicopathological information of 886 consecutive cases of HER2‐positive early breast cancer. The influences of the patients’ age, cancer stage, hormone receptor status and anti‐HER2 treatment were adjusted using a multivariate Cox regression model. Both HER2 copy numbers and HER2 ISH ratios of the IHC 3+ group were significantly higher than those of the IHC 2+/ISH+ group. The outcomes of IHC 3+ patients were significantly better than those of IHC 2+/ISH+ patients in the univariate and multivariate analyses. HER2 copy numbers of ≥8 represented the best prognostic value, and it was chosen to be the cut‐off value. The reflex ISH for IHC 2+ patients with high HER2 copy numbers (≥8) predicted a better overall survival than that for those with low HER2 copy numbers. Conclusion HER2 IHC scores and HER2 copy numbers can provide prognostic information for patients with HER2‐positive invasive breast cancer. Both IHC 3+ and IHC 2+ patients with high HER2 copy numbers had a better prognosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HER2 immunohistochemical scores provide prognostic information for patients with HER2‐type invasive breast cancer

et al. 2019

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“…An initial proteogenomic focus on ERBB2 is readily justified given the biological variability within tumors designated ERBB2 "positive". The testing guidelines are designed to offer as many patients anti-ERBB2 treatment as possible, even though it is recognized that this "catch all" approach likely includes a number of true-negative cases that do not benefit from these treatments 39 . Our analysis is not intended to be definitive or clinically actionable as the sample size is small and our pipeline is research-based.…”

Section: Discussionmentioning

confidence: 99%

Microscaled Proteogenomic Methods for Precision Oncology

Satpathy

Jaehnig

Krug

et al. 2019

Preprint

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and MJE: Matthew.Ellis@bcm.edu Running title: Microscaled Proteogenomic Methods for Precision Oncology Satpathy et al., Microscaled Proteogenomic Methods for Precision Oncology 2 AbstractCancer proteogenomics integrates genomics, transcriptomics and mass spectrometry (MS)-based proteomics to gain insights into cancer biology and treatment efficacy. A proteogenomics approach was therefore developed for frozen core biopsies using tissue-sparing specimen processing with a "microscaled" proteomics workflow. For technical proof-of-principle, biopsies from ERBB2 positive breast cancers before and 48-72 hours after the first dose of neoadjuvant trastuzumabbased chemotherapy were analyzed. ERBB2 protein and phosphosite levels, as well as mTOR target phosphosites, were significantly more suppressed upon treatment in cases associated with pathological complete response, suggesting MS-based pharmacodynamics is achievable. Furthermore, integrated analyses indicated potential causes of treatment resistance including the absence of ERBB2 amplification (false-ERBB2 positive) and insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2 positive). Candidate resistance features in true-ERBB2+ cases, including androgen receptor signaling, mucin expression and an inactive immune microenvironment were observed. Thus, proteogenomic analysis of needle core biopsies is feasible and clinical utility should be investigated. enriched PDX (WHIM) models with ERBB2 protein expression. B. MUC1 immunohistochemistry (IHC) of WHIM8, WHIM35 and BCN1369.

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“…Vaccines that generate antibody responses using carrier proteins may require cumbersome recombinant protein production and chemical conjugation processes, which can be costly, lead to batch-to-batch variability, and elicit off-target antibody responses against other T and B cell epitopes on the carrier protein itself [36] . To circumvent this issue, we designed peptide constructs that incorporate a promiscuous T-helper cell epitope derived from measles virus fusion protein oncogenic protein HER2/neu, a surface receptor that has been successfully targeted by monoclonal antibodies for the treatment of Her2 + breast and gastric cancer [37] . To specifically induce therapeutic antibodies, we used Her2613-626 as the B-cell epitope, as it is within the portion of the Finally, we investigated the anti-GnRH response generated against a synthetic MVFGnRH peptide antigen, comparing our MSR technology with a bolus vaccine and MVFGnRH formulated in the gold standard adjuvant Alum.…”

Section: Broad Potential Of Msr For Vaccination Against Small Moleculmentioning

confidence: 99%

Single-shot Mesoporous Silica Rods Scaffold for Induction of Humoral Responses Against Small Antigens

Dellacherie

et al. 2020

Preprint

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Vaccines have shown significant promise in eliciting protective and therapeutic responses.However, most effective vaccines require several booster shots, and it is challenging to generate potent responses against small molecules and synthetic peptide antigens often used to increase target specificity and improve vaccine stability. As continuous antigen uptake and processing by APCs and persistent toll-like receptor (TLR) priming have been shown to amplify antigen specific humoral immunity, we explored whether a single injection of a mesoporous silica micro-rod (MSR) vaccine containing synthetic molecules and peptides can effectively generate potent and durable antigen-specific humoral immunity. A single injection of the MSR vaccine against a gonadotropin-releasing hormone (GnRH) decapeptide elicited highly potent anti-GnRH response that lasted for over 12 months. The MSR vaccine generated higher titers than bolus or alhydrogel alum vaccine formulations. Moreover, a MSR vaccine directed against a Her2/neu peptide within the Trastuzumab binding domain showed immunoreactivity to native Her2 protein on tumor cell surface and, when directed against nicotine, generated long-term anti-nicotine antibodies.Mechanistically, we found that the MSR vaccine induced persistent germinal center (GC) B-cell activity for more than 3 weeks after a single injection, generation of memory B cells, and that at least 7 days of immunostimulation by the vaccine was required to generate an effective humoral response. Together, these data suggest that the MSR vaccine represents a promising technology for synthetic antigen vaccines to bypass the need for multiple immunizations and enhance longterm production of antibodies against endogenous antigens in the context of reproductive biology, cancer, and chronic addiction.

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Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab

Abstract: clinicaltrials.gov Identifier: NCT00045032.

Cited by 79 publications

References 24 publications

HER2 immunohistochemical scores provide prognostic information for patients with HER2‐type invasive breast cancer

HER2 immunohistochemical scores provide prognostic information for patients with HER2‐type invasive breast cancer

Microscaled Proteogenomic Methods for Precision Oncology

Single-shot Mesoporous Silica Rods Scaffold for Induction of Humoral Responses Against Small Antigens

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