Optimal specific radioactivity of anti-HER2 Affibody molecules enables discrimination between xenografts with high and low HER2 expression levels

2010 ◽  
Vol 38 (3) ◽  
pp. 531-539 ◽  
Author(s):  
Vladimir Tolmachev ◽  
Helena Wållberg ◽  
Mattias Sandström ◽  
Monika Hansson ◽  
Anders Wennborg ◽  
...  
Keyword(s):  
Specific Radioactivity ◽  
Her2 Expression ◽  
Affibody Molecules ◽  
Expression Levels

Breast cancer ER, PR, and HER2 expression variance by germline cancer predisposition genes.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10526-10526
Author(s):  
Grace Wei ◽  
Marilin Rosa ◽  
Maxine Chang ◽  
Brian J. Czerniecki ◽  
Xia Wang
Keyword(s):  
Breast Cancer ◽  
Cancer Diagnosis ◽  
Breast Cancer Diagnosis ◽  
Cancer Predisposition ◽  
Tumor Evolution ◽  
Breast Cancers ◽  
Her2 Expression ◽  
Expression Levels ◽  
Genetic Test Results ◽  
Predisposition Genes

10526 Background: The association between breast cancer characteristics and survival with estrogen receptor (ER) and progesterone receptor (PR) expression has been primarily studied via binomial categories, ER-positive and ER-negative. In order to better characterize germline genetic influences on these markers, we investigated their IHC expression semi-quantitatively in cancer predisposition germline pathogenic variant (PV) carriers of the following genes: BRCA1, BRCA2, PALB2, TP53, PTEN, CDH1, ATM, CHEK2, and Lynch syndrome genes. The HER2 expression was also analyzed. Methods: We conducted a retrospective chart review of patients with germline panel genetic testing for cancer predisposition genes at Moffitt Cancer Center’s GeneHome clinic. Inclusion criteria included 1) women ≥18 years old, 2) breast cancer diagnosis, 3) cancer predisposition germline panel genetic test results, 4) available ER and PR expression levels, and 5) available HER expression and/or amplification status. ER, PR, and HER2 status were compared between PV carriers and non-PV carriers via Mann-Whitney U at p>0.05. Results: A total of 847 cases were reviewed for the study. Among 658 patients with a breast cancer diagnosis and complete ER PR data, 365 cases (55.5%) were non-PV carriers and 293 cases (44.5%) carried a PV in at least one of the genes listed above. Among 635 cases with available HER2 expression/amplification status, 355 (55.9%) cases were non-PV carriers and 288 (45.4%) cases were PV-carriers. When compared with non-PV carrier controls, BRCA1 PV carriers’ breast tumors had significantly lower ER and/or PR expression. Further, BRCA2 and TP53 PV tumors also displayed moderately lower ER expression. Contrarily, CHEK2 tumors displayed higher ER and PR expression compared to controls. Further, BRCA1 and BRCA2 PV carriers were more likely to have HER2- breast cancers. Conclusions: Differences in ER, PR, HER2 expression levels were observed in germline PV carrier breast cancers, signaling differential impacts by germline PVs on the tumor evolution process. It is likely that tumor differences in PV carriers influence responses to therapies, including hormone therapy, anti-HER2 therapy, and subsequent survival.[Table: see text]

scholarly journals Affibody Molecules as Targeting Vectors for PET Imaging

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 651 ◽  
Author(s):  
Vladimir Tolmachev ◽  
Anna Orlova
Keyword(s):  
Molecular Targets ◽  
Scaffold Proteins ◽  
Preclinical Studies ◽  
Her2 Expression ◽  
Affibody Molecules ◽  
Breast Cancer Metastases ◽  
High Affinity ◽  
Factors Influencing ◽  
Cancer Metastases ◽  
Positron Emitters

Affibody molecules are small (58 amino acids) engineered scaffold proteins that can be selected to bind to a large variety of proteins with a high affinity. Their small size and high affinity make them attractive as targeting vectors for molecular imaging. High-affinity affibody binders have been selected for several cancer-associated molecular targets. Preclinical studies have shown that radiolabeled affibody molecules can provide highly specific and sensitive imaging on the day of injection; however, for a few targets, imaging on the next day further increased the imaging sensitivity. A phase I/II clinical trial showed that 68Ga-labeled affibody molecules permit an accurate and specific measurement of HER2 expression in breast cancer metastases. This paper provides an overview of the factors influencing the biodistribution and targeting properties of affibody molecules and the chemistry of their labeling using positron emitters.

Identification of a subpopulation of metastatic breast cancer patients with very high HER2 expression levels and possible resistance to trastuzumab

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1059-1059
Author(s):  
J. Sperinde ◽  
S. Ali ◽  
K. Leitzel ◽  
E. Fuchs ◽  
W. J. Köstler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Outcomes ◽  
Metastatic Breast ◽  
Primary Breast Tumor ◽  
P Value ◽  
Her2 Expression ◽  
Abrupt Decrease ◽  
Expression Levels ◽  
Very High

1059 Background: Many HER2-positive patients with metastatic breast cancer (MBC) fail to respond to trastuzumab. We previously reported that precise quantitation of HER2 expression (H2T) by the HERmark assay identified a sub-population of IHC 3+, FISH(+) (positive) patients with low H2T levels that responded poorly to trastuzumab (Lipton, San Antonio Breast Cancer Symposium 2008, abs #32). Here we identify a sub-population of FISH(+) patients with very high H2T levels, that experience clinical outcomes that are indistinguishable from those of FISH(-) (negative) patients with low H2T levels. Methods: The HERmark assay was used to measure H2T in formalin-fixed, paraffin-embedded (FFPE) primary breast tumor specimens from 99 women treated with trastuzumab for MBC. Specimens were also tested by central FISH. A sub-population treatment effect pattern plot (STEPP) was generated to examine the progression-free survival (PFS) rate at 12 months after treatment with trastuzumab across the distribution of H2T. Kaplan-Meier (KM) analyses were performed comparing the PFS of FISH(-), H2T low (log10H2T < 1.25) patients with those of FISH(+), H2T high (log10H2T ≥ 1.95) and FISH(+), H2T intermediate (1.25 < log10H2T < 1.95) groups. Cutoffs were identified by lowest p-value in a positional scanning analysis. Results: The PFS rate improved gradually with increasing H2T in STEPP analyses. At the highest levels of H2T, an abrupt decrease in the PFS rate was observed, consistent with a reduction in susceptibility to trastuzumab. KM analyses demonstrated that patients who were FISH(+), H2T intermediate had a significantly longer PFS than patients who were FISH(-), H2T low (median PFS 12.6 vs. 4.5 mos; HR = 0.34; p < 0.0001). Patients that were FISH(+), H2T high experienced a PFS that was no better than patients that were FISH(-), H2T low (median PFS 4.6 vs. 4.5 mos; HR = 0.87; p = 0.68). Conclusions: Precise quantitation of HER2 expression levels allows the identification of multiple sub-populations of HER2(+) patients that have different clinical outcomes on trastuzumab. MBC patients with very high levels of H2T could represent a sub-group with de novo resistance to trastuzumab who may benefit from combined therapy. [Table: see text]

Molecular profiles of gastric cancer: The UCSD experience.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 29-29
Author(s):  
Devon Marcus McGee ◽  
John P. Shen ◽  
Paul Timothy Fanta ◽  
Andrew M. Lowy
Keyword(s):  
Gastric Cancer ◽  
Statistical Significance ◽  
Accurate Determination ◽  
Prognostic Significance ◽  
Mrna Levels ◽  
Her2 Expression ◽  
Rt Pcr ◽  
Expression Levels ◽  
Platinum Based Chemotherapy ◽  
Molecular Studies

29 Background: Gastric cancer is the 2nd leading cause of cancer mortality globally. A small number of studies reported that low TS and ERCC1 mRNA levels are associated with improved survival, and may be important as prognostic factors. Methods: Intratumoral gene expression levels were assessed using laser-captured micro-dissection and quantitative Real-Time PCR on formalin fixed paraffin embedded tumor samples from 22 gastric adenocarcinomas. A retrospective chart review was performed to measure clinical parameters. Primary objectives were to determine the range of expression of TS, ERCC1, and HER2, and to investigate if these biomarkers are predictive of survival. Results: TS, ERCC1, and HER2 median expression levels using RT-PCR were 3.56, 1.54, and 0.085, respectively. Median OS was 62 months. Subjects with low TS trended towards improved survival (92 months vs. 34 months, p: 0.17), as did subjects with low ERCC1 (92 months vs. 55 months, p: 0.44). There was no association between HER2 expression and OS. All subjects had HER2 levels below 0.55. With regard to treatment, 90.9% of patients received platinum-based chemotherapy and 4.5% received HER2-guided therapy. Conclusions: Our results are consistent with prior reports that associate low TS and low ERCC1 with improved OS, and may imply prognostic significance. Although these trends did not reach statistical significance, they are consistent with prior studies. Further molecular studies are needed to better assess the utility of these markers as prognostic indicators. There was no clear trend between HER2 levels and OS, most likely because all subjects had low HER2 levels. However, as accurate determination of HER2 expression is becoming increasingly important in the management of gastric cancer patients, further research into the degree of concordance between RT-PCR assessment and FISH assessment of HER2 gene amplication is warranted. Overall, more molecular studies are needed to better stratify this disease into subtypes, and identify new drug targets for chemo-resistant subtypes.

scholarly journals Clinical Application of Multiple Reaction Monitoring-Mass Spectrometry to Human Epidermal Growth Factor Receptor 2 Measurements as a Potential Diagnostic Tool for Breast Cancer Therapy

2020 ◽  
Vol 66 (10) ◽  
pp. 1339-1348
Author(s):  
Misol Do ◽  
Hyunsoo Kim ◽  
Injoon Yeo ◽  
Jihyeon Lee ◽  
In Ae Park ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mass Spectrometry ◽  
Multiple Reaction Monitoring ◽  
Growth Factor Receptor ◽  
Specific Protein ◽  
Her2 Status ◽  
Reaction Monitoring ◽  
Her2 Expression ◽  
Expression Levels ◽  
Epidermal Growth

Abstract Background Human epidermal growth factor receptor 2 (HER2) is often overexpressed in breast cancer and correlates with a worse prognosis. Thus, the accurate detection of HER2 is crucial for providing the appropriate measures for patients. However, the current techniques used to detect HER2 status, immunohistochemistry and fluorescence in situ hybridization (FISH), have limitations. Specifically, FISH, which is mandatory for arbitrating 2+ cases, is time-consuming and costly. To address this shortcoming, we established a multiple reaction monitoring-mass spectrometry (MRM-MS) assay that improves on existing methods for differentiating HER2 status. Methods We quantified HER2 expression levels in 210 breast cancer formalin-fixed paraffin-embedded (FFPE) tissue samples by MRM-MS. We aimed to improve the accuracy and precision of HER2 quantification by simplifying the sample preparation through predicting the number of FFPE slides required to ensure an adequate amount of protein and using the expression levels of an epithelial cell-specific protein as a normalization factor when measuring HER2 expression levels. Results To assess the correlation between MRM-MS and IHC/FISH data, HER2 quantitative data from MRM-MS were divided by the expression levels of junctional adhesion molecule A, an epithelial cell-specific protein, prior to statistical analysis. The normalized HER2 amounts distinguished between HER2 2+/FISH-negative and 2+/FISH-positive groups (AUROC = 0.908), which could not be differentiated by IHC. In addition, all HER2 status were discriminated by MRM-MS. Conclusions This MRM-MS assay yields more accurate HER2 expression levels relative to immunohistochemistry and should help to guide clinicians toward the proper treatment for breast cancer patients, based on their HER2 expression.

scholarly journals Correlation of HER2 expression levels with the pathological stage of colorectal carcinomas

2011 ◽  
Vol 45 (1) ◽  
pp. 7-12
Author(s):  
Dusica Petrovic ◽  
Vesna Stankovic ◽  
Milos Milosavljevic ◽  
Danijela Milosev ◽  
Stevan Matic
Keyword(s):  
Colorectal Carcinomas ◽  
Her2 Expression ◽  
Pathological Stage ◽  
Expression Levels
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