Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer

Abstract Background High expression of human epidermal growth factor receptor type 2 (HER2) represents an aggressive subtype of breast cancer. Anti-HER2 treatment requires a theragnostic approach wherein sufficiently high receptor expression in biopsy material is mandatory. Heterogeneity and discordance of HER2 expression between primary tumour and metastases, as well as within a lesion, present a complication for the treatment and require multiple biopsies. Molecular imaging using the HER2-targeting Affibody peptide ABY-025 radiolabelled with 68Ga-gallium for PET/CT is currently under investigation as a non-invasive tool for whole-body evaluation of metastatic HER2 expression. Initial studies demonstrated a high correlation between 68Ga-ABY-025 standardized uptake values (SUVs) and histopathology. However, detecting small liver lesions might be compromised by high background uptake. This study aimed to explore the applicability of kinetic modelling and parametric image analysis for absolute quantification of 68Ga-ABY-025 uptake and HER2-receptor expression and how that relates to static SUVs. Methods Dynamic 68Ga-ABY-025 PET of the upper abdomen was performed 0-45 min post-injection in 16 patients with metastatic breast cancer. Five patients underwent two examinations to test reproducibility. Parametric images of tracer delivery (K1) and irreversible binding (Ki) were created with an irreversible two-tissue compartment model and Patlak graphical analysis using an image-derived input function from the descending aorta. A volume of interest (VOI)-based analysis was performed to validate parametric images. SUVs were calculated from 2 h and 4 h post-injection static whole-body images and compared to Ki. Results Characterization of HER2 expression in smaller liver metastases was improved using parametric images. Ki values from parametric images agreed very well with VOI-based gold standard (R2 > 0.99, p < 0.001). SUVs of metastases at 2 h and 4 h post-injection were highly correlated with Ki values from both the two-tissue compartment model and Patlak method (R2 = 0.87 and 0.95, both p < 0.001). 68Ga-ABY-025 PET yielded high test-retest reliability (relative repeatability coefficient for Patlak 30% and for the two-tissue compartment model 47%). Conclusion 68Ga-ABY-025 binding in HER2-positive metastases was well characterized by irreversible two-tissue compartment model wherein Ki highly correlated with SUVs at 2 and 4 h. Dynamic scanning with parametric image formation can be used to evaluate metastatic HER2 expression accurately.

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Comparison of contrast-enhanced CT, dual-layer detector spectral CT, and whole-body MRI in suspected metastatic breast cancer: a prospective diagnostic accuracy study

European Radiology ◽

10.1007/s00330-021-08041-2 ◽

2021 ◽

Author(s):

Thomas Winther Buus ◽

Finn Rasmussen ◽

Hanne Marie Nellemann ◽

Vibeke Løgager ◽

Anders Bonde Jensen ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast ◽

Whole Body ◽

Diagnostic Accuracy Study ◽

Spectral Ct ◽

Whole Body Mri ◽

Contrast Enhanced Ct ◽

Contrast Enhanced ◽

Enhanced Ct ◽

Accuracy Study

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Prediction of therapy response in bone-predominant metastatic breast cancer: comparison of [18F] fluorodeoxyglucose and [18F]-fluoride PET/CT with whole-body MRI with diffusion-weighted imaging

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-018-4223-9 ◽

2018 ◽

Vol 46 (4) ◽

pp. 821-830 ◽

Cited By ~ 6

Author(s):

Gurdip K. Azad ◽

Benjamin P. Taylor ◽

Adrian Green ◽

Ines Sandri ◽

Angela Swampillai ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Diffusion Weighted Imaging ◽

Metastatic Breast ◽

Therapy Response ◽

Whole Body ◽

Whole Body Mri ◽

Diffusion Weighted ◽

Pet Ct ◽

18F Fluoride

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The effect of androgen receptor expression on clinical characterization of metastatic breast cancer

Oncotarget ◽

10.18632/oncotarget.14414 ◽

2017 ◽

Vol 8 (5) ◽

pp. 8693-8706 ◽

Cited By ~ 5

Author(s):

Ji-Yeon Kim ◽

Kyunghee Park ◽

Eunjin Lee ◽

Hae Hyun Jung ◽

Jin Seok Ahn ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Androgen Receptor ◽

Metastatic Breast ◽

Receptor Expression ◽

Androgen Receptor Expression

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The association of HER2 low expression with the efficacy of CDK4/6 inhibitor in hormone receptor positive HER2 negative metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1052 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1052-1052

Author(s):

Kelvin K H Bao ◽

Leone Sutanto ◽

Shirley S W Tse ◽

Ka Man Cheung ◽

Jeffrey C H Chan

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cox Regression ◽

Endocrine Resistance ◽

Metastatic Breast ◽

Rank Test ◽

Her2 Expression ◽

Disease Extent ◽

Potential Marker ◽

Low Expression

1052 Background: Markers for the efficacy of CDK4/6 inhibitor in estrogen receptor (ER) positive, HER2 negative advanced breast cancer are limited. The bidirectional crosstalks that exist between ER and HER2 pathways contribute to endocrine resistance. We investigated the association between low levels of HER2 expression and the clinical outcome of patients with ER+ HER2- metastatic breast cancer (MBC) treated with CDK4/6 inhibitors. Methods: We identified consecutive patients with ER+ HER2- MBC who received CDK4/6 inhibitor plus either letrozole or fulvestrant between Mar 2017 - Jun 2020 from an institutional cancer registry. HER2-low expression was defined as IHC score 1+, or 2+ with a negative ISH. Progression-free survival (PFS) was defined as the time from the initiation of CDK4/6 inhibitor to the date of radiological or clinical progression, or death. The relationship between HER2 expression levels and PFS was evaluated using log-rank test and multivariable Cox regression modelling. Results: 106 women with MBC were eligible for analysis. Median age at treatment was 58 (23.0-91.4). The majority received palbociclib (84%) while the rest received ribociclib. CDK4/6 inhibitor was used as first-line treatment in 50.9% of cases. Most tumors were of ductal histology (83%) and progesterone receptor (PgR) positive (84.9%), and 22.6% of the patients had bone-only disease. 77.3% of cases were considered HER2-low expressing. HER2-low expression was associated with a significantly shorter PFS compared with HER2 IHC 0 counterpart (median, 8.9 vs 18.8 months, p= 0.014). In multivariate analysis, HER-2 low expression remained significantly associated with an inferior PFS (HR 1.96, 95%CI 1.03-3.75, p= 0.041) after adjusting for the line of treatment, PgR status and disease extent (bone only vs extra-osseous disease). Conclusions: In patients with ER+ HER2- MBC treated with CDK4/6 inhibitors, HER2-low expression was associated with an inferior PFS, and may serve as a potential marker candidate for CDK4/6 inhibitor efficacy. As novel anti-HER2 antibody-drug conjugates demonstrated efficacy in HER2-low expressing MBC, coupled with the emerging evidence for the combination of CDK4/6 inhibitors with anti-HER2 agents, this HER2-low expression subgroup warrants prospective evaluations in future trials.

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Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy

Cancers ◽

10.3390/cancers11050684 ◽

2019 ◽

Vol 11 (5) ◽

pp. 684 ◽

Cited By ~ 5

Author(s):

Nadiia Lypova ◽

Lilibeth Lanceta ◽

Alana Gipson ◽

Stephanie Vega ◽

Rodolfo Garza-Morales ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Viral Entry ◽

Metastatic Breast ◽

Receptor Expression ◽

Type I ◽

Development Of Resistance ◽

Estrogen Receptor Positive ◽

Entry Receptor ◽

Resistant Cells

While clinical responses to palbociclib have been promising, metastatic breast cancer remains incurable due to the development of resistance. We generated estrogen receptor-positive (ER+) and ER-negative (ER−) cell line models and determined their permissiveness and cellular responses to an oncolytic adenovirus (OAd) known as Ad5/3-delta24. Analysis of ER+ and ER− palbociclib-resistant cells revealed two clearly distinguishable responses to the OAd. While ER+ palbociclib-resistant cells displayed a hypersensitive phenotype to the effects of the OAd, ER− palbociclib-resistant cells showed a resistant phenotype to the OAd. Hypersensitivity to the OAd in ER+ palbociclib-resistant cells correlated with a decrease in type I interferon (IFN) signaling, an increase in viral entry receptor expression, and an increase in cyclin E expression. OAd resistance in ER− palbociclib-resistant cells correlated with an increase in type I IFN signaling and a marked decrease in viral entry receptor. Using the OAd as monotherapy caused significant cytotoxicity to both ER+ and ER− palbociclib-sensitive cell lines. However, the addition of palbociclib increased the oncolytic activity of the OAd only in ER+ palbociclib-sensitive cells. Our studies provide a mechanistic base for a novel anti-cancer regimen composed of an OAd in combination with palbociclib for the treatment of ER+ breast cancer.

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The Lack of Evidence for an Association between Cancer Biomarker Conversion Patterns and CTC-Status in Patients with Metastatic Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21062161 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2161

Author(s):

Stefan Stefanovic ◽

Thomas M. Deutsch ◽

Sabine Riethdorf ◽

Chiara Fischer ◽

Andreas Hartkopf ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Metastatic Breast ◽

Metastatic Tumor ◽

Circulating Tumor Cell ◽

Her2 Expression ◽

Change Pattern ◽

Kaplan Meier ◽

Prognostic Importance ◽

Genetic Profiles

Circulating tumor cell (CTC) detection is a prognostic factor in the metastatic breast cancer (MBC) setting. Discrepancies in primary (PT) and metastatic tumor (MT) genetic profiles are also of prognostic importance. Our study aimed to compare the CTC statuses and prognoses between those with subtype stable MBCs and MBCs with specific biomarker conversions. The study enrolled 261 MBC patients, treated at the National Center for Tumor Diseases, Heidelberg, Germany in a five-year period. All underwent PT and MT biopsies and subsequent CTC enumeration before the initiation of systemic therapy. ER and HER2 statuses of the PTs and MTs were determined and progression free survivals (PFSs) and overall survivals (OSs) were recorded. We compared CTC statuses, CTC counts, PFSs and OSs between subgroups of patients with different receptor change patterns. Patients who had tumors that converted to triple negative MTs had the shortest median OSs, while HER2 expression was not associated with a shorter median OS. No significant differences in PFSs and OSs have been demonstrated by Kaplan-Meier curve comparisons in any of the subgroup analyses. CTC counts were similar in all subgroups. CTCs were comparably less frequently detected in patients with a stable HER2 expression. Similar proportions of CTC positives were observed in all other subtype change pattern subgroups, barring the aforementioned HER2 stable subgroup. The detection of CTCs was of no appreciable prognostic value in different receptor change pattern subgroups in our cohort.

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