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Heterogeneity in Signaling Pathway Activity within Primary and between Primary and Metastatic Breast Cancer

SIMPLE SUMMARY: Personalized breast cancer treatment with targeted therapy (e.g., tamoxifen or PI3K inhibitors) requires identification of responder patients. Phenotypical heterogeneity within the primary, and between primary tumor and metastases, may however interfere with response to therapy, if b...

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Autores principales: Inda, Márcia A., van Swinderen, Paul, van Brussel, Anne, Moelans, Cathy B., Verhaegh, Wim, van Zon, Hans, den Biezen, Eveline, Bikker, Jan Willem, van Diest, Paul J., van de Stolpe, Anja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002348/
https://www.ncbi.nlm.nih.gov/pubmed/33809754
http://dx.doi.org/10.3390/cancers13061345
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author Inda, Márcia A.
van Swinderen, Paul
van Brussel, Anne
Moelans, Cathy B.
Verhaegh, Wim
van Zon, Hans
den Biezen, Eveline
Bikker, Jan Willem
van Diest, Paul J.
van de Stolpe, Anja
author_facet Inda, Márcia A.
van Swinderen, Paul
van Brussel, Anne
Moelans, Cathy B.
Verhaegh, Wim
van Zon, Hans
den Biezen, Eveline
Bikker, Jan Willem
van Diest, Paul J.
van de Stolpe, Anja
author_sort Inda, Márcia A.
collection PubMed
description SIMPLE SUMMARY: Personalized breast cancer treatment with targeted therapy (e.g., tamoxifen or PI3K inhibitors) requires identification of responder patients. Phenotypical heterogeneity within the primary, and between primary tumor and metastases, may however interfere with response to therapy, if based on a single primary tumor biopsy. In this study, we investigated this heterogeneity, using novel assays to measure activity of tumor-driving signal transduction pathways, e.g., estrogen receptor and PI3K pathways, in multiple samples distributed across the tumor and in metastases. Within the primary tumor, heterogeneity was dominant at microscale (biopsy block) and not at macroscale (across tumor), suggesting that a single biopsy is generally representative for the whole primary tumor. The differences found between pathway activity in primary tumor and metastases suggests that it is recommendable to analyze pathway activity in metastatic samples for treatment selection for late stage patients. ABSTRACT: Targeted therapy aims to block tumor-driving signaling pathways and is generally based on analysis of one primary tumor (PT) biopsy. Tumor heterogeneity within PT and between PT and metastatic breast lesions may, however, impact the effect of a chosen therapy. Whereas studies are available that investigate genetic heterogeneity, we present results on phenotypic heterogeneity by analyzing the variation in the functional activity of signal transduction pathways, using an earlier developed platform to measure such activity from mRNA measurements of pathways’ direct target genes. Statistical analysis comparing macro-scale variation in pathway activity on up to five spatially distributed PT tissue blocks (n = 35), to micro-scale variation in activity on four adjacent samples of a single PT tissue block (n = 17), showed that macro-scale variation was not larger than micro-scale variation, except possibly for the PI3K pathway. Simulations using a “checkerboard clone-size” model showed that multiple small clones could explain the higher micro-scale variation in activity found for the TGFβ and Hedgehog pathways, and that intermediate/large clones could explain the possibly higher macro-scale variation of the PI3K pathway. While within PT, pathway activities presented a highly positive correlation, correlations weakened between PT and lymph node metastases (n = 9), becoming even worse for PT and distant metastases (n = 9), including a negative correlation for the ER pathway. While analysis of multiple sub-samples of a single biopsy may be sufficient to predict PT response to targeted therapies, metastatic breast cancer treatment prediction requires analysis of metastatic biopsies. Our findings on phenotypic intra-tumor heterogeneity are compatible with emerging ideas on a Big Bang type of cancer evolution in which macro-scale heterogeneity appears not dominant.
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spelling pubmed-80023482021-03-28 Heterogeneity in Signaling Pathway Activity within Primary and between Primary and Metastatic Breast Cancer Inda, Márcia A. van Swinderen, Paul van Brussel, Anne Moelans, Cathy B. Verhaegh, Wim van Zon, Hans den Biezen, Eveline Bikker, Jan Willem van Diest, Paul J. van de Stolpe, Anja Cancers (Basel) Article SIMPLE SUMMARY: Personalized breast cancer treatment with targeted therapy (e.g., tamoxifen or PI3K inhibitors) requires identification of responder patients. Phenotypical heterogeneity within the primary, and between primary tumor and metastases, may however interfere with response to therapy, if based on a single primary tumor biopsy. In this study, we investigated this heterogeneity, using novel assays to measure activity of tumor-driving signal transduction pathways, e.g., estrogen receptor and PI3K pathways, in multiple samples distributed across the tumor and in metastases. Within the primary tumor, heterogeneity was dominant at microscale (biopsy block) and not at macroscale (across tumor), suggesting that a single biopsy is generally representative for the whole primary tumor. The differences found between pathway activity in primary tumor and metastases suggests that it is recommendable to analyze pathway activity in metastatic samples for treatment selection for late stage patients. ABSTRACT: Targeted therapy aims to block tumor-driving signaling pathways and is generally based on analysis of one primary tumor (PT) biopsy. Tumor heterogeneity within PT and between PT and metastatic breast lesions may, however, impact the effect of a chosen therapy. Whereas studies are available that investigate genetic heterogeneity, we present results on phenotypic heterogeneity by analyzing the variation in the functional activity of signal transduction pathways, using an earlier developed platform to measure such activity from mRNA measurements of pathways’ direct target genes. Statistical analysis comparing macro-scale variation in pathway activity on up to five spatially distributed PT tissue blocks (n = 35), to micro-scale variation in activity on four adjacent samples of a single PT tissue block (n = 17), showed that macro-scale variation was not larger than micro-scale variation, except possibly for the PI3K pathway. Simulations using a “checkerboard clone-size” model showed that multiple small clones could explain the higher micro-scale variation in activity found for the TGFβ and Hedgehog pathways, and that intermediate/large clones could explain the possibly higher macro-scale variation of the PI3K pathway. While within PT, pathway activities presented a highly positive correlation, correlations weakened between PT and lymph node metastases (n = 9), becoming even worse for PT and distant metastases (n = 9), including a negative correlation for the ER pathway. While analysis of multiple sub-samples of a single biopsy may be sufficient to predict PT response to targeted therapies, metastatic breast cancer treatment prediction requires analysis of metastatic biopsies. Our findings on phenotypic intra-tumor heterogeneity are compatible with emerging ideas on a Big Bang type of cancer evolution in which macro-scale heterogeneity appears not dominant. MDPI 2021-03-16 /pmc/articles/PMC8002348/ /pubmed/33809754 http://dx.doi.org/10.3390/cancers13061345 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Inda, Márcia A.
van Swinderen, Paul
van Brussel, Anne
Moelans, Cathy B.
Verhaegh, Wim
van Zon, Hans
den Biezen, Eveline
Bikker, Jan Willem
van Diest, Paul J.
van de Stolpe, Anja
Heterogeneity in Signaling Pathway Activity within Primary and between Primary and Metastatic Breast Cancer
title Heterogeneity in Signaling Pathway Activity within Primary and between Primary and Metastatic Breast Cancer
title_full Heterogeneity in Signaling Pathway Activity within Primary and between Primary and Metastatic Breast Cancer
title_fullStr Heterogeneity in Signaling Pathway Activity within Primary and between Primary and Metastatic Breast Cancer
title_full_unstemmed Heterogeneity in Signaling Pathway Activity within Primary and between Primary and Metastatic Breast Cancer
title_short Heterogeneity in Signaling Pathway Activity within Primary and between Primary and Metastatic Breast Cancer
title_sort heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002348/
https://www.ncbi.nlm.nih.gov/pubmed/33809754
http://dx.doi.org/10.3390/cancers13061345
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