PMID- 38167908
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240210
IS  - 2374-4677 (Print)
IS  - 2374-4677 (Electronic)
IS  - 2374-4677 (Linking)
VI  - 10
IP  - 1
DP  - 2024 Jan 2
TI  - Qualification of a multiplexed tissue imaging assay and detection of novel 
      patterns of HER2 heterogeneity in breast cancer.
PG  - 2
LID - 10.1038/s41523-023-00605-3 [doi]
LID - 2
AB  - Emerging data suggests that HER2 intratumoral heterogeneity (ITH) is associated 
      with therapy resistance, highlighting the need for new strategies to assess HER2 
      ITH. A promising approach is leveraging multiplexed tissue analysis techniques 
      such as cyclic immunofluorescence (CyCIF), which enable visualization and 
      quantification of 10-60 antigens at single-cell resolution from individual tissue 
      sections. In this study, we qualified a breast cancer-specific antibody panel, 
      including HER2, ER, and PR, for multiplexed tissue imaging. We then compared the 
      performance of these antibodies against established clinical standards using 
      pixel-, cell- and tissue-level analyses, utilizing 866 tissue cores (representing 
      294 patients). To ensure reliability, the CyCIF antibodies were qualified against 
      HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) 
      data from the same samples. Our findings demonstrate the successful qualification 
      of a breast cancer antibody panel for CyCIF, showing high concordance with 
      established clinical antibodies. Subsequently, we employed the qualified 
      antibodies, along with antibodies for CD45, CD68, PD-L1, p53, Ki67, pRB, and AR, 
      to characterize 567 HER2+ invasive breast cancer samples from 189 patients. 
      Through single-cell analysis, we identified four distinct cell clusters within 
      HER2+ breast cancer exhibiting heterogeneous HER2 expression. Furthermore, these 
      clusters displayed variations in ER, PR, p53, AR, and PD-L1 expression. To 
      quantify the extent of heterogeneity, we calculated heterogeneity scores based on 
      the diversity among these clusters. Our analysis revealed expression patterns 
      that are relevant to breast cancer biology, with correlations to HER2 ITH and 
      potential relevance to clinical outcomes.
CI  - (c) 2024. The Author(s).
FAU - Guerriero, Jennifer L
AU  - Guerriero JL
AUID- ORCID: 0000-0002-2104-5457
AD  - Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, 
      Boston, MA, 02115, USA. JGuerriero@bwh.harvard.edu.
AD  - Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, 
      02215, USA. JGuerriero@bwh.harvard.edu.
AD  - Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 
      02215, USA. JGuerriero@bwh.harvard.edu.
AD  - Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard 
      Medical School, Boston, MA, 02215, USA. JGuerriero@bwh.harvard.edu.
FAU - Lin, Jia-Ren
AU  - Lin JR
AD  - Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 
      02215, USA.
AD  - Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard 
      Medical School, Boston, MA, 02215, USA.
FAU - Pastorello, Ricardo G
AU  - Pastorello RG
AD  - Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, 
      02215, USA.
AD  - Department of Pathology, Hospital Sirio Libanes, Sao Paulo, SP, 01308-050, 
      Brazil.
FAU - Du, Ziming
AU  - Du Z
AUID- ORCID: 0000-0003-2667-4989
AD  - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
AD  - Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, 
      Guangzhou, China.
FAU - Chen, Yu-An
AU  - Chen YA
AD  - Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard 
      Medical School, Boston, MA, 02215, USA.
FAU - Townsend, Madeline G
AU  - Townsend MG
AD  - Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, 
      Boston, MA, 02115, USA.
AD  - Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, 
      02215, USA.
FAU - Shimada, Kenichi
AU  - Shimada K
AD  - Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, 
      Boston, MA, 02115, USA.
AD  - Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, 
      02215, USA.
AD  - Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 
      02215, USA.
AD  - Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard 
      Medical School, Boston, MA, 02215, USA.
FAU - Hughes, Melissa E
AU  - Hughes ME
AD  - Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, 
      MA, 02215, USA.
FAU - Ren, Siyang
AU  - Ren S
AUID- ORCID: 0000-0002-8516-6047
AD  - Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
FAU - Tayob, Nabihah
AU  - Tayob N
AUID- ORCID: 0000-0001-6088-167X
AD  - Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
FAU - Zheng, Kelly
AU  - Zheng K
AD  - Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, 
      Boston, MA, 02115, USA.
FAU - Mei, Shaolin
AU  - Mei S
AUID- ORCID: 0000-0002-2193-764X
AD  - Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard 
      Medical School, Boston, MA, 02215, USA.
FAU - Patterson, Alyssa
AU  - Patterson A
AD  - Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, 
      MA, 02215, USA.
FAU - Taneja, Krishan L
AU  - Taneja KL
AD  - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
FAU - Metzger, Otto
AU  - Metzger O
AD  - Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, 
      MA, 02215, USA.
FAU - Tolaney, Sara M
AU  - Tolaney SM
AUID- ORCID: 0000-0002-5940-8671
AD  - Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, 
      MA, 02215, USA.
FAU - Lin, Nancy U
AU  - Lin NU
AD  - Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, 
      MA, 02215, USA.
FAU - Dillon, Deborah A
AU  - Dillon DA
AD  - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
FAU - Schnitt, Stuart J
AU  - Schnitt SJ
AUID- ORCID: 0000-0002-3608-7828
AD  - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
FAU - Sorger, Peter K
AU  - Sorger PK
AD  - Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 
      02215, USA.
AD  - Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard 
      Medical School, Boston, MA, 02215, USA.
FAU - Mittendorf, Elizabeth A
AU  - Mittendorf EA
AD  - Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, 
      Boston, MA, 02115, USA.
AD  - Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, 
      02215, USA.
AD  - Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 
      02215, USA.
AD  - Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, 
      MA, 02215, USA.
FAU - Santagata, Sandro
AU  - Santagata S
AUID- ORCID: 0000-0002-7528-9668
AD  - Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 
      02215, USA.
AD  - Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard 
      Medical School, Boston, MA, 02215, USA.
AD  - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA, 02115, USA.
LA  - eng
GR  - U54 CA225088/CA/NCI NIH HHS/United States
GR  - R50 CA274277/CA/NCI NIH HHS/United States
GR  - P50 CA168504/CA/NCI NIH HHS/United States
GR  - U2C CA233280/CA/NCI NIH HHS/United States
GR  - U2C CA233262/CA/NCI NIH HHS/United States
GR  - R37 CA269499/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20240102
PL  - United States
TA  - NPJ Breast Cancer
JT  - NPJ breast cancer
JID - 101674891
PMC - PMC10761880
COIS- D.A.D. consults for Novartis, receives funding from Canon, Inc., and is on the 
      advisory board for Oncology Analytics, Inc. S.J.S. receives consulting fees from 
      Venn Therapeutics. P.K.S. serves on the SAB or BOD of Glencoe Software, Applied 
      Biomath, and RareCyte Inc. and has equity in these companies; he is a member of 
      the NanoString SAB and is also co-founder of Glencoe Software, which contributes 
      to and supports the open-source OME/OMERO image informatics software used in this 
      paper. In the last five years, the Sorger lab has received research funding from 
      Novartis and Merck. Sorger declares that none of these relationships are directly 
      or indirectly related to the content of this manuscript. E.A.M. is on the SAB for 
      AstraZeneca/Medimmune, Celgene, Genentech/Roche, Genomic Health (now Exact 
      Sciences), Merck, Peregrine Pharmaceuticals, SELLAS Lifescience, and Tapimmune, 
      is on steering committees for Bristol Myers Squibb and Roche/Genentech, has 
      clinical trial support to her former institution (MD Anderson Cancer Center) from 
      AstraZeneca/Medimmune, EMD-Serono, Galena Biopharma, and Genentech, has Genentech 
      and Gilead support to a SU2C grant, and has sponsored Research Support to the 
      laboratory from Glaxo-Smith Kline (GSK) and Eli Lilly. J.L.G. is a consultant for 
      GSK, Codagenix, Duke Street Bio, and Array BioPharma/Pfizer and has received 
      sponsored research support from GSK, Array BioPharma/Pfizer, Eli Lilly, and 
      Merck. S.S. and K.S. report no relevant disclosures. S.M.T.: Consulting or 
      Advisory Role: Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, 
      AstraZeneca, Puma Biotechnology, Genentech/Roche, Eisai, Sanofi Genzyme, Bristol 
      Myers Squibb, Seattle Genetics, Odonate Therapeutics, OncoPep, Kyowa Hakko Kirin, 
      Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, 
      Certara, Chugai Pharma, Ellipses Pharma, Infinity, 4D Pharma, OncoSec Medical 
      Inc., BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint 
      Medicines, Reveal Genomics, ARC Therapeutics; Institutional Research Funding: 
      Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, 
      Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Odonate 
      Therapeutics, Sanofi, Seattle Genetics.
EDAT- 2024/01/04 01:18
MHDA- 2024/01/04 01:19
PMCR- 2024/01/02
CRDT- 2024/01/03 10:18
PHST- 2022/07/16 00:00 [received]
PHST- 2023/12/02 00:00 [accepted]
PHST- 2024/01/04 01:19 [medline]
PHST- 2024/01/04 01:18 [pubmed]
PHST- 2024/01/03 10:18 [entrez]
PHST- 2024/01/02 00:00 [pmc-release]
AID - 10.1038/s41523-023-00605-3 [pii]
AID - 605 [pii]
AID - 10.1038/s41523-023-00605-3 [doi]
PST - epublish
SO  - NPJ Breast Cancer. 2024 Jan 2;10(1):2. doi: 10.1038/s41523-023-00605-3.