Genetic variants and tumor immune microenvironment: Clues for targeted therapies in inflammatory breast cancer (ibc)

Yulan Gong; Rajeswari Nagarathinam; Maria F. Arisi; Lorenzo Gerratana; Jennifer S. Winn; Michael Slifker; Jianming Pei; Kathy Q. Cai; Zachary Hasse; Elias Obeid; Julio Noriega; Christopher Sebastiano; Eric Ross; Katherine Alpaugh; Massimo Cristofanilli; Sandra V. Fernandez

doi:10.3390/ijms22168924

Genetic variants and tumor immune microenvironment: Clues for targeted therapies in inflammatory breast cancer (ibc)

Yulan Gong, Rajeswari Nagarathinam, Maria F. Arisi, Lorenzo Gerratana, Jennifer S. Winn, Michael Slifker, Jianming Pei, Kathy Q. Cai, Zachary Hasse, Elias Obeid, Julio Noriega, Christopher Sebastiano, Eric Ross, Katherine Alpaugh, Massimo Cristofanilli, Sandra V. Fernandez

Cancer Prevention and Control (CPC)

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) (n = 33) and paired DNA from tumor tissues (n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.

Original language	English
Article number	8924
Journal	International Journal of Molecular Sciences
Volume	22
Issue number	16
DOIs	https://doi.org/10.3390/ijms22168924
State	Published - Aug 2 2021

Keywords

Adult
Aged
B7-H1 Antigen/genetics
Biomarkers, Tumor/genetics
Cell-Free Nucleic Acids/analysis
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
High-Throughput Nucleotide Sequencing
Humans
Inflammatory Breast Neoplasms/genetics
Lymphocytes, Tumor-Infiltrating/immunology
Middle Aged
Molecular Targeted Therapy
Mutation
Prognosis
Receptor, ErbB-2/metabolism
Receptors, Estrogen/metabolism
Receptors, Progesterone/metabolism
Retrospective Studies
Survival Rate
Tumor Microenvironment/immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/ijms22168924

Cite this

Gong, Y., Nagarathinam, R., Arisi, M. F., Gerratana, L., Winn, J. S., Slifker, M., Pei, J., Cai, K. Q., Hasse, Z., Obeid, E., Noriega, J., Sebastiano, C., Ross, E., Alpaugh, K., Cristofanilli, M., & Fernandez, S. V. (2021). Genetic variants and tumor immune microenvironment: Clues for targeted therapies in inflammatory breast cancer (ibc). International Journal of Molecular Sciences, 22(16), Article 8924. https://doi.org/10.3390/ijms22168924

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title = "Genetic variants and tumor immune microenvironment: Clues for targeted therapies in inflammatory breast cancer (ibc)",

abstract = "To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) (n = 33) and paired DNA from tumor tissues (n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.",

keywords = "Adult, Aged, B7-H1 Antigen/genetics, Biomarkers, Tumor/genetics, Cell-Free Nucleic Acids/analysis, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, High-Throughput Nucleotide Sequencing, Humans, Inflammatory Breast Neoplasms/genetics, Lymphocytes, Tumor-Infiltrating/immunology, Middle Aged, Molecular Targeted Therapy, Mutation, Prognosis, Receptor, ErbB-2/metabolism, Receptors, Estrogen/metabolism, Receptors, Progesterone/metabolism, Retrospective Studies, Survival Rate, Tumor Microenvironment/immunology",

author = "Yulan Gong and Rajeswari Nagarathinam and Arisi, {Maria F.} and Lorenzo Gerratana and Winn, {Jennifer S.} and Michael Slifker and Jianming Pei and Cai, {Kathy Q.} and Zachary Hasse and Elias Obeid and Julio Noriega and Christopher Sebastiano and Eric Ross and Katherine Alpaugh and Massimo Cristofanilli and Fernandez, {Sandra V.}",

note = "Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = aug,

day = "2",

doi = "10.3390/ijms22168924",

language = "English",

volume = "22",

journal = "International Journal of Molecular Sciences",

issn = "1661-6596",

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Gong, Y, Nagarathinam, R, Arisi, MF, Gerratana, L, Winn, JS, Slifker, M, Pei, J, Cai, KQ, Hasse, Z, Obeid, E, Noriega, J, Sebastiano, C, Ross, E, Alpaugh, K, Cristofanilli, M & Fernandez, SV 2021, 'Genetic variants and tumor immune microenvironment: Clues for targeted therapies in inflammatory breast cancer (ibc)', International Journal of Molecular Sciences, vol. 22, no. 16, 8924. https://doi.org/10.3390/ijms22168924

TY - JOUR

T1 - Genetic variants and tumor immune microenvironment

T2 - Clues for targeted therapies in inflammatory breast cancer (ibc)

AU - Gong, Yulan

AU - Nagarathinam, Rajeswari

AU - Arisi, Maria F.

AU - Gerratana, Lorenzo

AU - Winn, Jennifer S.

AU - Slifker, Michael

AU - Pei, Jianming

AU - Cai, Kathy Q.

AU - Hasse, Zachary

AU - Obeid, Elias

AU - Noriega, Julio

AU - Sebastiano, Christopher

AU - Ross, Eric

AU - Alpaugh, Katherine

AU - Cristofanilli, Massimo

AU - Fernandez, Sandra V.

PY - 2021/8/2

Y1 - 2021/8/2

N2 - To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) (n = 33) and paired DNA from tumor tissues (n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.

AB - To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) (n = 33) and paired DNA from tumor tissues (n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.

KW - Adult

KW - Aged

KW - B7-H1 Antigen/genetics

KW - Biomarkers, Tumor/genetics

KW - Cell-Free Nucleic Acids/analysis

KW - Female

KW - Follow-Up Studies

KW - Gene Expression Regulation, Neoplastic

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Inflammatory Breast Neoplasms/genetics

KW - Lymphocytes, Tumor-Infiltrating/immunology

KW - Middle Aged

KW - Molecular Targeted Therapy

KW - Mutation

KW - Prognosis

KW - Receptor, ErbB-2/metabolism

KW - Receptors, Estrogen/metabolism

KW - Receptors, Progesterone/metabolism

KW - Retrospective Studies

KW - Survival Rate

KW - Tumor Microenvironment/immunology

UR - http://www.scopus.com/inward/record.url?scp=85113151652&partnerID=8YFLogxK

U2 - 10.3390/ijms22168924

DO - 10.3390/ijms22168924

M3 - Article

C2 - 34445631

SN - 1661-6596

VL - 22

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 16

M1 - 8924

ER -

Genetic variants and tumor immune microenvironment: Clues for targeted therapies in inflammatory breast cancer (ibc)

Abstract

Keywords

UN SDGs

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Genetic variants and tumor immune microenvironment: Clues for targeted therapies in inflammatory breast cancer (ibc)

Abstract

Keywords

UN SDGs

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Other files and links

Fingerprint

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Biostatistics and Bioinformatics Facility

Histopathology Facility

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