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^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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 (US)
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

Funding

Funding: This work was supported by NIH P30 CA006927 core grant “Comprehensive Cancer Center Program at Fox Chase Cancer Center”.

Keywords

Cell-free DNA (cfDNA)
Immune checkpoint inhibitors (ICIs)
PARP inhibitor
Poly (ADP-ribose) poly-merase
Programmed cell death-ligand 1 (PD-L1)
Tumor infiltrating lymphocytes (TILs)

ASJC Scopus subject areas

Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry

UN SDGs

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

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10.3390/ijms22168924

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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.",

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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.",

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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.

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KW - PARP inhibitor

KW - Poly (ADP-ribose) poly-merase

KW - Programmed cell death-ligand 1 (PD-L1)

KW - Tumor infiltrating lymphocytes (TILs)

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ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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