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.

• Authors: 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
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 16 (Aug 19 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34445631 (Publication Type: Journal Article)

Chemical References

• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• Cell-Free Nucleic Acids
• Receptors, Estrogen
• Receptors, Progesterone
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Adult
• Aged
• B7-H1 Antigen (genetics, metabolism)
• Biomarkers, Tumor (genetics)
• Cell-Free Nucleic Acids (analysis, genetics)
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• High-Throughput Nucleotide Sequencing
• Humans
• Inflammatory Breast Neoplasms (genetics, immunology, pathology)
• 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)