Genetic Variants and Tumor Immune Microenvironment: Clues for Targeted Therapies in Inflammatory Breast Cancer (IBC)

Int J Mol Sci. 2021 Aug 19;22(16):8924. doi: 10.3390/ijms22168924.


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: PARP inhibitor; cell-free DNA (cfDNA); immune checkpoint inhibitors (ICIs); poly (ADP-ribose) polymerase; programmed cell death-ligand 1 (PD-L1); tumor infiltrating lymphocytes (TILs).

MeSH terms

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


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