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.
Highlights
Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer
20–30% of IBC patients present with distant metastasis at diagnosis, compared to 6–10% of patients with non-inflammatory breast cancer [9]
42% were detected in both cell-free DNA (cfDNA) and paired tumor tissue samples, and 30% of somatic variants were detected only in cfDNA and 28% only in tumor tissue samples
Summary
Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. IBC is a relatively rare clinical subtype of locally advanced breast cancer, it is responsible for approximately 10% of breast cancer-associated deaths annually in the US, which translates into 4000 deaths per year [4,7]. 20–30% of IBC patients present with distant metastasis (stage IV disease) at diagnosis, compared to 6–10% of patients with non-inflammatory breast cancer (non-IBC) [9]. IBC is a heterogeneous disease and can occur as any of the five molecular subtypes, it is most commonly either triple-negative (TN) or HER2 overexpressing [10]. TN breast cancer, which is defined by an absence of estrogen and progesterone receptors, and a lack of HER2 overexpression, has a worse prognosis than other subtypes [11]. The rarity of the disease, misdiagnosis, and difficulty in sample collection before treatment has resulted in a limited number of published molecular studies [2,12,13,14,15,16]
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