Search

Background: Inflammatory breast cancer (IBC) is characterized by a young age at diagnosis, high metastatic potential, and poor overall survival. To better understand the etiology of this aggressive disease, we performed a retrospective study to evaluate genomic alterations and tumor microenvironment in IBC patients. Methods: Targeted next generation sequencing (NGS) was performed using blood cell-free DNA (cfDNA) (n=32), paired DNA from tumor tissues (n=29) and DNA from whole blood or normal tissue (n=20). 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. Results: Our results shown a high incidence of germline variants in patients with IBC that could be associated with an increased risk of developing the disease. Germline variants were found more frequently in patients with TN (38.9%) than non-TN IBC (28.6%). IHC staining revealed that in 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs. Patients with PD-L1&PD-1 positive biopsies had a lower OS (31 months) than patients with PD-L1&PD-1 negative (38 months) tumors, though the difference was not statistically significant. PD-L1&PD-1 positive tumors had significantly more CD8+ (cytotoxic T-cells), CD20+ (B-cells) and FoxP3+ (Tregs) cells than PD-L1&PD-1 negative ones. Furthermore, most IBC patients showed to have deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. All tumor biopsies showed positive staining for p-FAK1(Tyr 397). Conclusion: A subset of IBC patients (29%) expressed both PD-L1 and PD-1 on tumor immune cells infiltrates, providing rationale for testing PD-1/PD-L1 blocking therapies. IBC patients could have benefits from PD-1/PD-L1 blocking therapies alone or in combination with PARP or FAK (Tyr397) kinase inhibitors, both having the capacity of altering the tumor microenvironment. Citation Format: Maria F. Arisi, Yulan Gong, Rajeswari Nagarathinam, Lorenzo Gerratana, Jianming Pei, Kathy Q. Cai, Jennifer Winn, Zachary Hasse, Elias Obeid, Julio Noriega, Christopher Sebastiano, Eric Ross, R. Katherine Alpaugh, Massimo Cristofanilli, Sandra V Fernandez. Genetic variants and tumor microenvironment in inflammatory breast cancer: Clues for targeted therapies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-24-02.

In order to better understand the etiology of inflammatory breast cancer (IBC), we performed a retrospective study to evaluate genomic alterations in 32 IBC patients using circulating DNA from blood. In 20 patients, mutation analyses were also conducted on tumor tissue or tumor cells from pleural effusions; in 15 of these patients, blood and tissue or pleural effusions were collected at the same time. Next generation sequencing (NGS) and a panel of 93 breast cancer related genes (Qiagen) were used for these studies. We found that of the 32 total patients, 11 (34.4%) carried at least one putative pathogenic germline variant, and another 8 patients (25%) carried at least one likely pathogenic germline variant. Ten patients (31.3%) carried only germline variants of uncertain significance and in 3 patients (9.4%) germline variants were not detected. Putative germline pathogenic variants were observed in the BRCA2 (2/32), TP53 (2/32), BRCA1 (1/32), PALB2 (1/32), CHEK2 (1/32), ATM (1/32), PMS1 (1/32), MUTYH (1/32), and MSH2 (1/32) genes. In addition, putative germline likely pathogenic variants were observed in the BARD1 (10/32), RB1 (2/32), APC (1/32), FANCC (1/32), AR (1/32), RAD51C (1/32), RAD51D (1/32) and CASP8 (1/32) genes. Most of the patients in our study had a family history of cancer and seventeen of the patients (53.1%) had family history of breast cancer in particular. Of those patients, 7 had a family history of breast cancer at a young age ( Citation Format: Jennifer S. Winn, Zachary Hasse, Jianming Pei, Michael Slifker, Sebastian M. Arisi-Fernandez, Jacqueline N. Talarchek, Elias Obeid, Karthik Devarajan, Hong Wu, Yulan Gong, Massimo Cristofanilli, R.Katherine Alpaugh, Sandra Viviana Fernandez. Germline and somatic variants in patients with inflammatory breast cancer (IBC) detected using cell-free DNA [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-11.