Peripheral blood TCR clonotype diversity as an age-associated marker of breast cancer progression.

Immune escape is a prerequisite for tumor growth. We previously described a decline in intratumor activated cytotoxic T cells and T cell receptor (TCR) clonotype diversity in invasive breast carcinomas compared to ductal carcinoma in situ (DCIS), implying a central role of decreasing T cell responses in tumor progression. To determine potential associations between peripheral immunity and breast tumor progression, here, we assessed the peripheral blood TCR clonotype of 485 breast cancer patients diagnosed with either DCIS or de novo stage IV disease at younger (<45) or older (≥45) age. TCR clonotype diversity was significantly lower in older compared to younger breast cancer patients regardless of tumor stage at diagnosis. In the younger age group, TCR-α clonotype diversity was lower in patients diagnosed with de novo stage IV breast cancer compared to those diagnosed with DCIS. In the older age group, DCIS patients with higher TCR-α clonotype diversity were more likely to have a recurrence compared to those with lower diversity. Whole blood transcriptome profiles were distinct depending on the TCR-α Chao1 diversity score. There were more CD8+ T cells and a more active immune environment in DCIS tumors of young patients with higher peripheral blood TCR-α Chao1 diversity than in those with lower diversity. These results provide insights into the role that host immunity plays in breast cancer development across different age groups.

Clinicogenomic characterization of inflammatory breast cancer.

Background: Inflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined-partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. Patients and Methods: A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases. Results: Clinicopathologic differences between IBC and non-IBC cases were consistent with prior reports-including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). A multivariate logistic regression analysis revealed a significant enrichment in TP53 SNVs in IBC; particularly in HER2-positive and HR-positive disease which was associated with worse outcomes. Tumor mutational burden (TMB) did not differ substantially between IBC and non-IBC cases and a pathway analysis revealed an enrichment in NOTCH pathway alterations in HER2-positive disease. Conclusion: Taken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of TP53 mutations and a potential enrichment in NOTCH pathway activation-but overall; a lack of major genomic differences. These results both reinforce the importance of TP53 alterations in IBC pathogenesis as well as their influence on clinical outcomes; but also suggest additional analyses beyond somatic DNA-level changes are warranted.

Comprehensive genomic characterization of HER2-low and HER2-0 breast cancer.

The molecular underpinnings of HER2-low and HER2-0 (IHC 0) breast tumors remain poorly defined. Using genomic findings from 1039 patients with HER2-negative metastatic breast cancer undergoing next-generation sequencing from 7/2013-12/2020, we compare results between HER2-low (n = 487, 47%) and HER2-0 tumors (n = 552, 53%). A significantly higher number of ERBB2 alleles (median copy count: 2.05) are observed among HER2-low tumors compared to HER2-0 (median copy count: 1.79; P = 2.36e-6), with HER2-0 tumors harboring a higher rate of ERBB2 hemideletions (31.1% vs. 14.5%). No other genomic alteration reaches significance after accounting for multiple hypothesis testing, and no significant differences in tumor mutational burden are observed between HER2-low and HER2-0 tumors (median: 7.26 mutations/megabase vs. 7.60 mutations/megabase, p = 0.24). Here, we show that the genomic landscape of HER2-low and HER2-0 tumors does not differ significantly, apart from a higher ERBB2 copy count among HER2-low tumors, and a higher rate of ERBB2 hemideletions in HER2-0 tumors.