Abstract
The fact that 20–40% of all breast cancer (BC) patients develop recurrence when 5 year survival is 90% strongly suggests that late recurrence, i.e. more than 5 years after diagnosis, is the remaining challenge to decrease the absolute number of BC deaths. Better understanding late recurrence is an essential first step to address this issue. We hypothesized that primary tumors with a distinctive tumor immune microenvironment will develop late recurrence. Accordingly, we evaluated the relationship between the timing of cancer recurrence, clinical factors, gene expression profiles, and immune status utilizing two published large cohorts. 308 primary BCs in TCGA were analyzed and categorized as: recurrence ≤2 years (Early, n = 49), between 2–5 years (Mid, n = 54), recurrence >5 years (Late, n = 20), and no recurrence >5 years (Survivors, n = 185). 1,727 primary BCs in METABRIC were analyzed and categorized similarly: Early, n = 170; distant (D), n = 19; local (L), Mid, n = 213; D, n = 21; L, Late, n = 199; D, n = 57, L, and Survivors, n = 1048. Utilizing pre-ranked GSEA, we showed that primary tumors with Survivors were associated with anti-cancer signaling such as INF-α/-γ response and TNF-α signaling, compared with all recurrence groups in pre-ranked GSEA. Furtherrmore, we found that host defense immunity (leukocyte fraction, lymphocyte infiltration, and macrophage fractions) was decreased in primary tumors with Late recurrence compared with Survivors. Utilizing the CIBERSORT algorithm, we showed anti-cancer lymphocytes, memory CD4+ T cells and γδT cells, were significantly lower, and pro-cancerous regulatory T cells were significantly higher in Late tumors compared with Survivors. In agreement, cytolytic activity score that assesses immune cell cytolytic activity was significantly lower in Late compared with Survivors. We demonstrated that not only host defense immunity, but also pro-cancerous immune cells and immune cell cytolytic activity in primary BC was associated with late recurrence.
Highlights
The fact that 20–40% of all breast cancer (BC) patients develop recurrence when 5 year survival is 90% strongly suggests that late recurrence, i.e. more than 5 years after diagnosis, is the remaining challenge to decrease the absolute number of BC deaths
We studied the relationship between clinical features of the primary tumor and the timing of cancer recurrence in The Cancer Genome Atlas (TCGA) BC cohort (Table 1) and METABRIC cohort (Tables 2 and 3)
We showed that BC patient who develop recurrence earlier (Early and Mid) had primary tumors associated with more aggressive clinical characteristics such as larger tumor, more lymph node metastases, higher pathological grades, higher Stages, and negative estrogen receptor (ER) and progesterone receptor (PgR), compared to Survivors; clinical characteristics of primary tumors with Late recurrence were almost the same as Survivors (Tables 1–3)
Summary
The fact that 20–40% of all breast cancer (BC) patients develop recurrence when 5 year survival is 90% strongly suggests that late recurrence, i.e. more than 5 years after diagnosis, is the remaining challenge to decrease the absolute number of BC deaths. 20–40% of estrogen receptor (ER) + BC patients eventually develop distant metastasis, and half of these events occur five or more years after diagnosis of the primary tumor[6] This is in sharp contrast to ER-negative tumors, for which the recurrence rate peaks at around two years, but the rate diminishes after five years[7]. There have been attempts to utilize multi-parametric molecular assays, such as IHC4, OncotypeDX, EndoPredict, PAM50 risk of recurrence score, and Breast Cancer Index, to predict late recurrence in addition to early recurrence (relapse less than five years after initial treatment)[1,8]. We examined the relationship between the timing of cancer recurrence and clinical factors, gene expression profiles, and immune status utilizing collected data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) primary BC cohorts
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