Immune landscape of breast tumors with low and intermediate estrogen receptor expression

Abstract

Immune checkpoint blockade (ICB) is currently approved for patients with triple-negative breast cancer (TNBC), whereas responses to ICB are also observed in a small subgroup of Estrogen Receptor (ER)-positive breast cancer. The cut-off for ER-positivity (≥1%) is based on likelihood of endocrine treatment response, but ER-positive breast cancer represents a very heterogeneous group. This raises the question whether selection based on ER-negativity should be revisited to select patients for ICB treatment in the context of clinical trials. Stromal tumor-infiltrating lymphocytes (sTILs) and other immune parameters are higher in TNBC compared to ER-positive breast cancer, but it is unknown whether lower ER levels are associated with more inflamed tumor microenvironments (TME). We collected a consecutive series of primary tumors from 173 HER2-negative breast cancer patients, enriched for tumors with ER expression between 1 and 99% and found levels of stromal TILs, CD8 + T cells, and PD-L1 positivity in breast tumors with ER 1–9% and ER 10–50% to be comparable to tumors with ER 0%. Expression of immune-related gene signatures in tumors with ER 1–9% and ER 10–50% was comparable to ER 0%, and higher than in tumors with ER 51–99% and ER 100%. Our results suggest that the immune landscape of ER low tumors (1–9%) and ER intermediate tumors (10–50%) mimic that of primary TNBC.

Oestrogen receptor low positive breast cancer: associations with prognosis

“…Similar to our findings, a recent study showed that ER Low Positive tumours were more frequently grade 3 and had a higher expression of Ki-67, compared to BCs with intermediate or high expression of ER [ 31 ]. Furthermore, they found that the expression of immune-related biomarkers in ER Low Positive was similar to that of ER-negative tumours.…”

Real-world overall survival and characteristics of patients with ER-zero and ER-low HER2-negative breast cancer treated as triple-negative breast cancer: a Swedish population-based cohort study

“… 22 , 23 Furthermore, the degree of tumor infiltrating lymphocytes (TILs) in ER-negative and ER-low tumors seem to be the same with a high infiltration indicating that both groups are equally immunogenic. 10 , 24 Up to 15–20% of women with TNBC harbor a BRCA mutation, 25 , 26 and the incidence of BRCA 1/2 mutations seems to be at the same level in women with ER-low tumors. 27 …”

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer

“…This is in line with accumulating evidence showing that ER-low/HER2-negative BC share similar molecular and immunological features and clinical behavior with ER-negative (0%) BCs. 60 , 61 , 62 , 63 Given that current eTNBC clinical trials investigating the use of new targeted agents such as immunotherapy are often limited to tumors with ER <1%, the inclusion of the ER low-positive subgroup in these trials is encouraged. 62 …”

“… 60 , 61 , 62 , 63 Given that current eTNBC clinical trials investigating the use of new targeted agents such as immunotherapy are often limited to tumors with ER <1%, the inclusion of the ER low-positive subgroup in these trials is encouraged. 62 …”