1MO Tumor immune microenvironment in ER-negative vs ER-low, HER2-neg breast cancer

The recommended cut-off of <1% positive cells to define estrogen receptor (ER) negative status in breast cancer (BC) is highly debated. We compared the tumor immune microenvironment (TME) of HER2-neg BC according to ER status (ER-neg: 0% vs ER-low: 1-9%). This multicentric study included patients with stage I-III HER2-neg BC from centers across Italy and France: Istituto Oncologico Veneto IOV; Montpellier Cancer Institute MCI; Istituto Nazionale Tumori Milano; Istituto Europeo di Oncologia. Tumor samples were reviewed for ER: ER-neg and ER-low pts were eligible, pts with ER intermediate expression (ER-int: 10-50%) were included in a control cohort. Tumor-infiltrating lymphocytes (TILs) were evaluated on full-face H&E slides. CD8, FOXP3 and PD-L1 (SP142) status was assessed by IHC and quantified by digital pathology in samples from IOV (full-face slides) and MCI (tissue-microarray). Of 753 pts included, 613 had ER-neg BC, 80 had ER-low BC, and 60 had ER-int disease. TME characterization in these tumor specimens is summarized in the table. TILs levels were similar in ER-neg and ER-low tumors, and in both subgroups significantly higher than in ER-int samples. Compared to ER-neg, ER-low BC had significantly higher levels of CD8+ and FOXP3+ cells, with a similar CD8/FOXP3 ratio. The rate of PD-L1 -positive tumors was similar between ER-neg and ER-low BC pts. At the validated ≥30% cut-off, higher TILs were associated with better relapse-free survival in ER-neg (5-yr rates: 89% vs 71%, p<0.001) and ER-low BC pts (93% vs 58%, p=0.047), but not in the ER-int group, where we found an opposite trend (43% vs 69%, p=0.114).Tabled 1Table: 1MOTILsER-neg (n=613)ER-low (n=80)ER-int (n=60)PTILs median (Q1:Q3)6% (3:20)10% (5:20)5% (2:10)ER-neg vs ER- low: 0.093ER-neg vs ER-int: 0.026ER-low vs ER-int: 0.003CD8 and FOXP3ER-negER-lowP(n=219 IOV, n=248 MCI)(n=30 IOV, n=19 MCI)CD8 cells/mm2IOV median (Q1:Q3)227 (103:562)343 (201:545)0.040MCI median (Q1:Q3)341 (86:760)1100 (168-1596)0.071FOXP3 cells/mm2IOV median (Q1:Q3)53 (19:122)91 (44:168)0.011MCI median (Q1:Q3)2 (0:22)38 (1:91)0.036CD8/FOXP3 ratioIOV median (Q1:Q3)4 (2:8)4 (2:7)0.495MCI median (Q1:Q3)29 (6:98)15 (5:33)0.464PD-L1ER-negER-lowP(n=77 IOV; n=249 MCI)(n=13 IOV; n=17 MCI)PDL1 ≥1%IOV (%)64.9%69.2%0.091MCI (%)73.9%94.1%0.062 Open table in a new tab TME composition is similar in ER-neg vs ER-low HER2-neg BC tumors and TILs have a similar prognostic role in these cohorts. Our results support the claim that HER2-neg/ER-low BC pts should be granted access to drugs developed for triple-negative BC, including immune checkpoint inhibitors. Gene expression analysis will be presented at the meeting.