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). Table: 1MO
TILs ER-neg (n=613) ER-low (n=80) ER-int (n=60) P TILs median (Q1:Q3) 6% (3:20) 10% (5:20) 5% (2:10) ER-neg vs ER- low: 0.093 ER-neg vs ER-int: 0.026 ER-low vs ER-int: 0.003 CD8 and FOXP3 ER-neg ER-low P (n=219 IOV, n=248 MCI) (n=30 IOV, n=19 MCI) CD8 cells/mm2 IOV median (Q1:Q3) 227 (103:562) 343 (201:545) 0.040 MCI median (Q1:Q3) 341 (86:760) 1100 (168-1596) 0.071 FOXP3 cells/mm2 IOV median (Q1:Q3) 53 (19:122) 91 (44:168) 0.011 MCI median (Q1:Q3) 2 (0:22) 38 (1:91) 0.036 CD8/FOXP3 ratio IOV median (Q1:Q3) 4 (2:8) 4 (2:7) 0.495 MCI median (Q1:Q3) 29 (6:98) 15 (5:33) 0.464 PD-L1 ER-neg ER-low P (n=77 IOV; n=249 MCI) (n=13 IOV; n=17 MCI) PDL1 ≥1% IOV (%) 64.9% 69.2% 0.091 MCI (%) 73.9% 94.1% 0.062
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.
The authors.
Funding from Merck KGaA, Darmstadt, Germany and Institutional funding from Istituto Oncologico Veneto - Ricerca Corrente.
D. Massa: Financial Interests, Personal, Sponsor/Funding, Travel Support: Eli Lilly. C. Vernieri: Financial Interests, Personal, Advisory Role: Novartis, Daiichi Sankyo, Pfizer; Financial Interests, Personal, Invited Speaker: Novartis, Eli Lilly, Istituto Gentili; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, Travel Grant: Novartis, Daiichi Sankyo, Pfizer, Eli Lilly, Istituto Gentili. C. Criscitiello: Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Eli Lilly, Roche, Gilead; Financial Interests, Personal, Advisory Board: MSD, Seagen, AstraZeneca, Daiichi Sankyo. G. Griguolo: Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis; Financial Interests, Personal, Other, Travel Support: Gilead, Eli Lilly, Pfizer, Novartis, Daiichi Sankyo, Amgen. F. Miglietta: Financial Interests, Personal, Sponsor/Funding: Roche, Novartis, Gilead. A. Vingiani: Financial Interests, Personal, Invited Speaker: Roche, Eli Lilly. R. Lobefaro: Financial Interests, Personal, Advisory Role: Pfizer, Lilly, Daiichi Sankyo, AstraZeneca. G. Pruneri: Financial Interests, Personal, Advisory Board: ADS Biotec; Financial Interests, Personal, Other, Honoraria: Exact Sciences, Novartis, Eli Lilly, AstraZeneca; Financial Interests, Personal, Research Grant: Roche. M. Fassan: Financial Interests, Personal, Advisory Role: Astellas Pharma, Pierre Fabre, MSD, AstraZeneca, Janssen, GlaxoSmithKline, Amgen, Novartis , Roche; Financial Interests, Personal, Research Grant: Astellas Pharma, QED Therapeutics, Diaceutics and Macrophage Pharma. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Invited Speaker, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Sanofi, Merck Serono, Exact Sciences, Eisai, Olema Oncology; Financial Interests, Personal, Expert Testimony: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, Glaxo Smith Kline, Daiichi Sankyo, Nerviano; Non-Financial Interests, Member: ASCO. W. Jacot: Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, Novartis, Roche, Pfizer, Eli Lilly, MSD, BMS, Chugai, Seagen, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, Daiichi Sankyo; Financial Interests, Invited Speaker: Roche, Novartis, Daiichi Sankyo, Daiichi Sankyo. M.V. Dieci: Financial Interests, Personal, Advisory Role: Eli Lilly, Pfizer, Novartis, Seagen, Gilead, MSD, Exact Sciences, AstraZeneca, Roche, Daiichi Sankyo. All other authors have declared no conflicts of interest.