Abstract 56P
Background
Increased antitumor immune response correlates with improved rates of pathologic complete response (pCR) in early HER2+ breast cancer (BC) patients treated with neoadjuvant anti-HER2 therapy. However, the systemic and local immune responses and temporal evolution in patients treated with neoadjuvant antibody-drug conjugates have not been investigated.
Methods
Serial plasma samples were collected at baseline and on-treatment (at cycle 2) from early HER2+ BC patients treated with trastuzumab emtansine (T-DM1) in the neoadjuvant PREDIX HER2 phase II trial (NCT02568839). The Olink Proximity Extension Assay (Uppsala, Sweden) was used for multiplexed plasma proteomics analysis (92 immuno-oncology proteins). TILs enumeration was performed on H&E-stained tissue from core biopsies at the same timepoints. Correlations were performed with patient clinicopathological characteristics/outcomes.
Results
Baseline and on-treatment plasma proteomic data were available for 90 and 59 patients, respectively. At baseline, specific chemokines (i.e. CCL3, DCN, MCP-1/4, MMP7) inversely correlated with Ki67 but positively correlated with age. Immune-inhibitory checkpoints were significantly upregulated in patients with lymph node metastases (i.e. PDCD1, LAG3; p<0.01). The systemic proteomic landscape revealed a number of proteins (i.e. LAP TGF-beta-1, LAMP3, IL-7, IL-18, CXCL11, CRTAM) significantly enriched in non-pCR patients. This systemic response was accompanied by lower baseline mean TILs levels in non-pCR patients (non-pCR= 19% vs pCR=24.3%, n=87), but only CXCL11 inversely correlated with TILs (Spearman’s r=-0.26, p=0.02). Increased on-treatment circulating IL-33 levels were observed in patients who reached pCR. The systemic IL-33 upregulation was accompanied with significantly increased on-treatment TILs levels (deltaTILs: non-pCR= 8.8% vs pCR=34.4%, p=0.018; n=32).
Conclusions
Longitudinal plasma protein profiling revealed systemic immune markers of response and/or resistance to neoadjuvant T-DM1-only treatment in early HER2+ BC. Further validation studies are needed.
Clinical trial identification
NCT02568839.
Legal entity responsible for the study
The authors.
Funding
Swedish Cancer Society, Research Funds at Radiumhemmet, Region Stockholm.
Disclosure
J. Hartman: Financial Interests, Personal and Institutional, Advisory Board, or speaker's honoraria: Roche, Novartis; Financial Interests, Personal, Advisory Board, or speaker's honoraria: Pfizer, Eli Lilly, MSD; Financial Interests, Institutional, Other: AstraZeneca; Financial Interests, Personal, Ownership Interest, co-founder and shareholder: Stratipath AB. T. Hatschek: Financial Interests, Personal, Advisory Board, Meeting of a group of specialists for discussion on translational research twice yearly: Pfizer; Financial Interests, Institutional, Invited Speaker, Grants related to the academic PREDIX LumB trial: Pfizer. J. Bergh: Other, Fees (honoraria) to Coronis and Asklepios Cancer Research AB as an invited speaker/chair from AstraZeneca and Roche, respectively: Coronis and Asklepios Cancer Research AB.; Other, Institutional honoraria as chapter co-author for UpToDate to Asklepios Medicin HB. Co-author on a chapter on “Prognostic and Predictive factors in early, non-metastatic breast cancer”: Asklepios Medicin; Other, Institutional research grants received more than ten years ago to Karolinska Institutet and/or University Hospital for molecular marker studies/ clinical studies (we are still working with the material). No personal payments for these activities: Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche and Sanofi-Aventis; Other, Stocks in Stratipath AB. The company is involved in AI based diagnostics for breast cancer: Stratipath AB. A. Matikas: Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Invited Speaker, International co-PI of academic trial ARIADNE (EU CT: 2022-501504-95-00): AstraZeneca, Novartis, Veracyte; Financial Interests, Institutional, Invited Speaker, Registry study: Merck; Non-Financial Interests, Advisory Role: Veracyte, Roche. T. Foukakis: Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Gilead Sciences; Financial Interests, Personal, Royalties, Authorship of two chapters in UpToDate: Wolters Kluwer; Financial Interests, Institutional, Invited Speaker, Clinical trial support (research grant and study drug): AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical trial support (research grant and study drug): Novartis; Financial Interests, Institutional, Invited Speaker, Discount on the Prosigna PAM50 assay in ARIADNE clinical trial: Veracyte. All other authors have declared no conflicts of interest.