Abstract 23P
Background
All four intrinsic subtypes (Luminal A, Luminal B, HER2-enriched [HER2-E] and Basal-like) are identified in clinically HER2-positive breast cancer (HER2+ BC). In this study, we evaluated the distribution, longitudinal changes, and prognostic implications of PAM50 subtypes in patients receiving neoadjuvant HER2-targeted therapy in the randomized phase II PREDIX HER2 trial.
Methods
RNA sequencing was performed on 195 baseline (of 197 randomized patients), 168 on-treatment and 127 surgical fresh-frozen tissue specimens from early HER2+ BC patients treated with docetaxel, trastuzumab and pertuzumab (THP) or trastuzumab emtansine (T-DM1) within the PREDIX HER2 trial. PAM50 subtypes were calculated by the sspbc. subtype-PAM50 model. Baseline PAM50 subtype correlations with pathologic complete response (pCR) and event-free survival (EFS) were analyzed using multivariate logistic and Cox regression, respectively. The shift in subtype from baseline to on-treatment is described among patients with paired samples available.
Results
PAM50 intrinsic subtypes at baseline, on-treatment, and post-surgical stages were calculated for all patients sequenced across the three time points, while paired samples for baseline and on-treatment were available for 167 patients. At baseline, 108 (55%) patients were classified as HER2-E, 36 (18%) as luminal A, 35 (18%) as luminal B and 16 (8%) as basal-like. Baseline HER2-E subtype was significantly associated with pCR (ORadj=4.05; 95% CI, 2.02-8.38; P <0.001) and EFS (HRadj=0.17; 95% CI, 0.06-0.55; P =0.003). Among patients with paired baseline and on-treatment samples, 71/93 baseline HER2-E patients switched to a non-HER2-E subtype (McNemar's P<0.001). A 50% agreement of PAM50 subtypes was observed in 14 patients with two available baseline biopsies.
Conclusions
Molecular subtypes are prognostic for response to neoadjuvant HER2-targeted treatment and for long-term outcomes. Subtypes exhibit significant intratumoral and temporal heterogeneity. Ongoing analyses investigate the prognostic implications of subtype switch.
Clinical trial identification
NCT02568839.
Legal entity responsible for the study
The authors.
Funding
Swedish Research Council, Swedish Cancer Society, The Research Funds at Radiumhemmet, Region Stockholm, Roche Sweden.
Disclosure
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. 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. 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.