Immunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials

Mattia Rediti, Aranzazu Fernandez-Martinez, David Venet, Françoise Rothé, Katherine A. Hoadley, Joel S. Parker, Baljit Singh, Jordan D. Campbell, Karla V. Ballman, David W. Hillman, Eric P. Winer, Sarra El-Abed, Martine Piccart, Serena Di Cosimo, William Fraser Symmans, Ian E. Krop, Roberto Salgado, Sherene Loi, Lajos Pusztai, Charles M. Perou, Lisa A. Carey and Christos Sotiriou ()
Additional contact information
Mattia Rediti: Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB)
Aranzazu Fernandez-Martinez: University of North Carolina
David Venet: Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB)
Françoise Rothé: Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB)
Katherine A. Hoadley: University of North Carolina
Joel S. Parker: University of North Carolina
Baljit Singh: White Plains Hospital
Jordan D. Campbell: Mayo Clinic
Karla V. Ballman: Weill Cornell Medicine
David W. Hillman: Mayo Clinic
Eric P. Winer: Yale School of Medicine
Sarra El-Abed: Breast International Group
Martine Piccart: Institut Jules Bordet and l’Université Libre de Bruxelles (U.L.B.)
Serena Di Cosimo: Fondazione IRCCS Istituto Nazionale dei Tumori
William Fraser Symmans: MD Anderson Cancer Center
Ian E. Krop: Yale School of Medicine
Roberto Salgado: GZA-ZNA Ziekenhuizen
Sherene Loi: Peter MacCallum Cancer Centre
Lajos Pusztai: Yale School of Medicine
Charles M. Perou: University of North Carolina
Lisa A. Carey: University of North Carolina at Chapel Hill
Christos Sotiriou: Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB)

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease.

Date: 2023
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DOI: 10.1038/s41467-023-42635-2

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