Dynamics of molecular heterogeneity in high-risk luminal breast cancer-From intrinsic to adaptive subtyping

We evaluate therapy-induced molecular heterogeneity in longitudinal samples from high-risk, hormone-receptor positive/HER2-negative breast cancer patients with residual tumor after neoadjuvant chemotherapy from the Penelope-B trial (NCT01864746; EudraCT 2013-001040-62). Intrinsic subtypes are prognostic in pre-therapeutic (Tx) samples (n = 629, p < 0.0001) and post-Tx residual tumors (n = 782, p < 0.0001). After neoadjuvant chemotherapy, a shift of intrinsic subtypes is observed from pre-Tx luminal (Lum) B to post-Tx LumA, with reverse transition back to LumB in metastases. In a combined analysis of 540 paired pre-Tx and post-Tx samples, we identify five adaptive clusters (AC-1-5) based on transcriptomic changes before and after neoadjuvant chemotherapy. These AC-subtypes are prognostic beyond classical intrinsic subtyping, categorizing patients into groups with excellent prognosis (AC-1 and AC-2), poor prognosis (AC-3 and AC-4), and very poor prognosis (AC-5, enriched for basal-like subtype). Our analysis provides a basis for an extended molecular classification of breast cancer patients and improved identification of high-risk patient populations.

• Denkert, C.
• Rachakonda, S.
• Karn, T.
• Weber, K.
• Martin, M.
• Marmé, F.
• Untch, M.
• Bonnefoi, H.
• Kim, S. B.
• Seiler, S.
• Bear, H. D.
• Witkiewicz, A. K.
• Im, S. A.
• DeMichele, A.
• Pehl, A.
• Van't Veer, L.
• McCarthy, N.
• Stiewe, T.
• Jank, P.
• Gelmon, K. A.
• García-Sáenz, J. A.
• Westhoff, C. C.
• Kelly, C. M.
• Reimer, T.
• Felder, B.
• Olivé, M. M.
• Knudsen, E. S.
• Turner, N.
• Rojo, F.
• Schmitt, W. D.
• Fasching, P. A.
• Teply-Szymanski, J.
• Zhang, Z.
• Toi, M.
• Rugo, H. S.
• Gnant, M.
• Makris, A.
• Holtschmidt, J.
• Nekljudova, V.
• Loibl, S.