ER and immune-related signatures define benefit to palbociclib, trastuzumab, pertuzumab +/- fulvestrant in ER+/HER2+ breast cancer patients in the NA-PHER2 trial.
Authors: Giampaolo Bianchini, Matteo Dugo, Balazs Gyorffy, Giancarlo Bisagni, Marco Colleoni, Mauro Mansutti, Claudio Zamagni, Lucia Del Mastro, Stefania Zambelli, Antonio Frassoldati, Luca Licata, Barbara Galbardi, Maria Olivia Biasi, Lucia Viganò, Alberta Locatelli, Chanel Smart, Giuseppe Viale, Pinuccia Valagussa, Maurizio Callari, Luca Gianni
Journal: Journal of Clinical Oncology (2021)

555 Background: In the NA-PHER2 study we assessed the association between biological pathways with pathological complete response (pCR) and Ki67 down-regulation Methods: Patients with centrally confirmed ER+ ( &gt; 10%) HER2+ breast cancer (BC) were treated in two independent, non-randomized cohorts with neoadjuvant trastuzumab, pertuzumab, palbocilib with (Fulv, n = 30) or without (NoFulv, n = 28) fulvestrant (+/-LHRH analogues). We assessed RNA-seq on core-biopsies obtained pre-treatment [n = 53/58 (91.4%)], at day 14 [n = 49/58 (84.5%)], and on residual disease at surgery [n = 42/45 (93.3%)]. We investigated biomarker dynamics and association with pCR or Ki67 down-regulation (centrally evaluated) at day 14 and at surgery. In the overall population and in each cohort, we primarily assessed three pre-defined biomarkers (ER-metagene [from OncotypeDX], a CD8-metagene and ERBB2 expression), and secondarily we explored a pre-defined list of genesets. Continuous and categorical (median cut-point) variables were evaluated. Results: In the biomarker population, pCR rate was 22.5% (28.6% and 16.0% in Fulv and NoFulv cohorts). At baseline, continuous CD8-metagene (OR 1.85 [1.12-3.06], p = 0.016) and ER-metagene (OR 0.56 [0.34-0.90], p = 0.016) associated with higher and lower pCR rate, respectively. High ERBB2 (above median) was marginally associated with pCR (OR 3.83 [0.90-16.3], p = 0.068). Only ER- and CD8-metagenes retained significance in multivariate analysis and were similarly predictive in both cohorts. Combining categorical variables, the groups with high-CD8/low-ER and low-CD8/high-ER had 61.5% and 0% pCR rate respectively, whereas low-CD8/low-ER and high-CD8/high-ER had similar 15% pCR (p = 0.001). The association was significant in both cohorts (p = 0.019 Fulv; p = 0.028 NoFulv). Dynamic assessment of the same biomarkers at day 14 did not improve prediction. Higher ER-metagene at baseline, but not CD8 and ERBB2, was associated with robust down-regulation of Ki67 at day 14 (Ki67 &lt; 2.7%, complete cell cycle arrest) only in Fulv cohort (p = 0.016). ER-metagene also associated with retained Ki67 down-regulation (Ki67 &lt; 10%) at surgery (p = 0.002). Alternative ER- and immune-related signatures provided very similar results. The comprehensive landscape of complex molecular dynamics and exploratory association with outcome will be presented. Conclusions: In ER+/HER2+ BC, low expression of ER-related and high expression of immune-related genes identified patients with very high likelihood of achieving pCR with a chemo-free regimen. In the fulvestrant cohort, the group with high ER-metagene, despite a lower pCR rate, had higher Ki67 down-regulation at day 14, which has been associated with long-term benefit in luminal tumors. These findings provide a potential tool for tailored de-escalation strategies.