Abstract P4-14-01: Modulation of tumor infiltrating lymphocytes (TILs) by palbociclib, trastuzumab, pertuzumab +/- fulvestrant in ER+/HER2+ patients (pts) enrolled in the Michelangelo NA-PHER2 trial
Authors: Bianchini Giampaolo , Smart Chanel , Bisagni Giancarlo , Colleoni Marco , Mansutti Mauro , Zamagni Claudio , Mastro Lucia Del , Zambelli Stefania , Licata Luca , Frassoldati Antonio , Viale Giuseppe , Valagussa Pinuccia , Gianni Luca 
Published: March 2020

Background We assessed TILs before and during treatment in patients with ER+/HER2+ breast cancer (BC) enrolled in the NA-PHER2 study, and evaluated the association between TILs and their modulation over treatment with likelihood of achieving a pCR. Methods In the NA-PHER2 study (NCT02530424), patients with centrally confirmed ER+ (&gt;10%) HER2+ BC were treated in two independent, non-randomized, cohorts with neoadjuvant trastuzumab, pertuzumab, palbocilib with (Cohort A, n=30) or without (Cohort B, n=28) fulvestrant (+/-LHRH analogues). We measured TILs by optical evaluation on core-biopsies obtained pre-treatment [pre-CBX, n=56/58 (96.5%)], at 14 days if invasive tumor cells [14d-CBX, n=52/53 (98.1%)], and on residual disease at surgery [SX, n=45/45 (100%)]. We scored TILs as stromal and intratumoral TILs (sTILs, iTILs), and hotspot TILs (hTILs) i.e. the fields of highest TILs density. We investigated the association between baseline and 14 days TILs with pCR, including the early TILs changes (pre vs 14 days) [delta TILs (ΔTILs) was the absolute percentage change). TILs biomarkers were assessed as continuous variable (10% increase). Results The three TILs metrics were significantly correlated at all time-points (all p&lt;1E-04, all corr &gt;0.55). TILs metrics were not associated with T and N stage, PgR status. sTILs were correlated with Ki67 as continuous variable at 14 days (corr 0.41 p=0.003) and surgery (corr 0.34, p=0.025), but not at baseline. At baseline (pre-CBX), only high sTILs were associated with pCR (OR 1.55 [1.01-2.37], p=0.044). At 14 days (on treatment), all TILs assessments were associated with pCR (OR 1.96 [1.16-3.31], p=0.011 for sTILs; OR 5.85 [1.39-24.6], p=0.016 for iTILs; OR 1.58 [1.16-2.14], p=0.004). When combined in multivariate model, they did not provide independent information. Considering early changes of TILs (baseline vs 14 days), only ΔiTILs was associated with pCR (OR 3.09 [1.50-6.38], p=0.002). When baseline, 14 days and dynamic biomarker was assessed in multivariate, only ΔiTILs retained the significance. The predictive value of TILs was similar in the two treatment cohorts. Overall, there was not average difference between any TILs assessment method comparing the three time points. By evaluating only patients with RD and TILs assessment available at all three time points (n=41/45, 91.1%), some intra-patient variability emerged. ΔTIL higher than 10% was observed in 13/41 (31.7%) cases. Seven (17.1%) had an increase, 4 (9.7%) a mixed behavior and 2 (4.9%) had a decrease. Dynamic change of TILs was not associated with change in Ki67. When TILs infiltration in the two treatment cohort was compared at different time points, it was different only at surgery, when sTILs and iTILs were lower in patients treated with Fulvestrant in Cohort A (p=0.19 and p=0.013, respectively). Conclusions In the NA-PHER2 study, we show that in ER+/HER2+ BC the likelihood of achieving pCR using a chemo-free regimen is larger in patients with higher sTILs infiltration. TILs assessment on core biopsies after 14 days was also predictive of pCR, and early changes of iTILs was the most informative predictor suggesting that treatment may facilitate T cell infiltration in agreement with the postulated contribution of CDK4/6 to immune evasion (Goel S Nature 2017, Jerby-Arnon L Cell 2018). No average modulation of immune biomarkers was found. However, individual pts modulation suggests that immune effect might be relevant also for some patients not achieving a pCR. Notably, the presence of endocrine treatment may contribute to dampen immune activation. Changes of Ki67 and TILs were not associated suggesting that they capture different biological phenomena. Supported in part by an unrestricted grant from Pfizer Italia S.r.l. and from Roche S.p.a. Italia

Citation Format: Giampaolo Bianchini, Chanel Smart, Giancarlo Bisagni, Marco Colleoni, Mauro Mansutti, Claudio Zamagni, Lucia Del Mastro, Stefania Zambelli, Luca Licata, Antonio Frassoldati, Giuseppe Viale, Pinuccia Valagussa, Luca Gianni. Modulation of tumor infiltrating lymphocytes (TILs) by palbociclib, trastuzumab, pertuzumab +/- fulvestrant in ER+/HER2+ patients (pts) enrolled in the Michelangelo NA-PHER2 trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-14-01.