2/10 BioItaLEE is a phase 3B trial which enrolled postmenopausal pts with endocrine-sensitive HR+/HER2− aBC receiving ribociclib/letrozole as first-line therapy and prospectively collect blood samples to investigate potential biomarkers of response and resistence

3/10 Thymidine kinase 1 (TK1) is an enzyme with a role in cell proliferation, and with downstream activity to CDK4/6 pathway 👉attractive marker of CDK4/6 inhibitor efficacy TK1 activity can be measured in serum as a readout of tumor proliferation

4/10 TKa were assessed at baseline (D0), day 15 of cycle 1 (D15), day 1 of cycle 2 (C2D1) and at first imaging (FI, 12 weeks) We evaluated the prognostic role of TKa level at baseline and the predictive role of TKa dynamics

5/10 High TKa (value >median) at baseline was associated with poor prognosis (HR for disease progression 2.21; 95% CI 1.45,3.37; p=0.0002) 👉Baseline TKa is a strong PROGNOSTIC factor

6/10 The PREDICTIVE role of TKa dynamics explored by defining three patterns (LOD=Limit Of Detection) - Pattern 1: TKa <LOD at D15 and C2D1 (persistent suppression) - Pattern 2: TKa <LOD at D15 and >LOD at C2D1 (reboud at C2D1) - Pattern 3: TKa >LOD at D15 (primary resistence)

7/10 TKa dynamic patterns were strongly predictive of PFS - Pattern 2 (reboud at C2D1) had worse PFS compared with P1 (persistent suppression) (HR 2.89; 95% CI 1.57,5.31;p=0.0006) - Pattern 3 (primary resistance) had an even shorter PFS (HR 5.65; 95% CI 2.84,11.23;p<0.0001)

8/10 Baseline TKa (high vs low) and TKa dynamic patterns provided independent prognostic information

9/10 Take home messages (I) In HR+/HER2− aBC treated with RIB + LET as first-line 👉Baseline TKa is PROGNOSTIC 👉TKa dynamic is PREDICTIVE 👉Baseline and dynamic TKa changes provided independent information

10/10 Take home messages (II) 👉Lack of TKa decrease at D15 identify patients with primary resistance 👉TKa rebound at C2D1 may indicate early tumor adaptation to RIB + LET (average prognosis) 👉Persistent TKa decrease identify pts with excellent prognosis Confirmation warreted

@BianchiniGP @LMalorni @puglisi_fabio @FilippoMontemu1 @delmastro_lucia @GraziaArpino very nice work!

@prat_aleix @LMalorni @puglisi_fabio @FilippoMontemu1 @delmastro_lucia @GraziaArpino Thank you @prat_aleix