Abstract PS5-05: Serum thymidine kinase activity in patients with luminal metastatic breast cancer treated with palbociclib and fulvestrant within the PYTHIA trial
Authors: Malorni Luca , Tyekucheva Svitlana , Hilbers Florentine S , Ignatiadis Michail , Neven Patrick , Colleoni Marco , Henry Stéphanie , Ballestrero Alberto , Bonetti Andrea , Jerusalem Guy , Papadimitriou Konstantinos , Bernardo Antonio , Duhoux Francois , MacPherson Iain , Thomson Alastair , Davies David Mark , Bergqvist Mattias , Benelli Matteo , McCartney Amelia , De Swert Heidi , Ruepp Barbara , Rabaglio Manuela , Maibach Rudolf , Piccart Martine , Regan Meredith M 
Published: February 2021

Background: The CDK4/6 inhibitor palbociclib (P) plus fulvestrant (F) is approved for the treatment of patients (pts) with luminal metastatic breast cancer (MBC) progressed on prior endocrine therapy (ET). Despite clinical activity, a significant proportion of pts in this setting show primary resistance to P+F, with treatment failure within 3-6 months of initiation. To date there is no validated biomarker to identify such pts. Thymidine kinase 1 is a cancer proliferation marker downstream of the CDK4/6 pathway, whose activity can be measured in serum as a readout of tumour proliferation. Circulating thymidine kinase activity (TKa) is a potential prognostic and monitoring marker in pts treated with ET alone or in combination with P for MBC. However, the prognostic value of early changes in TKa during P+F treatment and its role in identifying pts with primary resistance are not yet defined. Here we prospectively investigated the role of serum TKa measured at different timepoints in pts treated with P+F within the PYTHIA trial (IBCSG 53-14/BIG 14-04; NCT02536742), a downstream trial of the AURORA platform (BIG 14-01; NCT02102165).

Methods: PYTHIA is a biomarker discovery phase II trial including pts (Aug ‘16 to Jun ’19) with ET-resistant luminal MBC who received P+F at standard schedule and dose with 3-monthly imaging. Serum samples were collected at baseline (D0; n=122), on-treatment at day 11-16 of cycle 1 (D15; n=108), and during the one week off P before initiating cycle 2 (D28: Day 24-37 of Cycle 1; n=108). TKa was measured with DiviTum®, a refined ELISA-based assay. Complete TKa response (CTR) was defined as TKa below the limit of detection (LOD; 20 Du/L) at D15. Cox models evaluated association of log-transformed TKa measurements with progression-free survival (PFS; from initiation of therapy until progression by RECIST criteria or death). Kaplan-Meier method estimated median, 3 and 6 months (95% CI) PFS in groups of patients defined by dichotomizing TKa as “high” or “low” at the median or by CTR. A sample size of 120 provided 80% power to detect a hazard ratio of 2.0 for biomarker with 30-50% prevalence (two-sided α=0.05) after ≥80 events.

Results: A total of 122 pts were enrolled. About half had received one prior line of ET for MBC, and 18% had received one prior line of chemotherapy. 48% had visceral metastases and 31% had bone-only disease. TKa at D0 was not associated with clinical characteristics. Median TKa (mTKa) at D0 was 87 Du/L. Overall, 82 pts experienced progression, with a median PFS (mPFS) of 11 months (95% CI: 8.6 - 16). P+F dramatically suppressed mTKa levels at D15, with 90/108 (83%) pts achieving CTR. At D28, TKa showed some rebound in most pts. At each timepoint, higher TKa was significantly and consistently associated with shorter PFS (each p&lt;0.001). The effect of TKa on PFS remained statistically significant after adjusting for clinical variables. At 6 months, the largest difference between PFS probabilities was observed between patients with CTR versus no CTR at D15.

Conclusions: TKa is an independent prognostic biomarker in pts treated with P+F. High baseline TKa and incomplete suppression of TKa during treatment may identify pts with poor prognosis and primary resistance to P+F. TKa may represent a novel biomarker to select pts for alternative treatment modalities. These results warrant further investigation in prospective comparative trials.

TimepointBaseline (D0)D151D28TK median value (Du/L) (range)87 (&lt;20 - 14,510)&lt;20 (&lt;20 - 7,060)52 (&lt;20 - 3,533)Sample sizeHigh TKa611854Low TKa619054mPFS (months) (95% CI)High TKa7.4 m (5.5 - 8.7)4.9 m (2.8 - 5.9)8.3 m (5.6 - 11)Low TKa17.0 m (14 - NR2)16.0 m (11 - 30)19.0 m (17 - NR2)PFS at 3 months(95% CI)High Tka79% (43% - 68%)61% (42% - 88%)78% (67% - 90%)Low TKa93% (87% - 100%)92% (87% - 98%)96% (91% - 100%)PFS at 6 months(95% CI)High TKa54% (43% - 68%)17% (6% - 47%)56% (44% - 71%)Low TKa88% (81% - 97%)85% (78% - 93%)92% (86% - 100%)1For D15 High/Low TKa correspond to no CTR/CTR; 2 NR = not reached

Citation Format: Luca Malorni, Svitlana Tyekucheva, Florentine S Hilbers, Michail Ignatiadis, Patrick Neven, Marco Colleoni, Stéphanie Henry, Alberto Ballestrero, Andrea Bonetti, Guy Jerusalem, Konstantinos Papadimitriou, Antonio Bernardo, Francois Duhoux, Iain MacPherson, Alastair Thomson, David Mark Davies, Mattias Bergqvist, Matteo Benelli, Amelia McCartney, Heidi De Swert, Barbara Ruepp, Manuela Rabaglio, Rudolf Maibach, Martine Piccart, Meredith M Regan. Serum thymidine kinase activity in patients with luminal metastatic breast cancer treated with palbociclib and fulvestrant within the PYTHIA trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-05.