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Biomarkers for cyclin-dependent kinase 4/6 inhibitors, such as palbociclib, for patients with hormone receptor-positive/HER2-negative metastatic breast cancer are lacking. Thymidine kinase is a proliferation marker downstream of the cyclin-dependent kinase 4/6 pathway. We prospectively investigated the prognostic role of serum thymidine kinase activity (sTKa), in patients treated with Palbociclib + fulvestrant. PYTHIA was a phase II, single-arm, multicentre, trial that enrolled 124 post-menopausal women with endocrine-resistant hormone receptor-positive/HER2-negative metastatic breast cancer. Serum samples were collected pre-treatment (pre-trt; n = 122), at day 15 of cycle 1 (D15; n = 108), during the one week-off palbociclib before initiating cycle 2 (D28; n = 108) and at end of treatment (n = 76). sTKa was determined centrally using Divitum®, a refined ELISA-based assay with a limit of detection of 20 Divitum Units (Du)/L. The primary study endpoint was progression-free survival, assessed for its association with pre- and on-treatment sTKa. Data from 122 women were analysed. Pre-treatment sTKa was not associated with clinical characteristics and moderately correlated with tissue Ki-67. Palbociclib + fulvestrant markedly suppressed sTKa levels at D15, with 83% of patients recording levels below limit of detection. At D28, sTKa showed a rebound in 60% of patients. At each timepoint, higher sTKa was associated with shorter progression-free survival (each p < 0.001), with the strongest effect at D15. STKa is an independent prognostic biomarker in patients treated with palbociclib. High pre-treatment sTKa and its incomplete suppression during treatment may identify patients with poorer prognosis and primary resistance. This warrants validation in prospective comparative trials. CLINICALTRIALS. NCT02536742; EudraCT 2014-005387-15.

Tuberous sclerosis is an autosomal dominant multisystem disorder characterised by the development of benign tumours in many organs, including the brain, skin, kidneys and heart, seizures and intellectual disability. The condition results from mutations in either of two genes, TSC1 (encoding TSC1) or TSC2 (encoding TSC2). Loss of functional TSC1 or TSC2 leads to activation of mTORCl (mammalian target of rapamycin complex 1), a key regulator of multiple cellular processes including cell growth and division. Lymphangioleiomyomatosis (LAM) is a lung disorder which can lead to respiratory failure and is characterised by the proliferation of abnormal 'LAM' cells LAM occurs in patients with tuberous sclerosis and can also occur as a sporadic disorder due to acquired mutations in TSC2. Renal angiomyolipomas are benign tumours which affects80% of patients with tuberous sclerosis and 40% of patients with sporadic LAM. Sirolimus is an inhibitor of mTORCl and is used in clinical practice as an immunosuppressant. Preclinical studies suggest that TSC1 or TSC2 deficiency renders cells sensitive to mTOR inhibition. This thesis describes a phase 2 trial to assess the safety and efficacy of 2 years of treatment with sirolimus for renal angiomyolipomas in patients with tuberous sclerosis or LAM. Response of angiomyolipoma was the primary efficacy end point. Effects of sirolimus on lung function and neurocognitive function are also reported. Our data show an angiomyolipoma response rate, by RECIST criteria, of 50% in the intention to treat population. There was little change in lung function. Recall but not recognition memory tended to improve. Adverse events were common and consistent with the known toxicities of sirolimus. Our findings suggest that mTOR inhibition is a potential therapeutic strategy in the treatment of tuberous sclerosis and lymphangioleiomyomatosis.

Tuberous sclerosis is an autosomal dominant multisystem disorder characterised by the development of benign tumours in many organs, including the brain, skin, kidneys and heart, seizures and intellectual disability. The condition results from mutations in either of two genes, TSC1 (encoding TSC1) or TSC2 (encoding TSC2). Loss of functional TSC1 or TSC2 leads to activation of mTORCl (mammalian target of rapamycin complex 1), a key regulator of multiple cellular processes including cell growth and division. Lymphangioleiomyomatosis (LAM) is a lung disorder which can lead to respiratory failure and is characterised by the proliferation of abnormal 'LAM' cells LAM occurs in patients with tuberous sclerosis and can also occur as a sporadic disorder due to acquired mutations in TSC2. Renal angiomyolipomas are benign tumours which affects80% of patients with tuberous sclerosis and 40% of patients with sporadic LAM. Sirolimus is an inhibitor of mTORCl and is used in clinical practice as an immunosuppressant. Preclinical studies suggest that TSC1 or TSC2 deficiency renders cells sensitive to mTOR inhibition. This thesis describes a phase 2 trial to assess the safety and efficacy of 2 years of treatment with sirolimus for renal angiomyolipomas in patients with tuberous sclerosis or LAM. Response of angiomyolipoma was the primary efficacy end point. Effects of sirolimus on lung function and neurocognitive function are also reported. Our data show an angiomyolipoma response rate, by RECIST criteria, of 50% in the intention to treat population. There was little change in lung function. Recall but not recognition memory tended to improve. Adverse events were common and consistent with the known toxicities of sirolimus. Our findings suggest that mTOR inhibition is a potential therapeutic strategy in the treatment of tuberous sclerosis and lymphangioleiomyomatosis.