Effect of Capivasertib on ctDNA in ER Positive Breast Cancer

Early stage (I-III) ER positive HER2 negative breast cancer is treated with intensive multi-modal treatment which may include chemotherapy, radiotherapy and endocrine therapy given with curative intent. In spite of this, 10-40% of patients will ultimately relapse with incurable metastatic disease which will be terminal and life limiting. There is therefore a need to identify which patients are more at risk of relapse and develop strategies to alter the disease course in these patients. There is a now a body of evidence that circulating tumour DNA (ctDNA) can be detected in the blood of patients who are going to relapse and that detection of this ctDNA antecedes clinical recurrence by approximately 9 months (Coombes et al, Garcia-Murillas et al). This presents an ideal circumstance in which to intervene by considering ctDNA positive patients to have micrometastatic disease/molecular relapse and treating them with agents designed to modify the otherwise predictable outcome of relapse and ultimately death from their disease. Capivasertib is a potent, selective inhibitor of the kinase activity of the serine/threonine Akt/PKB (protein kinase B) that is being developed as a potential treatment for solid and haematological malignancies. AZD5363 inhibits all three Akt isoforms and therefore has the potential to provide clinical benefit over a range of therapeutic indications. Given the recent success of Capivasertib in extending progression free survival in metastatic ER positive breast cancer (FAKTION trial: Jones et al) it is proposed that treating ctDNA positive patients with this drug at this earlier stage may influence ctDNA levels and potentially the outcomes for these patients. It is porposed to identify a cohort of ctDNA positive patients and treat them with Capivasertib and monitor their ctDNA levels prospectively over time whilst following the patients for toxicity and clinical outcomes. Given that ctDNA positivity in ER positive breast cancer portends relapse whether Capivasertib affects ctDNA levels in patients who have detectable ctDNA will be established. Moreover, there is limited data on how ctDNA levels change over time especially in response to treatments and this study will offer valuable insights into that area which can feed into larger studies in the near future. It is proposed to screen a number of patients who have completed standard of care curative intent treatment for their ER positive breast cancer and are established on aromatase inhibitor therapy (\>6 months) and are planned to have ongoing endocrine therapy for at least another two years. Patients meeting the inclusion criteria will be screened until 20 ctDNA positive patients have been enrolled. The plan is to take blood at a single time point for each patient and will screen for ctDNA positivity using a personalised ctDNA assay as previously described (Coombes et al, Garcia-Murillas et al). Commercially available Signatera assay will be used to determine ctDNA positivity. Patients who are found to be ctDNA positive will then be started on treatment with Capivasertib and ctDNA levels will be followed over time. If patients are ctDNA negative on their first ctDNA sample they will have an opportunity to be re-tested for ctDNA every 3 months until the end of the screening period (which will end once 20 patients are recruited to start treatment). This is based on data that shows that ctDNA positivity pick-up rate improves with serial testing in patients over time (Coombes et al). The hypothesis is that treating these ctDNA positive patients with Capivasertib will have an effect on the dynamics of the ctDNA measurements. Patients will also be followed over time to assess toxicity and acceptability of the drug and to monitor for overt metastatic relapse. The outcome measures of the study is: To monitor ctDNA dynamics during treatment with Capivasertib * Percentage of patients with ctDNA clearance compared to baseline * Duration of ctDNA clearance * Percentage of patients with \>50% decrease in ctDNA mean variant allele frequency (VAF) compared to baseline