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Background: CDK7 inhibition is a promising therapeutic strategy in cancer; acting as a regulator of the cell cycle, transcription and endocrine receptor signalling [1]. Patients with HR+BC post CDK4/6 inhibitor treatment have a poor prognosis; median progression free survival (mPFS) of ~ 8 weeks for fulvestrant post CDK4/6i in HR+BC [2,3]. Pre-clinical HR+BC models indicate the potential for synergy when the CDK7 inhibitor samuraciclib is combined with the Selective Estrogen Receptor Degrader fulvestrant [4]Materials and Methods: This single arm cohort assessed the tolerability and efficacy of samuraciclib in combination with standard dose fulvestrant in patients with advanced HR+BC; all patients had previously received an aromatase inhibitor and a CDK4/6i for advanced disease.Results: 31 patients with HR+BC received the combination of standard dose with fulvestrant and samuraciclib. 6 patients received samuraciclib dose of 240mg once daily (QD) and 25 patients a dose of 360mg QD. The combination treatment was generally well tolerated, with adverse drug reactions (AE) of note being G1-2 nausea, vomiting and diarrhoea; the majority of patients staying on treatment until disease progression.RECIST evaluation indicates evidence of reduction in tumor disease burden, including a partial response in one patient who has been on treatment for ~ 1 year.Graphic illustrations of data, including ‘waterfall’ and ‘swimmer’ plots, will be presented along with stratification data based on demographic factors such as hepatic involvement and cfDNA analysis (ESR1m, PI3Km).Conclusions: Samuraciclib has demonstrated an acceptable safety profile with evidence of anti-tumour activity in combination with fulvestrant for patients with advanced HR+BC who have progressed on their prior CDK4/6i.References:1.Patel et al., Mol Cancer Therap. 20182.Juric et al., SABCS 20183.Lindeman et al., JCO 20214.Jeselsohn et al., SABCS 2019 Citation Format: Charles Coombes, Sasha J Howell, Matthew G Krebs, Simon Lord, Laura M Kenny, Ash Bahl, Glen Clack, Edward Ainscow, Paul A Dickinson, Raluca Fostea, Janine Mansi, Carlo Palmieri, Gianflippo Bertelli, Rinath Jeselsohn, Zahi Mitri, William J Gradishar, Sagar Sardesai, Joyce O'Shaughnessy, Patrick Ward, Pavani Chalasani, Manfred Lehnert, Simak Ali, Stuart McIntosh. Study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced hormone receptor positive HER2 negative breast cancer (HR+BC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS3-10.

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.