Abstract OT2-07-08: Substantially improving the cure rate of high-risk BRCA1-like breast cancer patients with personalized therapy (SUBITO) - an international randomized phase III trial
Authors: Vliek S , Jager A , Jonge-Lavrencic M , Lotz J-P , Gonçalves A , Graeser M , Nitz U , Mandjes IAM , Holtkamp MJ , Schot M , Retel VP , Kuip EJ , Wymenga MN , Konings IR , Tjan-Heijnen VCG , Kroep JR , Schroeder CP , Van der Wall E , Linn SC 
Published: February 2018

Abstract
Background: An intact homologous repair (HR) pathway is essential for error-free repair of DNA double strand breaks (DSB). Preclinical and clinical data have shown that breast cancer (BC) cells with a defect in the HR pathway are a target for DNA DSB inducing agents and PARP inhibition. HR deficiency (HRD) causes genomic instability with a typical profile of DNA copy number aberrations (CNA) as seen in tumors of patients with a BRCA1 germline mutation. In the Netherlands Cancer Institute (NKI) the BRCA1-like test, a biomarker for HRD, was developed. The test calculates the probability that the genomic profile of DNA CNA of a breast tumor is similar to that of BRCA1 mutated BCs. When this probability is above a certain cutoff, depending on the platform, the test is positive in a small percentage of estrogen receptor positive and over 50% of triple negative BCs. In retrospective analyses, the test appeared to be a predictive biomarker for sensitivity to adjuvant intensified alkylating chemotherapy with autologous stem cell rescue (IA-CT). For example in stage III HER2-negative BRCA1-like BC, the 7-year recurrence free survival improved from 30% with 5 cycles of 5-fluorouracil-epirubicin-cyclophosphamide (FEC) to 78% when treated with 4 cycles of FEC followed by IA-CT (adjusted hazard rate 0.12; p=0.001). There was no benefit in non-BRCA1-like patients.
Prospective validation in a randomized phase III trial is eagerly awaited and will possibly result in a practice changing outcome. We hypothesize that, although treatment with IA-CT is controversial, by selecting the right patients, we may substantially improve survival in high risk BRCA1-like BC.
Eligibility criteria: Patients, 18 to 66 years old, with HER2-negative BRCA1-like or germline BRCA1 or BRCA 2 related stage III BC, who are fit to undergo IA-CT.
Trial Design: In this phase III trial, patients will be randomized to (neo)adjuvant treatment with 4 cycles of dose dense doxorubicin-cyclophosphamide (ddAC) followed by two cycles of IA-CT or followed by 4 cycles of carboplatin(q3)-paclitaxel(q1) and one year of olaparib (300mg twice daily). Adjuvant endocrine treatment is added according to guidelines.
Primary outcome is overall survival (OS), analyzed with the intention to treat principle. To detect an improvement of 35% OS (40% vs 75%) with a 2-sided alpha of 0.05 and a power of 0.8 at 10 years, 174 patients should be enrolled. Secondary outcomes are toxicity, quality of life, cost-effectiveness and cognitive function. Additionally we plan to analyze potential biomarkers, like 53BP1 and cancer-immune interaction.
The SUBITO trial is part of a Coverage with Evidence Development program, which is a policy which allows conditional funding of a promising health intervention while more conclusive evidence is gathered to prove its (cost-)effectiveness.
Since January 2017 we recruited 8 patients in 2 hospitals. Ten other hospitals, including two in France and one in Germany, are expected to start enrollment soon. The Medical Ethical Committee approved the trial. The trial is registered at clinicaltrials.gov (NCT02810743).
Contact information for people with a specific interest in the trial: e-mail: subito@nki.nl
Citation Format: Vliek S, Jager A, Jonge-Lavrencic M, Lotz J-P, Gonçalves A, Graeser M, Nitz U, Mandjes IAM, Holtkamp MJ, Schot M, Retel VP, Kuip EJ, Wymenga MN, Konings IR, Tjan-Heijnen VCG, Kroep JR, Schroeder CP, Van der Wall E, Linn SC. Substantially improving the cure rate of high-risk BRCA1-like breast cancer patients with personalized therapy (SUBITO) - an international randomized phase III trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-08.