Abstract OT3-02-07: Neo-DDRD: A biomarker-driven neoadjuvant feasibility study in breast cancer
Authors: McIntosh SA , Parkes EE , James CR , Lioe T , Lowry K , Keating KE , Khambata-Ford S , Kennedy RD 
Published: May 2016

Abstract
Background
Anthracycline-based chemotherapy reduces the risk of early breast cancer recurrence but to date it has not been possible to predict which patients specifically benefit from this treatment. The Almac DDRD assay, a 44 gene signature, has been developed to detect DNA damage response deficiency (DDRD) within breast and other cancer types. The DDRD assay has been shown to predict benefit from DNA damaging chemotherapy in retrospective analyses in neoadjuvant and adjuvant settings (Mulligan et al, JNCI 2014). This pilot study aims to prospectively evaluate the feasibility and utility of this signature in the neoadjuvant setting in breast cancer. It will inform the design of a phase II randomised study where the DDRD assay will be utilised to guide neoadjuvant chemotherapy selection.
Study design
A single-centre, non-randomised feasibility study of 30 women with a histologically confirmed diagnosis of breast cancer, where neoadjuvant chemotherapy is the treatment modality of choice.
Inclusion criteria:
Age &gt;18 years
Early (T1-2, N0-1), locally advanced or inflammatory breast cancer
Normal left ventricular function, haematological and biochemical parameters
ECOG PS 0-1
Exclusion criteria:
Metastatic disease
Bilateral breast cancer
Pregnancy/breastfeeding
Inability to give informed consent
At diagnosis, patients consented to providing two core needle biopsies in addition to a diagnostic biopsy. Axillary nodal status was determined by axillary ultrasound, fine needle aspiration cytology, and pre-treatment sentinel node biopsy if pre-operative axillary staging was negative.
Chemotherapy was administered as per standard institutional practice: 6 cycles fluourouracil, epirubicin and cyclophosphamide (FEC) in node-negative patients; 3 cycles of FEC followed by 3 cycles of docetaxel in node positive patients. Neoadjuvant trastuzumab was given in Her2 positive patients. Imaging (mammography and ultrasound) was repeated after three cycles, and repeat FFPE and snap frozen core biopsies undertaken. At conclusion of treatment, patients underwent surgery as appropriate (mastectomy or breast conservation at the discretion of the operating surgeon), with axillary node clearance for patients who were node positive at diagnosis. Further biopsies (FFPE and fresh frozen) were taken intra-operatively. Plasma samples were obtained at diagnosis, mid-treatment and surgery. Pathological reporting of the surgical specimen was standardised using the residual cancer burden (RCB) reporting system.
Aims
· To assess the feasibility of carrying out the DDRD assay on diagnostic core biopsy specimens
· To evaluate the turn-around time for the assay to assess feasibility of integration into the breast cancer treatment pathway
· To assess the correlation of DDRD assay scores and pathological tumour response
· Exploratory biomarker analysis will be carried out within Queen's University, Belfast, including:
o correlation of DDRD score with changes in Ki67 protein level after three cycles of chemotherapy
o exploratory analysis of chemokine expression in peripheral plasma samples, and correlation with pathological response to treatment
Accrual
The study opened in April 2014. Accrual to date is 14 patients.
Citation Format: McIntosh SA, Parkes EE, James CR, Lioe T, Lowry K, Keating KE, Khambata-Ford S, Kennedy RD. Neo-DDRD: A biomarker-driven neoadjuvant feasibility study in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-07.