Lobular carcinoma in situ (LCIS) is considered to be a risk factor for the development of invasive breast carcinoma, but it may also be a non-obligate precursor to invasive lobular carcinoma (ILC). Many LCIS lesions do not progress to ILC, and the molecular changes that are necessary for progression from LCIS to ILC are poorly understood. Disruption in the E-cadherin complex is the hallmark of lobular lesions, but other signaling molecules, such as PIK3CA and c-src, are consistently altered in LCIS. This review focuses on the molecular drivers of lobular carcinoma, a more complete understanding of which may give perspective on which LCIS lesions progress, and which will not, thus having immense clinical implications.

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Background: The DDRD assay was developed to prospectively identify a molecular subtype of cancers defined by DNA damage activated immune signalling. This 44-gene assay has been validated to predict response to anthracycline-cyclophosphamide chemotherapy in both the adjuvant and neoadjuvant settings in breast cancer. The biomarker phase Neo-DDRD trial assessed the clinical utility of this assay prospectively in patients receiving neoadjuvant chemotherapy (NAC). Methods: 48 patients receiving NAC for early (T1-2, N0-1) or locally advanced non-metastatic breast cancer were recruited from March 2014 – Sept 2017. Chemotherapy regimen was selected according to local standard-of-care guidelines (FEC “100” in N0, FEC-D in N1, FEC-DH in HER2 +ve, with the addition of pertuzumab when approved). The DDRD score was applied to RNA expression data obtained from pre-treatment FFPE core biopsies using a custom cDNA microarray (Breast Cancer DSA™). Response to NAC was assessed on resection specimens following definitive surgical treatment by pathologists blinded to the DDRD scores, using the Residual Cancer Burden (RCB) assessment tool. Results: Patients with a positive DDRD assay call had an odds ratio for pathological complete response (pCR) or minimal residual disease (RCB0/RCB1) of 4.64 (95%CI 1.31-16.42; p = 0.0174). Patients with RCB0/RCB1 had significantly higher DDRD assay score than those with class RCB2/RCB3 responses (p =0.0011; unpaired t-test). Tumour subtype and DDRD call are summarised in Table 1. In total, 29.2% of patients had a pathological complete response (pCR) (RCB0). Tumor infiltrating lymphocytes (TILs) were assessed on baseline pre-treatment samples. Increasing DDRD assay score was not significantly associated with increasing stromal TILs (p=0.1403; Pearson correlation). In assessing correlation between stromal TILs and response to chemotherapy, there was no significant difference found across RCB categories (p=0.45; one way ANOVA). Table 1:tumour subtype distribution and DDRD assay resultSubtypeDDRD+DDRD-TotalTriple negative7613HER2+ ER-527HER2+ ER+6612ER+ HER2-8816 Conclusions: Preliminary results from the Neo-DDRD biomarker phase trial support the ability of the DDRD assay to predict response to neoadjuvant chemotherapy. The DDRD assay was confirmed to be a better predictor of neoadjuvant chemotherapy response than the presence of TILs. Translational work from this trial is ongoing: serial tissue and plasma samples collected at treatment mid-point and surgical resection will be used to study changes in RNA expression profiles in both DDRD assay positive and negative during chemotherapy, as well as changes in tumour immune infiltrates, peripheral chemokines and circulating tumour DNA profiles. Based on the results from this pilot study, we propose a biomarker-driven phase II trial in the neoadjuvant setting using the DDRD assay to stratify patients for treatment. Citation Format: Parkes EE, James CR, Lioe T, Walker S, Savage KI, Lowry K, Knight L, McCavigan A, Logan G, Hurwitz J, Kirk SJ, Harkin P, Kennedy RD, McIntosh SA. Biomarker phase neo-DDRD trial: Predicting response to neoadjuvant chemotherapy (NAC) in early breast cancer using the DNA damage repair deficiency (DDRD) assay [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-12.