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541 Background: The meiotic DNA break regulator HORMAD1 is aberrantly expressed in many cancers and is associated with increased genomic instability. The susceptibility of HORMAD1 expressing tumors to agents targeting DNA damage repair (DDR) pathways is poorly understood since clinical data within the context of a randomized clinical trial (RCT) is lacking. Here, we retrospectively studied HORMAD1 expression as a putative predictive biomarker in an RCT for benefit of adjuvant high-dose platinum-based chemotherapy (HDCT) with autologous stem cell support in patients with high-risk HER2-negative early breast cancer (BC). Methods: Patients with stage III BC participated in an RCT comparing HDCT to conventional chemotherapy (CDCT; Rodenhuis et all, NEJM, 2003; Steenbruggen et all, JAMA Oncol, 2020). We studied the subgroup with HER2-negative BC for whom tumor BRCA1-like classification was previously determined using a validated DNA comparative genomic hybridization algorithm (Vollebergh et all, BCR, 2014). Tumor HORMAD1 expression was determined on FFPE samples using RNAscope, an RNA in situ hybridization method, and classified as negative (no expression) or positive (any expression detected). Results: For 195/246 (79.3%) HER2-negative patients treated according to protocol, HORMAD1 RNAscope status was available; dropout was due to absence or insufficient quality of tumor specimens. HORMAD1 positivity was enriched in triple-negative breast cancer (TNBC) (23/47; 48.9%). Furthermore, in all HER2-negative BCs, HORMAD1 positivity (45/195; 23.1%) was associated with age ≤40 years, histological grade III, 10%. Such association, although not significant, was also observed within TNBC. During a median follow-up of 20.3 years, 124 (63.6%) recurrences and 115 deaths (59.0%) occurred. The prognostic effect of HORMAD1 positivity on overall survival (OS) varied with follow-up time and was borderline significant at 10 years and significant thereafter (10-year: adjusted (adj.) HR 0.47, 95% CI 0.21-1.04; 15-year: adj. HR 0.25, 95% CI 0.07-0.91). Benefit on RFS from HDCT over CDCT was stronger in patients with HORMAD1-positive tumors (adj. HR 0.18, 95% CI 0.06-0.54) than in patients with HORMAD1-negative tumors (adj. HR 0.69, 95% CI 0.46-1.02) (P-interaction = 0.02). Similar results were observed for OS. Conclusions: In this retrospective sub study of 195 patients with high-risk HER2-negative BC participating in an RCT, tumor HORMAD1 expression is predictive for benefit of high-dose platinum-based chemotherapy. Our observations are consistent with the prior observations that HORMAD1 expression is associated with genomic instability and impaired DDR pathways. Further research is warranted to validate our findings. Clinical trial information: NCT03087409.

1074 Background: In the Triple Negative Trial we observed no improved response rate (RR) to C over D in aTNBC [Tutt et al, Nat Med 2018], but we did in BRCA1/2 mutated (mut) patients (pts). We hypothesise tumors with other aberrant DNA damage response (DDR) characteristics having higher RR to DNA damage inducing C than D. Methods: We tested the predictive value of DDR process related gene expression signatures (PARPi7, chromosomal instability CIN70, TP53 & DDR Deficiency (DDRD)) on 192 treatment naïve primary tumours (PT) by total RNA-sequencing. Odds ratio (OR) for RR are reported. Paired PT & recurrent (REC) signature scores were compared. Results: Unexpectedly, high DDRD and PARPi7 were associated with higher RR to D than C ( p =0.01 & 0.06). No effect was observed for CIN70 or TP53 signature. To assess whether the unexpected results were due to biological changes 12 PT-REC pairs were available from pts who received chemotherapy (CT) between PT & REC. CIN70 increased from PT to REC, DDRD (non-significantly) & PARPi7 decreased. 4/5 TP53 wildtype classified PT samples classified as mut in REC. The BRCA1/2 & DDRD-treatment interactions only held in pts who received CT before trial entry (table). The PARPi7-treatment interaction only held in CT naïve pts. In CT naïve pts, high CIN70 tumors suggested higher C RR as hypothesized. Restricted to the 149 PAM50 basal-like pts, results were non-significant but similar trends seen. Conclusions: In this trial of aTNBC, DDRD high pts with prior CT had better RR to D than C. A possible explanation for this unexpected result is selective pressure of adjuvant DNA damaging CT and selection for relative taxane sensitivity in those who recur despite a high DDRD score. The hypothesised CIN70 treatment interaction was observed in CT naïve pts. Our results suggest care is required in application of signatures to initial diagnostic material when predicting response to DNA damaging agents at REC particularly in pts with prior CT. [Table: see text]

e15129Background: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting the immune checkpoint molecules PD-1 and CTLA-4. However, as a significant number of patien...

1019 Background: The majority of triple negative breast cancers are of basal-like subtype (BLBC). There is uncertainty about concordance of intrinsic subtypes and ROR scores by PAM50 between matche...

11082 Background: Inflammation and infiltration of the tumor tissue by host immune cells have been shown to promote tumor cell invasion and metastasis. The exact molecular mechanisms mediating tumo...