Biallelic methylation of BRCA 1 associated with a case of exquisitely platinum-sensitive mTNBC.

Background: The cytotoxic agent eribulin has been shown to promote EMT reversion, reduce treatment resistance, and potentially enhance responses to a range of therapeutic agents. Methods: We examined the effects of eribulin in patient-derived breast cancer tissues and a phenotypically heterogeneous breast cancer cell line to assess EMT and chemotherapy response. Results: Nanostring-based analysis of EMT-associated gene expression in breast cancers from patients receiving standard-of-care TAC neoadjuvant chemotherapy compared to a cohort receiving neoadjuvant eribulin (NeoEribulin trial) showed markedly reduced expression of EMT markers in cancers treated with eribulin versus TAC. Through single-cell immunofluorescent imaging and analysis, we identified that HCC38 triple-negative breast cancer (TNBC) cells exhibited a shift towards an epithelial-like state marked by E-cadherin upregulation following acute eribulin exposure, but not with other chemotherapeutic agents. Investigation of primary breast cancer cultures derived from pre-neoadjuvant biopsies also revealed that HER2-enriched primary breast cancer cells displayed heightened chemosensitisation to doxorubicin (Adriamycin), which was not recapitulated in TNBC cultures. Conclusions: Our data highlight the presence of contextual parameters which govern the degree of EMT regulation by eribulin.

E15034 Background: Identification of somatic variants in cancer by high-throughput sequencing has become common clinical practice largely because many of these variants may be predictive biomarkers for targeted therapies. However, there can be high sample QC failure rates for some assays (sometimes up to 40%), preventing the return of results that may affect patient treatment decisions. Pillar Biosciences has incorporated their patented SLIMamp technology into commercially available cancer NGS testing kits with the claim that these kits can successfully interrogate challenging formalin-fixed paraffin-embedded tissue (FFPET) samples with low tumor purity, poor DNA quality, and/or low input DNA, resulting in a high sample QC pass rate. The aim of this study was to substantiate that claim using Pillar’s amplicon-based oncoReveal Solid Tumor Panel. Methods: We acquired 48 tumor samples that had failed one or more pre-analytical QC sample parameters for whole exome sequencing (WES) from ATGC’s ISO15189 accredited diagnostic genomics laboratory. XING Genomic Services performed an exploratory data analysis using our pre-analytical QC assays to characterise the samples and then sequenced the samples in our ISO15189 accredited laboratory using the validated oncoReveal Solid Tumor Panel. Results: We were able to achieve high sequencing coverage (>3000X) for all 48 samples and explored the determinants of sample “success”. We were able to generate clinical reports for 45 samples (94%), of which 38 (79%) contained clinically actionable or significant variants that would not have otherwise been identified. Ten samples had a higher number of total variant calls with over-representation of C>T transitions representing stochastically-amplified, formalin-induced artefacts in samples with very low input template DNA. Of these, 7 cases had reportable variants and 3 were deemed unreportable. We demonstrated that DNA integrity is the major determinant of success even in samples with low input DNA or low tumor purity and were able to further refine pre-analytical and post-analytical QC metrics to better identify samples with poor quality DNA that can be sequenced reliably. Conclusions: In this study, we showed that the Pillar Biosciences oncoReveal Solid Tumor Panel, which uses SLIMam technology, was able to generate reliable, interpretable results for 94% of samples that failed pre-analytical QC for WES, substantiating Pillar’s claim.