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BackgroundGenetic testing for hereditary cancer susceptibility has advanced over time due to the discovery of new risk genes, improved technology and decreased cost. In the province of Ontario, testing eligibility criteria were initially developed to include hereditary breast, ovarian and colorectal cancer syndromes. The rapid evolution of genetic technologies has facilitated the ability to interrogate a large number of genes concurrently. This, coupled with new knowledge about risk genes, necessitated a coordinated approach to expanding the scope of genes and indications tested and synchronisation of access and test utilisation across the province as required in a publicly funded universal healthcare system.MethodsOntario Health—Cancer Care Ontario convened expert working groups to develop a standardised and comprehensive cancer gene list for adults and accompanying hereditary cancer testing (HCT) criteria using an evidence-based framework and broad laboratory and clinical genetics engagement.ResultsA standardised 76-cancer-gene panel, organised into 13 larger disease site panels and 25 single/small gene panels, was developed and endorsed by the working groups. Provincial genetic testing eligibility criteria were updated to align with the new panels and to guide clinical decision-making. In the first year following the implementation of these changes, 10 564 HCT panels were performed with an overall mutation detection rate of 12.2%.ConclusionUsing an evidence framework and broad clinical engagement to develop and endorse an updated guidance document, cancer genetic testing for adults in Ontario is now standardised and coordinated across the province.

605 Background: The INVINCIBLE study is a randomized, Phase 2 presurgical Window-Of-Opportunity trial for IT INT230-6 (comprising VINblastine (VIN) Cisplatin (VIN)) evaluating clinical and BioLogical Effects in patients with early-stage operable Breast Cancer. INT230-6 also contains a dispersion enhancer molecule designed to facilitate diffusion of the cytotoxic agents into cancer cells and cause tumor necrosis. We have previously demonstrated that INT230-6 halts cancer cell replication and induces apoptosis while maturing dendritic cells and recruiting T-cells to the tumor microenvironment. In this trial, IT injections of INT230-6 are conducted to 1) exploit the potential of regional cytotoxic chemotherapy on breast cancer in vivo and 2) assess the potential for an immune response in the tumor microenvironment and host prior to surgical resection. Methods: Up to 90 women with newly diagnosed operable early-stage intermediate or high-grade T1-T2 invasive breast cancers are randomly allocated (2:1) prior to resection to IT injections of INT230-6, no treatment or saline sham. This study has two parts. Part I (N=29) was a randomized trial comparing 1-3 doses of INT230-6 injected weekly vs no treatment prior to surgery to evaluate safety, feasibility, and optimal drug dosing. Part II is a double-blinded randomized trial of up to 60 patients where patients will receive one IT dose of INT230-6 vs saline injection (2:1). The primary endpoint is to estimate the proportion of patients who achieve a complete cell cycle arrest post-surgery compared to the diagnosis biopsy. Secondary endpoints include an evaluation of the rate of pathological complete response, the percent of residual cancer, and safety. The study will also profile changes in CD4/CD8 and the T-cell repertoire. Results: Part I demonstrated feasibility, safety and tolerability of presurgical IT injections in breast cancer patients. Twenty patients with tumors ranging from 1-4.4cm were injected with at least one dose up to 48 hours prior to surgery. No surgeries were delayed or altered and the most common (>10%) AEs were injection site pain (100%), infusion site extravasation, injection site reaction and vomiting (10% each). Preliminary data show histologic evidence of up to 95% tumor necrosis in varying biologic subtypes and an increase in intratumoral TILs in injected tumors compared to controls. Part II is ongoing. Conclusions: Preliminary evidence shows that a single dose of INT230-6 can cause intratumoral necrosis and stimulate an immune response in breast cancers prior to surgery with minimal adverse effects and good tolerability. The results of Part II of the study will further evaluate the potential cytotoxic, immunomodulatory and other biologic effects of INT230-6 and its role as a potential cancer therapy in breast cancer patients awaiting surgery. Clinical trial information: NCT04781725.

Choosing Wisely (CW)® was created by the American Board of Internal Medicine (ABIM) to promote patient-physician conversations about unnecessary medical interventions. Similarly, other countries created their own panels of experts called "CW® campaigns" which review recommendations submitted by that country's oncology societies. We performed a scoping review to consolidate CW® recommendations from different groups with respect to breast cancer care.A systematic search of Medline and Embase was designed by an information specialist for publications presenting CW® recommendations for breast cancer care practices from 2011-2020. We also reviewed the websites of all CW® campaigns and reference sections of each CW® recommendation. Two reviewers independently screened studies for inclusion and performed data extraction. Findings were summarized narratively.Review of ABIM CW® recommendations showed 19 breast cancer-related recommendations pertaining to; screening (n = 4), radiological staging (n = 2), treatment (n = 10), surveillance (n = 2), and miscellaneous (genetic testing; n = 1). Of 22 countries with CW® campaigns, 10 published recommendations for breast cancer. Over half (57%) of recommendations were supported by more than one country. No recommendations were refuted between campaigns. Two campaigns developed 3 novel recommendations on new topics, including chemotherapy in ductal carcinoma in situ (Italy) and comparison of screening imaging modalities (Portugal).CW® recommendations focus on reducing overutilization of investigations and treatments. There was a high rate of consensus between different CW® campaigns. As health care systems globally move attention to reduce low-value care, further studies are required to address adherence to these current recommendations and develop new recommendations.

The proportion of breast cancer patients enrolled in clinical trials is falling. The Rethinking Clinical Trials (REaCT) program was developed to challenge some of the contemporary barriers responsible for this fall in accrual. In this article, we review the successes and challenges our program has faced.The REaCT program was created to improve care and outcomes for cancer patients through surveys of patients and healthcare providers, systematic reviews, economic evaluations, and the performance of pragmatic randomized trials with patient-centered outcomes. Likely, the greatest difference to conventional trial methodologies has been our widespread use of the integrated consent model (ICM) incorporating oral consent.Between 2014 and 2018, the program has recruited over 2000 patients to 15 randomized studies at 11 Canadian cancer centers. The REaCT program has completed and published five patient surveys, six healthcare provider surveys, ten systematic reviews, performed four economic evaluations, opened 15 clinical trials comparing standard of care interventions (two surgical, two adjuvant chemotherapy, five adjuvant supportive care, one radiology, two vascular devices, two palliative supportive care, and one molecular diagnostics). Patient surveys have shown high levels of satisfaction with the ICM.The REaCT program was developed to tackle important practice questions that will better guide optimal practice and to increase the availability of pragmatic clinical trials. While many challenges remain, future strategies will involve including more study sites and efforts to integrate novel information technology strategies.

7001 Background: Docetaxel-cyclophosphamide (TC) adjuvant chemotherapy is commonly used in patients with early stage breast cancer (EBC). Due to the risk of febrile neutropenia (FN) with TC, primary prophylaxis with either ciprofloxacin (cipro) or granulocyte-colony stimulating factors (G-CSF) is recommended. Despite significant differences in costs (7-120 $US/course [cipro] vs. 2100-7000 $US/dose [G-CSF]) and toxicity profiles, optimal primary FN prophylaxis is unknown. We performed a pragmatic randomised trial comparing the superiority of G-CSF to cipro. Methods: EBC patients receiving TC chemo were randomized to receive cipro or G-CSF as primary FN prophylaxis. The primary outcome is a composite of either treatment-related hospitalisations or FN. Secondary outcomes included: chemo dose reductions, delays, discontinuations and incidence of C. difficile infections. Primary analysis was performed with the intention to treat (ITT) population. Results: 455 eligible patients were randomized to cipro (227) or G-CSF (228). 37/227 (16.3%) patients on cipro had a hospitalization, compared with 25/228 (11.0%) on G-CSF (Fisher’s exact test p-value=0.10). Relative risk (RR) of hospitalization for patients on G-CSF:0.68, 95%CI=0.42 to 1.09. Patients on cipro were statistically significantly more likely to be hospitalized for FN (30/227, 13.2%) vs 9/228 (4.0%) patients on G-CSF(p

Cell populations able to generate a large repertoire of genetic variants have increased potential to generate tumor cells that survive through the multiple selection steps involved in tumor progression. A mechanism for the generation of aneuploid cancer cells involves passage through a tetraploid stage. Supernumerary centrosomes, however, can lead to multipolar mitosis and cell death. Using tissue culture and transgenic mouse models of breast cancer, we report that Cut homeobox 1 (CUX1) causes chromosomal instability by activating a transcriptional program that prevents multipolar divisions and enables the survival of tetraploid cells that evolve to become genetically unstable and tumorigenic. Transcriptional targets of CUX1 involved in DNA replication and bipolar mitosis defined a gene expression signature that, across 12 breast cancer gene expression datasets, was associated with poor clinical outcome. The signature not only was higher in breast tumor subtypes of worse prognosis, like the basal-like and HER2 + subtypes, but also identified poor outcome among estrogen receptor-positive/node-negative tumors, a subgroup considered to be at lower risk. The CUX1 signature therefore represents a unique criterion to stratify patients and provides insight into the molecular determinants of poor clinical outcome.

Background Overexpression of the Cut homeobox 1 gene, CUX1, inverselycorrelates with patient survival in breast cancers. Cell-based assays andmolecular studies have revealed that transcriptional regulation byCUX1 involves mostly the proteolytically processed p110isoform. As there is no antibody specific to p110 CUX1 only, an alternatestrategy must be employed to identify its targets. Results We expressed physiological levels of a tagged-p110 CUX1 protein and performedchromatin affinity purification followed by hybridization on ENCODE andpromoter arrays. Targets were validated by chromatin immunoprecipitation andtranscriptional regulation by CUX1 was analyzed in expression profiling andRT-qPCR assays following CUX1 knockdown or p110 CUX1 overexpression.Approximately 47% and 14% of CUX1 binding sites were respectively mappedless than 4 Kbp, or more than 40 Kbp, away from a transcription start site.More genes exhibited changes in expression following CUX1 knockdown thanp110 CUX1 overexpression. CUX1 directly activated or repressed 7.4% and 8.4%of putative targets identified on the ENCODE and promoter arraysrespectively. This proportion increased to 11.2% for targets with 2 bindingsites or more. Transcriptional repression was observed in a slightly higherproportion of target genes. The CUX1 consensus binding motif, ATCRAT, wasfound at 47.2% of the CUX1 binding sites, yet only 8.3% of the CUX1consensus motifs present on the array were bound in vivo. Thepresence of a consensus binding motif did not have an impact on whether atarget gene was repressed or activated. Interestingly, the distance betweena binding site and a transcription start site did not significantly reducedthe ability of CUX1 to regulate a target gene. Moreover, CUX1 not only wasable to regulate the next adjacent gene, but also regulated the gene locatedbeyond this one as well as the gene located further away in the oppositedirection. Conclusion Our results demonstrate that p110 CUX1 can activate or repress transcriptionwhen bound at a distance and can regulate more than one gene on certaingenomic loci.

We conducted a comprehensive analysis of a manually curated human signaling network containing 1634 nodes and 5089 signaling regulatory relations by integrating cancer-associated genetically and epigenetically altered genes. We find that cancer mutated genes are enriched in positive signaling regulatory loops, whereas the cancer-associated methylated genes are enriched in negative signaling regulatory loops. We further characterized an overall picture of the cancer-signaling architectural and functional organization. From the network, we extracted an oncogene-signaling map, which contains 326 nodes, 892 links and the interconnections of mutated and methylated genes. The map can be decomposed into 12 topological regions or oncogene-signaling blocks, including a few 'oncogene-signaling-dependent blocks' in which frequently used oncogene-signaling events are enriched. One such block, in which the genes are highly mutated and methylated, appears in most tumors and thus plays a central role in cancer signaling. Functional collaborations between two oncogene-signaling-dependent blocks occur in most tumors, although breast and lung tumors exhibit more complex collaborative patterns between multiple blocks than other cancer types. Benchmarking two data sets derived from systematic screening of mutations in tumors further reinforced our findings that, although the mutations are tremendously diverse and complex at the gene level, clear patterns of oncogene-signaling collaborations emerge recurrently at the network level. Finally, the mutated genes in the network could be used to discover novel cancer-associated genes and biomarkers.

Mutations or overexpression of signalling genes can result in cancer development and metastasis. In this study, we manually assembled a human cellular signalling network and developed a robust bioinformatics strategy for extracting cancer-associated single nucleotide polymorphisms (SNPs) using expressed sequence tags (ESTs). We then investigated the relationships of cancer-associated genes [cancer-associated SNP genes, known as cancer genes (CG) and cell mobility genes (CMGs)] in a signalling network context. Through a graph-theory-based analysis, we found that CGs are significantly enriched in network hub proteins and cancer-associated genes are significantly enriched or depleted in some particular network motif types. Furthermore, we identified a substantial number of hotspots, the three- and four-node network motifs in which all nodes are either CGs or CMGs. More importantly, we uncovered that CGs are enriched in the convergent target nodes of most network motifs, although CMGs are enriched in the source nodes of most motifs. These results have implications for the foundations of the regulatory mechanisms of cancer development and metastasis.