Citations

Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Abstract Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase known to regulate immune cell function, cell adhesion, and vascular development. Here, we report that Syk can be expressed in high grade serous ovarian cancer and triple negative breast cancers and promotes DNA double strand break resection, homologous recombination (HR) and therapeutic resistance. We found that Syk is activated by ATM following DNA damage and is recruited to DNA double strand breaks by NBS1. Once at the break site, Syk phosphorylates CtIP, a key mediator of resection and HR, at Thr-847 to promote repair activity, specifically in Syk expressing cancer cells. Syk inhibition or genetic deletion abolished CtIP Thr-847 phosphorylation and overcame the resistant phenotype. Collectively, our findings suggest that Syk drives therapeutic resistance by promoting DNA resection and HR through a novel ATM-Syk-CtIP pathway, and that Syk is a new tumor-specific target to sensitize Syk-expressing tumors to PARPi and other DNA targeted therapy.

e21030 Background: Docetaxel +/- ramucirumab remains the standard of care therapy after progression on platinum doublet and immune checkpoint blockade (ICB) in patients with metastatic non-small cell lung cancer (NSCLC). However, the clinical benefit from docetaxel is short-lived with substantial toxicity. Additionally, whether cancer gene mutation status impacts the benefit from docetaxel has not been systemically studied. In this real-world study, we aim to investigate whether cancer gene mutation status is associated with benefit from docetaxel. We also explored whether IMPOWER150-based regimens (ABCP-atezolizumab + bevacizumab + carboplatin + paclitaxel; ACP-atezolizumab + carboplatin + paclitaxel; BCP-bevacizumab + carboplatin+paclitaxel) may serve as alternative options with better efficacy in this patient population. Methods: We retrospectively queried MD Anderson Cancer Center GEMINI database for patients with metastatic NSCLC who received docetaxel, docetaxel+ramucirumab, or one of the above-mentioned IMPOWER150-based regimens after progression on concomitant or sequential platinum-doublet and ICI. Primary endpoints include progression-free survival (PFS) and overall survival (OS). Results: 274 patients were analyzed (docetaxel n = 99; docetaxel +ramucirumab n = 142; ABCP n = 28; BCP n = 4, ACP n = 1). No significant difference was observed in mPFS (3.00m versus 3.93m, P = 0.156) or mOS (8.40m vs.8.67m, P = 0.737) between patients from docetaxel monotherapy group and docetaxel+ ramucirumab group. Cancer gene mutations in EGFR, KRAS, TP53 or PD-L1 expression (0-1%; 1-49%; ≥50%) were not associated with PFS or OS in the 241 patients treated with docetaxel +/- ramucirumab. Furthermore, there was no difference in mPFS (5.50m versus 3.47m, P = 0.516) or mOS (10.40m versus 8.83m, P = 0.737) in patients who received IMPOWER 150-based regimens compared to those who were treated with docetaxel+/- ramucirumab. The median treatment duration was 1.60m (0.70m-20.23m), 1.90m (0.70m-32.90m), 4.80m(0.70m-33.47m) and 11 patients (11.11%), 20 patients (14.08%), and 3 patients (9.09%) discontinued treatment due to adverse events in the patients treated with docetaxel monotherapy, docetaxel+ramucirumab combined therapy, and the IMPOWER150 regimens, respectively. Conclusions: These results from this real-world study suggested that unlike for ICI therapy, where onco-driver mutations have profound impact on the clinical benefit, the cancer gene mutation status does not impact the benefit from docetaxel +/- ramucirumab in NSCLC patients who progressed on platinum doublets and ICI. Furthermore, the clinical benefit from docetaxel +/- ramucirumab is short-lived. Novel treatment regimens are urgently needed in this clinical setting.

e19501 Background: Relapsed and/or refractory (R/R) disease is observed in patients who receive CD19 targeting chimeric antigen receptor (CAR)-T cells to treat B-cell lymphoid leukemias and lymphomas. We generated a novel CAR, MC10029 that targets B-cell activating factor receptor (BAFF-R) to address this unmet medical need. Methods: We engineered a second-generation BAFF-R CAR (MC10029 CAR). The construct includes the single chain variable fragment (scFv) of our newly developed BAFF-R antibody with CD28 costimulatory and CD3ζ signaling domains. We confirmed MC10029 CAR-T cell antigen-specific activation with in vitro degranulation assays and a direct cytolytic assay. We used BAFF-R positive leukemia and lymphoma cell lines in both in vitro and in vivo models to further characterize MC10029 CAR-T cells, and finally, we enriched tumor primary cells from chronic lymphocytic leukemia (CLL) patients as a target for MC10029 CAR-T cells. In preparation for our Phase I clinical trial, we have manufactured three batches of CAR-T cells using a MC10029-encoding lentiviral vector produced under GMP conditions. The production batches of MC10029 CAR-T cells were evaluated for product quality with Viability, Identity and Potency as well as Safety from adventitious viral agents. Antigen specific cytotoxicity of the MC10029 CAR-T cells was confirmed using our standard degranulation assay. Results: MC10029 CAR-T cells elicited in vitro antigen-specific cytotoxicity against Nalm-6 cells, Z138 cells, MEC-1 cells, and a CD19 knock out Nalm-6 model designed to mimic CD19-negative R/R disease. We demonstrated in vivo antitumor effects of MC10029 CAR-T cells in NSG mice challenged with these same cell lines. We showed cytotoxicity of MC10029 CAR-T cells against CLL patients’ tumors. We also showed our quality control results to highlight our clinical trial trajectory. Conclusions: Novel MC10029 CAR-T cells showed broad utility against BAFF-R positive B-cell lymphoid malignancies in a series of in vitro, in vivo, and ex vivo models. With these robust data, we have moved forward to generate clinical grade MC10029 CAR-T cells using cGMP manufacturing and quality protocols in preparation of a MC10029 CAR-T cell Phase I clinical trial.

Introduction Heart rate variability (HRV) reflects the activity of the autonomic nervous system (ANS) and can be used as a potential predictor of stress-related cardiovascular diseases. This study aimed to assess whether physical and mental strain during the performance of cerebral endovascular procedure influence time-domain HRV parameters in operating surgeon. Materials and Methods Heart rate (HR) and HRV metrics were measured using a HR sensor chest strap before, during, and after neuroendovascular interventions performed by a single neurosurgeon. Three consecutive data series were reported by recording time domain: before procedure, during and after performing endovascular procedures. HR and HRV parameters were recorded during diagnostic and interventional neuroendovascular procedures. HR and HRV measures were analyzed by procedure type and recording time domain. Results HRV measures of a single endovascular neurosurgeon were recorded during 50 procedures. The median intraprocedural HRV score was the lowest and the median HR was the highest (HRV: 52, HR: 89 bpm) compared to preprocedural (HRV: 59, HR: 70 bpm) and postprocedural cardiovascular measures (HRV: 53, HR: 79, bpm, p < 0.001). On univariate linear regression, a negative association of interventional procedures with lower intraprocedural (β = −0.905, p = 0.001) and postprocedural (β = −1.12, p < 0.001) HRV scores compared to the diagnostic procedures was noted. Conclusions HRV is a reliable tool to measure cardiovascular and mental stress. Interventional neuro-endovascular procedures seem to negatively impact the cardiovascular measures of neurointerventionalists. Further longitudinal studies utilizing HRV are warranted to address their long-term effects on the mental health of physicians.

Abstract Zinc finger E-box–binding homeobox 1 (ZEB1) is a transcription factor that can promote tumor invasion and metastasis by inducing epithelial-to-mesenchymal transition (EMT). To date, regulation of ZEB1 by RAS/RAF signaling remains unclear, and few studies have examined posttranslation modification of ZEB1, including its ubiquitination. In human colorectal cancer cell lines with RAS/RAF/MEK/ERK activation, an interaction of ZEB1 with the deubiquitinase ubiquitin-specific protease 10 (USP10) was identified whereby USP10 modifies ZEB1 ubiquitination and promotes its proteasomal degradation. Regulation of the USP10–ZEB1 interaction by MEK–ERK signaling was shown whereby constitutive activation of ERK can phosphorylate USP10 at Ser236 to impair its interaction with ZEB1 and enable ZEB1 protein stabilization. Stabilized ZEB1 was shown to promote colorectal cancer metastatic colonization in a mouse tail vein injection model. Conversely, MEK–ERK inhibition blocked USP10 phosphorylation and enhanced the USP10–ZEB1 interaction shown to suppress ZEB1-mediated tumor cell migration and metastasis. In conclusion, we demonstrate a novel function of USP10 in the regulation of ZEB1 protein stability and its ability to mediate tumor metastasis in a preclinical model. Implications: The MEK–ERK-regulated interaction of USP10 with ZEB1 can promote the proteasomal degradation of ZEB1 and thereby suppress its demonstrated ability to mediate tumor metastasis.

Abstract Background: Engaging diverse populations in cancer genomics research is of critical importance and is a fundamental goal of the NCI Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Established as part of the Cancer Moonshot, PE-CGS is a consortium of stakeholders including clinicians, scientists, genetic counselors, and representatives of potential study participants and their communities. Participant engagement is an ongoing, bidirectional, and mutually beneficial interaction between study participants and researchers. PE-CGS sought to set priorities in participant engagement for conducting the network's research. Methods: PE-CGS deliberatively engaged its stakeholders in the following four-phase process to set the network's research priorities in participant engagement: (i) a brainstorming exercise to elicit potential priorities; (ii) a 2-day virtual meeting to discuss priorities; (iii) recommendations from the PE-CGS External Advisory Panel to refine priorities; and (iv) a virtual meeting to set priorities. Results: Nearly 150 PE-CGS stakeholders engaged in the process. Five priorities were set: (i) tailor education and communication materials for participants throughout the research process; (ii) identify measures of participant engagement; (iii) identify optimal participant engagement strategies; (iv) understand cancer disparities in the context of cancer genomics research; and (v) personalize the return of genomics findings to participants. Conclusions: PE-CGS is pursuing these priorities to meaningfully engage diverse and underrepresented patients with cancer and posttreatment cancer survivors as participants in cancer genomics research and, subsequently, generate new discoveries. Impact: Data from PE-CGS will be shared with the broader scientific community in a manner consistent with participant informed consent and community agreement.

Abstract Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. We aimed to assess the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Analyses were based on 82,701 women diagnosed with invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations of treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR(95%CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR(95%CI) :1.30 (1.09–1.56)]. In conclusion, systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk. (Main MS: 3201 words)