Citations

18037 Background: Platinum compounds are major chemotherapeutic agents in lung cancer and are metabolized by the glutathione pathway enzymes. We reported that genotypes of glutathione-related enzymes, especially GCLC, may be host factors in predicting survival of patients with stage IIIB/IV non-small cell lung cancer who were stable or responding from prior platinum-based chemotherapy (Yang et al., ASCO 2006). NCCTG investigators previously correlated allelic variants in 5-FU metabolizing genes with QOL in colorectal cancer patients (Sloan et al., ASCO 2004). We sought to evaluate the role of glutathione pathway genotypes on QOL. Methods: DNA samples were analyzed using 6 polymorphic DNA markers in the glutathione metabolic pathway. The contrasting genotypes in the analysis were GSTM1 and GSTT1 (null vs. present), GSTP1-I105V (AA vs. GA/GG), GSTP1-A114V (CC vs. CT/TT), GPX1 (CC vs. TT/TC), and GCLC (homozygous repeat 77 vs. heterozygous 7*). Forty-six patients completed the FACT-L and the UNISCALE QOL questionnaires at baseline and week-8, and we have results for all 6 genotypes. A clinically significant decline (CSD) in QOL was defined as a 10% decrease from baseline to week-8. A multivariate logistic regression model was used to evaluate the association of all 6 genotypes with a CSD in QOL. Results: Patients carrying the GPX1-CC genotype had a CSD in the UNISCALE (Odds Ratio (OR): 10.0; p=0.02), total FACT-L score (OR: 7.9; p=0.03), the FACT-L physical well being construct (OR: 13.7; p=0.02), and the FACT-L functional well being construct (OR: 5.3; p=0.05). Other constructs, i.e., emotional, social and family, and additional concerns were not significantly associated with the genotypes. Conclusions: Genotypes of glutathione-related enzymes, especially GPX1 may be inherited factors in predicting patients’ QOL after platinum-based chemotherapy. Further investigation to define and measure the direct or indirect effects of these genes on QOL is critical, particularly, via drug responses, toxicities, and disease recurrence. (This work was partly supported by NIH grants CA77118, CA80127, and CA84354.) No significant financial relationships to disclose.

7613 Background: Factors influencing the pattern of disease relapse after curative surgical resection in early stage NSCLC is unknown. We sought to evaluate the effect of tumor- and patient-related characteristics on the pattern of disease recurrence (local relapse and/or metastatic disease) and survival in relation to surgical resection for NSCLC. Methods: A consecutive retrospective series of 488 patients seen at Mayo Clinic Rochester who had complete resection of NSCLC between 1997 and 1998 was utilized. Cox proportional hazards model was used to evaluate the effect of age, gender, smoking status, TNM stage, number of lymph node (LN) involved, number of LN resected, and histopathologic diagnosis on RFS. Logistic regression was used to evaluate the effect on recurrence or death within the first 2 years after surgical resection. Results: Data on 342 patients with a median follow-up of 85 months (range: 0.1 to 162) are reported. 60% were male, and 81% had N0 stage at diagnosis. There were 26 (7.6%) never smokers. Median number of LN resected was 20 (interquartile range [IQR]: 14–29). Median age at surgery was 71 years (IQR: 64 to 76). A bi-modal pattern of local recurrence (N=62) after surgery for early stage NSCLC was observed, with 57% of patients having a local recurrence within 2 years and 21% of patients having a local recurrence from 5–7 years post-surgery. The median duration from surgery to first documented recurrence was 16 months (IQR: 8 to 39). While age, N stage, number of LN involved, and T stage were significant predictors of RFS univariately, only lesser LN resected (p=0.008), older age (p<0.0001) and higher T-stage (p=0.003) were significant adverse predictors of RFS in the multivariate analysis when adjusted for all factors. Higher T-Stage was associated with a significantly increased risk of recurrence or death within the first 2 years after surgical resection (p =0.004). Updated results using data from all 488 patients will be presented in the meeting. Conclusions: A trend towards a bimodal distribution of local recurrences after surgical resection of early stage NSCLC was observed. Increased number of LN resected, younger age and lower T stage were associated with better RFS. No significant financial relationships to disclose.

2038 The effects of combining histone deacetylase (HDAC) inhibitors and proteasome inhibitors were evaluated in both established glioblastoma multiforme (GBM) cell lines and short-term cultures derived from the Mayo Clinic xenograft GBM panel. Co-exposure of LBH589 (LBH) and botezomib (btzmb) results in a striking induction of apoptosis, at minimally toxic doses of either drug alone, in established U251, U87, and D37 GBM cell lines, as well as in GBM8 (G-8), GBM10 (G-10), GBM12 (G-12), GBM14 (G-14), and GBM56 (G-56) cells, which have been developed from the Mayo xenograft GBM panel and maintained in short-term cultures. Synergism of apoptosis induction was also observed in U251 cells when co-exposing other HDAC inhibitors, including LAQ824 (LAQ) and trichostatin A (TSA), with another proteasome inhibitor MG132, demonstarting a class effect. In U251 cells, btzmb alone or in combination with LBH decreased Raf-1 levels and inactivated Akt and Erk. Either LBH589 or bortezomib alone increased expression of the cell cycle regulators p21 and p27. Additionally, the combination, but not the individual agents, markedly increased JNK activation. In addition, cell death after exposure to LBH589 and bortezomib is associated with cytochrome c release, Bax translocation, as well as caspase and PARP cleavage. Bax translocation may contribute to the synergistic cytotoxicity of the combination of LBH and btzmb in glioma cells since Bax translocation to mitochondria is known to precede cytochrome c release and apoptosis, but other pathways are likely to be involved. This combination regimen warrants further preclinical and possible clinical study for glioma patients. No significant financial relationships to disclose.

OBJECTIVE This study’s purpose was to improve understanding of the forces driving the complex mechanical interaction between embolic material and current stroke thrombectomy devices by analyzing the histological composition and strength of emboli retrieved from patients and by evaluating the mechanical forces necessary for retrieval of such emboli in a middle cerebral artery (MCA) bifurcation model. METHODS Embolus analogs (EAs) were generated and embolized under physiological pressure and flow conditions in a glass tube model of the MCA. The forces involved in EA removal using conventional endovascular techniques were described, analyzed, and categorized. Then, 16 embolic specimens were retrieved from 11 stroke patients with large-vessel occlusions, and the tensile strength and response to stress were measured with a quasi-static uniaxial tensile test using a custom-made platform. Embolus compositions were analyzed and quantified by histology. RESULTS Uniaxial tension on the EAs led to deformation, elongation, thinning, fracture, and embolization. Uniaxial tensile testing of patients’ emboli revealed similar soft-material behavior, including elongation under tension and differential fracture patterns. At the final fracture of the embolus (or dissociation), the amount of elongation, quantified as strain, ranged from 1.05 to 4.89 (2.41 ± 1.04 [mean ± SD]) and the embolus-generated force, quantified as stress, ranged from 63 to 2396 kPa (569 ± 695 kPa). The ultimate tensile strain of the emboli increased with a higher platelet percentage, and the ultimate tensile stress increased with a higher fibrin percentage and decreased with a higher red blood cell percentage. CONCLUSIONS Current thrombectomy devices remove emboli mostly by applying linear tensile forces, under which emboli elongate until dissociation. Embolus resistance to dissociation is determined by embolus strength, which significantly correlates with composition and varies within and among patients and within the same thrombus. The dynamic intravascular weakening of emboli during removal may lead to iatrogenic embolization.

AbstractImmune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Abstract Combination of carfilzomib with dexamethasone (Kd) is approved for use in relapsed and/or refractory multiple myeloma (RRMM), with carfilzomib administered twice weekly at 56 mg/m 2 (Kd56 BIW) or once weekly at 70 mg/m 2 (Kd70 QW). Post hoc cross‐trial comparisons were performed to compare efficacy and safety profiles of Kd70 QW vs Kd56 BIW dosing schedules using data from three trials of patients with RRMM: A.R.R.O.W., CHAMPION‐1, and ENDEAVOR. To select for comparable patient populations, side‐by‐side efficacy and safety comparisons were performed in subgroups of patients with 2‐3 prior lines of therapy who were not refractory to bortezomib. The overall response rate (ORR) was 69.9% (95% confidence interval [CI], 61.7‐77.2) for Kd70 QW and 72.4% (95% CI, 65.9‐78.2) for Kd56 BIW. Median progression‐free survival (PFS) was 12.1 months (95% CI, 8.4‐14.3) for Kd70 QW and 14.5 months (95% CI, 10.2—not evaluable) for Kd56 BIW. Frequency of grade ≥ 3 adverse events (AEs) was 67.6% for Kd70 QW and 85.3% for Kd56 BIW. Regression analyses (adjusting for prognostic factors) of all patients in the trials who received Kd70 QW vs Kd56 BIW estimated a PFS hazard ratio of 0.91 (95% CI, 0.69‐1.19; P = .47) and an ORR odds ratio of 1.12 (95% CI, 0.74‐1.69; P = .61). These results suggest that Kd70 QW has a comparable efficacy profile compared with Kd56 BIW and represents a convenient and well‐tolerated treatment for patients with RRMM.

Abstract Background The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32–36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44–46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

11003 Background: ES is a rare soft tissue sarcoma that metastasizes in approximately 30% to 50% of cases. More than 90% of ES tumors lack expression of INI1, an important component of epigenetic regulation. Loss of INI1 function allows another epigenetic modifier, EZH2, to become an oncogenic driver in tumor cells. Tazemetostat, a first-in-class, selective, oral inhibitor of EZH2, has demonstrated tumor regression and favorable safety in phase 1/2 trials. Methods: Data from a phase 2 open-label, multicenter trial of pts with locally advanced or metastatic ES are reported. Efficacy was assessed with primary and secondary endpoints including objective response rate (ORR) by RECIST 1.1, disease control rate (DCR; objective confirmed response of any duration or stable disease [SD] lasting ≥32 weeks), duration of response (DOR), progression-free survival (PFS), overall survival (OS); safety and tolerability were also evaluated. Results: As of September 17, 2018, 62 INI1-negative ES pts were enrolled and treated with tazemetostat 800 mg BID. The median number of prior lines of therapy was 1 (range: 0-9). There were 9/62 (15%) confirmed partial responses (PRs) with an ORR of 15% and DCR of 26%. The DOR ranged from 7.1+ weeks to 103.0+ weeks (median: not reached) with a median OS of 82.4 weeks (95% CI: 47.4, not estimable) for all 62 pts. Tazemetostat was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild to moderate with the most commonly reported adverse events (AEs; ≥10% incidence) regardless of attribution being fatigue (24/62; 39%), nausea (22/62; 35%), and cancer pain (20/62; 32%). Any treatment-related TEAEs of grade ≥3 were reported in 10/62 (16%) pts. TEAEs grade ≥3 reported in ≥2 pts included anemia (6%) and decreased weight (3%). There were no drug-related deaths and a low discontinuation rate (1.7%). Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat achieved disease control in 26% of pts with advanced ES who entered this study. Durable clinical response of the drug was documented. Tazemetostat demonstrated favorable safety with few pts with treatment-related AEs grade ≥3. Clinical trial information: NCT02601950.