Decreased Progression Free Survival Research Articles

PD-L1 Expression Varies in Thyroid Cancer Types and Is Associated with Decreased Progression Free Survival (PFS) in Patients with Anaplastic Thyroid Cancer

Background: Thyroid cancer (TC) remains a significant clinical challenge worldwide, with a subset of patients facing aggressive disease progression and therapeutic resistance. Immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) have emerged as promising therapeutic approaches for various malignancies, yet their efficacy in TC remains uncertain. The objective of this study was to investigate PD-L1 expression in aggressive TC and its association with histological subtypes, molecular mutation, and progression-free survival. Methods: This is a retrospective study of patients with advanced TC seen in two tertiary health care centers. Included in this study were patients with advanced TC with recurrence or progression on therapy for whom tumor molecular profiling and PD-L1 status were available. Kaplan–Meier estimators were utilized to analyze the progression-free survival (PFS) between patients with PD-L1 positive and negative status in Anaplastic TC (ATC) subgroup. Results: A total of 176 patients with advanced thyroid cancer were included (48.9% female). Of the patients, 13 had ATC, 11 Medullary TC (MTC), 81 Papillary TC Classic Variant (PTCCV), 20 Follicular TC (FTC), 8 Oncocytic TC (OTC), 10 Poorly Differentiated TC (PDTC), and 30 had the Papillary TC Follicular Variant (PTCFV). BRAF mutation was present in 41%, TERT in 30%, RAS in 19%, TP53 in 10%, and RET in 8.6% of patients. PD-L1 positivity was significantly different across different TC types and histological subtypes (p < 0.01): Patients with OTC had the highest frequency of PD-L1 positivity (71%), followed by ATC (69%), PTCCV (28.5%), and FTC (11%). Patients with MTC and PTCFV did not exhibit any PD-L1 positivity. TP53 mutation was positively associated with PD-L1 expression (21.6% vs. 7.5%, p = 0.03), and RAS mutation was negatively associated with PD-L1 expression (8.1% vs. 24.2% p = 0.04). Among patients with ATC, positive PD-L1 expression was associated with lower PFS (p = 0.002). Conclusions: PD-L1 expression varies across different TC types and histological subtypes and may be modulated by the mutational landscape. PD-L1 expression in ATC is associated with shorter PFS. Follow up studies are warranted to elucidate the molecular mechanism driving the observed differences in immune pathways, potentially paving the way for the development of more effective and personalized immune therapies for patients with aggressive TC.

Oncologic and Perioperative Outcomes of Robot-Assisted Versus Conventional Laparoscopy for the Treatment of Clinically Uterine-Confined High-Grade Adenocarcinoma.

The aim of this study was to compare oncologic and perioperative outcomes of robot-assisted laparoscopy (RA) and conventional laparoscopy (LSC) in apparent clinically uterine-confined, high-grade adenocarcinoma. A retrospective review was conducted to identify patients with newly diagnosed high-grade uterine adenocarcinoma treated at our institution between 1 January 2009 and 30 June 2021. Exclusion criteria included bulky extrauterine disease, no lymph node assessment, or synchronous tumors. Clinicopathologic details were obtained from medical records. Postoperative complications were classified using the Memorial Sloan Kettering Cancer Center Surgical Secondary Events system, and statistical analysis was performed using appropriate tests. Of 901 patients identified, 748 (83%) underwent RA and 153 (17%) underwent LSC. Median age was 65 years (range 25-92) and median body mass index was 30 kg/m2 (range 15-60). Overall, 650 patients (72%) had 2009 International Federation of Obstetrics and Gynecology (FIGO) stage I disease. Forty-one patients (4.6%) converted to laparotomy-26 (3.5%) from RA versus 15 (9.8%) from LSC (p=0.02). Postoperative complications occurred in 81 patients (9.0%), with no significant differences in type or rate between groups. Median operative time was 192mins (range 88-936) for RA versus 168 mins (range 90-372) for LSC (p=0.002). Median follow-up was 52 months (range 1-163) for RA and 66 months (range 7-165) for LSC. Four-year progression-free survival (PFS) and disease-specific survival (DSS) were similar between groups. Multivariate analysis showed stage, histology, peritoneal cytology, and lymphovascular invasion predicated a decrease in PFS and DSS. RA demonstrated comparable oncologic outcomes to LSC in patients with high-grade endometrial carcinoma, with no significant difference in postoperative complications or long-term survival.

Immunotherapy and PD-L1 Tumor Expression in Moroccan Non-Small Cell Lung Cancer Patients with Various Metastasis.

The question of whether tumor expression of PD-L1 and the presence of distant metastasis could influence the efficacy of immunotherapy represents a major challenge and needs to be further elucidated. The aim of this study is to evaluate the predictive significance of tumor expression of PD-L1 as well as the number and site of metastasis in non-small cell lung cancer (NSCLC) among Moroccan patients treated with immunotherapy. Between January 2019 and February 2023, we recruited Moroccan patients with metastatic NSCLC. All were treated with immunotherapy, either as monotherapy or in combination with chemotherapy. Immunohistochemistry was used to assess PD-L1 (clone 22C3) and ALK (clone D5F3) status. EGFR status was established by qPCR. Tumor PD-L1 expression was classified into 2 levels: TPS <1% (negative expression) and TPS ≥1% (positive expression). Statistical analysis was performed using SPSS Statistics V.21 software. The median age of patients (N=40) was 67 years (39- 92 years) and the sex ratio was 9. Disease dissemination revealed that 22.5% (N=9) of patients had a metastatic burden ≥ 3 (MB≥3). As for the sites of metastasis, the results showed that 20% (N=8), 10% (N=4), 42.5% (N=17), 22.5% (N=9), 27.5% (N=11), 45% (N=18) and 27.5% (N=11) of patients had developed lymph node, liver, bone, brain, pleural, contralateral lung and adrenal metastasis respectively. Positive PD-L1 expression was significantly associated with shorter overall survival (OS = 17.19 vs. 28.85 months, p=0.01). High metastatic burden (MB ≥ 3) was associated with lower objective response rate (ORR), shorter progression-free survival (PFS), and reduced OS, respectively (ORR = 0 vs. 58.06%, p=0.002; PFS = 10.23 vs. 25.27 months, p=0.001; and OS = 11.60 vs. 27.91 months, p=0.003). Only the presence of osseous metastasis was significantly associated with lower ORR, shorter PFS, and OS compared to other metastatic locations (ORR = 5.88 vs. 73.9%, p=0.000; PFS = 10.72 vs. 31.33 months, p=0.000; and OS = 11.39 vs. 36.17 months, p=0.000). Finally, the presence of hepatic metastasis was significantly associated with shorter PFS (10.75 months) compared to those without hepatic metastasis (22.53 months) (p=0.046). Finally, the results of the multivariate analysis revealed that the presence of bone metastasis was strongly correlated with a significant decrease in progression-free survival (p=0.001) as well as overall survival (p=0.002). Our results suggest that tumor expression of PD-L1 and metastatic burden should play a significant role in predicting the response to immunotherapy. Furthermore, it is important to note that the presence of osseous and hepatic metastasis could negatively influence the clinical outcomes of immunotherapy.

Comprehensive genomic profiling in solid tumors: Enhancing treatment selection and prognosis.

e13631 Background: The emergence of novel therapeutic targets, targeted drugs, and immune checkpoint inhibitors has catalyzed a paradigm shift from single-target testing to comprehensive genomic profiling in the treatment of solid tumors. However, the tangible benefits of this shift in terms of treatment optimization and patient prognosis improvement have yet to be fully substantiated. Methods: In this retrospective study, we analyzed genomic data from 1032 patients with solid tumors to identify actionable genetic alterations, calculate tumor mutation burden (TMB), measure PD-L1 expression via immunohistochemistry, and assess microsatellite instability (MSI) status. These assessments were utilized to evaluate potential therapeutic targets and immunotherapy-related markers for each patient. Results: Between January 2018 and July 2020, 1032 patients underwent genomic profiling, received treatment, and were followed up. Of 1156 treatment episodes, 423 involved targeted monotherapy or combination therapy, 114 involved immune checkpoint inhibitor therapy, and 619 involved chemotherapy or anti-angiogenic therapy. Patients receiving matched therapy (n=491) demonstrated significantly higher partial response rates (31.7% vs 10.4%, P&lt;0.001) and longer median progression-free survival (PFS) (159 days vs 96 days, P&lt;0.001) compared to those receiving unmatched therapy (n=665). Based on the highest level of mutation carried, there were 475, 8, 153, 405, and 115 patients with grade I, II, III, IV, and V alterations, respectively. Among patients with grade I-II alterations, 65.63% received targeted therapy, resulting in significantly longer PFS compared to those undergoing immunotherapy or chemotherapy (200 days vs 109 days vs 94 days). Conversely, only 16.8% of patients with grade III-IV alterations received targeted treatment, with marginal PFS improvement (112 days vs 114 days vs 92 days). Notably, an increase in the number of actionable variants was associated with a significant decrease in PFS among patients receiving targeted therapy. However, the number of actionable variants did not significantly affect PFS in patients receiving chemotherapy or immunotherapy. Within our cohort, 44 patients with cancer of unknown primary (CUP) underwent molecular diagnostic evaluation, leading to the reclassification of 32 patients based on their molecular profiles. Notably, 24 patients harbored actionable genetic variants, 9 patients had a high TMB (≥10 Muts/Mb), and 3 patients exhibited high PD-L1 expression (TPS ≥50%). Conclusions: Comprehensive genomic profiling demonstrates clinical utility in guiding treatment decisions and improving prognosis for patients with advanced solid tumors. These findings advocate for the integration of next-generation sequencing into the therapeutic regimens for these malignancies.

Clear cell and non-clear cell renal cell carcinoma in young adults: clinicopathological features, survival outcomes and prognostic factors.

Renal cell carcinoma (RCC) is infrequent among young adults. Few studies reported the outcome of RCC in young adults by pathological subtypes. The purpose of this study was to explore the clinicopathological features, survival outcomes and prognostic factors of young adult patients with clear cell (CCRCC) and non-clear cell renal cell carcinoma (NCCRCC). This study included young adult patients aged 18-40years who were diagnosed as renal cell carcinoma (RCC) between 2012 and 2022 at Peking University Third Hospital. All patients underwent either partial nephrectomy or radical nephrectomy, and some received adjuvant therapy. A comparative analysis was performed to investigate the differences in clinicopathological characteristics between the cohort of CCRCC and NCCRCC. Kaplan-Meier survival analysis was utilized to plot survival curves for young adults with RCC. The univariate and multifactorial prognostic analyses were conducted using the log-rank test and COX proportional hazards model. A total of 300 RCC patients aged 18-40years were performed, of which 201 were diagnosed with CCRCC (67%) and 99 were diagnosed with NCCRCC(33%). The NCCRCC included 29 cases (9.7%) of chromophobe RCC, 28 cases (9.3%) of MiT family translocation RCC, 22 cases (7.3%) of papillary RCC, 11 cases (3.7%) of low malignant potential multifocal cystic RCC, and 6 cases of unclassified RCC (2.0%), 2 cases of mucinous tubule and spindle cell carcinoma (0.7%), and 1 case of FH-deficient RCC (0.3%).The mean age was 33.4±6.1years old. The overall and progression free 5-year survival rate was 99.1 and 95.3%, respectively. The NCCRCC cohort demonstrated a statistically significant decrease in progression-free survival (PFS) rate when compared to the CCRCC cohort (p<0.001). There was no statistically significant difference observed in overall survival (OS) (p=0.069). Pathological stage was a significant independent predictor for OS (p=0.045). Pathological stage and nuclear grade were both independent predictors for PFS (p=0.020; p=0.005). The clinical and pathological features of young adults diagnosed with CCRCC exhibit notable distinctions from those of NCCRCC patients. The survival outcome was significantly influenced by the pathological stage, while both the nuclear grade and pathological stage had a significant impact on tumor progression. This study offered significant contributions to the understanding of the clinicopathological characteristics and prognostic determinants of renal cell carcinoma (RCC) in young adults.

Abstract C076: New insights into the role of FOXA1- HNF4 axis in pancreatic cancer

Abstract Despite recent advances in the treatment of pancreatic adenocarcinoma (PDAC), the median survival remains &amp;lt;12 months. Patients typically present with late-stage disease and have limited treatment options. Therefore, there is an immediate need for the generation of new and innovative therapeutic targets. Little is known about the role of pioneer factors such as FOXA1 and their interaction partners in a PDAC context. Inspired by literature reports implicating FOXA1 and GATA5/GATA6 in regulating pancreatic cancer resistance and metastasis, our study hypothesised the possibility of an undiscovered nuclear receptor that works with FOXA1 (similar to Estrogen receptor in breast cancer). Using innovative ‘omic’ based approaches (RIME) developed in our laboratory 1 we discovered a nuclear receptor (NR) complex involving HNF4A and HNF4G in the classical sub-type of pancreatic cancer. Subsequently the interaction was independently validated in Whipple surgical biopsies from PDAC patients using ChIP-sequencing studies. Across multiple patient tumors (n=7) a binding overlap specifically between FOXA1 and HNF4G (3461 sites) was established. To investigate the therapeutic potential of HNF4G in the classical subtype of PDAC, we generated CRISPR deletions (KO) of HNF4G in the HPAF-II cells. HNF4G-KO cells were orthotopically implanted into the pancreas of NSG mice. A significant survival advantage of 12 days (&amp;lt;0.001) and reduced growth (&amp;lt;0.02) was observed in these mice compared to the controls. To better understand the impact of HNF4G-KO on gene expression, the orthotopic tumors were subjected to RNA-seq analyses. Gene set enrichment and pathway analysis revealed significantly down-regulated pathways to include EMT transition. TCGA data highlighted HNF4G amplification in 9% of PDAC patients with concomitant decreased progression free survival. These data point towards HNF4G being a therapeutically viable target for further exploration. Protein Arginine Methyl Transferase 1 (PRMT1) is a common interactor of both FOXA1 and HNF4G. Our study reveals a unique dependency of PRMT1 on the HNF4G-FOXA1 complex in PDAC biopsies. HNF4G-KO drastically reduces the chromatin binding of PRMT1, implicating them as functionally dependent. Treatment of HNF4G-KO cells with GSK3368715 (PRMT1 inhibitor) further sensitizes these cells and results in a significant survival advantage (10 days &amp;lt;0.02). We propose a model of HNF4G inhibition in combination with PRMT1 as a novel therapeutic opportunity to treat the classical sub-type of PDAC. Further, our study reveals a unique reliance of primary classical tumors on HNF4G. Although HNF4G appears to dominate FOXA1 functionality in the primary disease, FOXA1 remains instrumental in priming metastasis and enhancer reprograming. 1. Papachristou EK, Kishore K, Holding AN, Harvey K, Roumeliotis TI, Chilamakuri CSR, et al. A quantitative mass spectrometry-based approach to monitor the dynamics of endogenous chromatin-associated protein complexes. Nature Communications. 2018;9(1):2311. Citation Format: Shalini V. Rao, Lisa Young, Danya Cheeseman, Stephanie Mack, Jill Temple, Chandra Shekar Reddy Chilamakuri, Evangelia Papachristou, Catherina Pelicano, Amy Smith, Dominique-Laurent Couturier, Michael Gill, Duncan Jodrell Jodrell, Alasdair Russell, Igor Chernukhin, Jason Carroll. New insights into the role of FOXA1- HNF4 axis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C076.

TMIC-40. BIOPHYSICAL ANALYSIS OF GLIOBLASTOMA CORE AND RIM REVEAL UNIQUE MECHANICAL AND ULTRASTRUCTURAL SIGNATURES

Abstract Glioblastoma (GBM) is a highly aggressive and invasive brain cancer, carrying a median survival of 15 months. This poor prognosis is due, in part, to its resistance to therapy through tumor adaptations mediated by the tumor microenvironment (TME). Efforts to describe the tumor-protective cues in the TME may aid in the development of strategies to combat resistance. Emerging work has indicated that GBM biophysical properties are significant modulators of tumor progression; however, these parameters are poorly described. Here, we investigate the mechanical, extracellular matrix (ECM), and ultrastructural characteristics of tumors in patient matched GBM core and rim tissue. Using atomic force microscopy, immunohistochemistry, and scanning electron microscopy techniques, we find that GBM core is abnormally stiff and dense with large amounts of ECM, while the rim is softer and more porous. The GBM core is uniquely rich in hyaluronic acid and Tenascin-C, ECM proteins known to correlate with tumor stiffness and tumor supportive function. Additionally, dense matrix along with increased levels of hyaluronic acid and Tenascin-C correlate with decreased progression free survival. These data suggest that the stiff core provides increased pro-malignant mechanotransductive cues while the rim presents more permissive routes for GBM invasion. These results reveal a biophysical basis for tumor progression and provides a novel framework for diagnostic strategies and therapeutic intervention.

Bendamustine Lymphodepletion (LD) Prior to Idecabtagene Vicleucel (Ide-cel) Is Associated with Inferior Outcomes in Relapsed Refractory Multiple Myeloma (RRMM)

Background Chimeric antigen receptor therapy (CART) has revolutionized the management of RRMM. LD prior to CART cells modulates the immune environment creating optimal conditions for T cell expansion and subsequent efficacy. Fludarabine/cyclophosphamide (FLU/CY) is an effective LD regimen, and its use has been adopted widely prior to CART cells for all indications. Since the safety of FLU/CY is not established in patients with substantial renal impairment and given recent nationwide fludarabine shortage, alternative lymphodepletion strategies have been explored. Bendamustine (BENDA) has been shown to be a safe alternative with equivalent efficacy and reduced toxicity in non-Hodgkin's lymphoma (NHL). While its use has been extrapolated to RRMM, efficacy and long-term outcomes have not been examined. Methods We retrieved and analyzed data on sequential patients (pts) with RRMM treated with commercial Ide-cel at a single institution from its approval in 3/2021 until 5/2023. We captured baseline patient, disease and treatment characteristics. We used IgG (with monoclonal component deducted) and uninvolved FLC as indirect surrogate of CAR-T expansion and on target, off tumor killing of non-malignant plasma cells. We assessed cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity (ICANS) based on the American Society for Transplantation and Cellular Therapy criteria and disease responses using the International Myeloma Working Group response criteria. We graded hematologic toxicity using the Common Terminology Criteria for Adverse Events version 5.0. We compared efficacy between the cohorts using overall response rate (ORR) and progression-free survival (PFS), since overall survival is expected to be affected by choice of subsequent, often experimental therapies. Results We identified 28 pts with RRMM who met the inclusion criteria. Nine pts received alternative LD with BENDA (2 pts - renal dysfunction with creatinine clearance &amp;lt;30ml/min; 7 - fludarabine shortage) and 19 received FLU/CY as LD. Baseline characteristics are summarized in Table. Prior autologous stem cell transplant (ASCT) and prior B cell maturation antigen (BCMA) targeting therapy were more frequent in the FLU/CY cohort. Median absolute lymphocyte count (measured in 10^3/ cmm) prior to LD chemotherapy was similar in both cohorts (0.85 in BENDA vs 0.80 in FLU/CY). Median duration of absolute neutrophil count &amp;lt;1,000/μL was shorter in the BENDA cohort. The incidence of any grade CRS (56% vs. 90%, p=0.06) and tocilizumab use (56% vs. 84%, p=0.16) was lower with BENDA compared to FLU/CY. In the absence of ide-cel expansion data, we used nadir polyclonal IgG and uninvolved free light chain (uFLC) in the initial 90 days post CART cell infusion as surrogate of non-malignant plasma burden and therefore ide-cel expansion. We noted lower median uFLC and median IgG with FLU/CY vs. BENDA. The overall response rate was lower with BENDA (22%) vs. FLU/CY (79%, p=0.01). With median follow up of 4.8 mo., all pts in the BENDA cohort progressed with median PFS of 1.6 months vs 7.8 months for FLU/CY (p&amp;lt;0.001, Figure). The median OS for both cohorts is not yet reached. Conclusion: BENDA LD prior to ide-cel infusion results in suboptimal lymphodepletion and subsequent inferior outcomes including low rate of objective responses and decreased progression free survival. The inferior efficacy of BENDA as LD likely results from inferior ide-cel expansion and persistence resulting in less frequent and severe CRS and cytopenias and less suppression of unaffected immunoglobulins. Future efforts to study alternative lymphodepletion approaches is essential given inability to use fludarabine in patients with severe renal dysfunction and periods of critical drug shortages. While there is a need to develop alternatives for LD prior to ide-cel, BENDA is an inadequate substitute of FLU/CY.

The timing of durvalumab administration affects the risk of pneumonitis in patients with locally advanced non-small cell lung cancer: a systematic review and meta-analysis

PurposeThe PACIFIC study has demonstrated that the administration of durvalumab following concurrent chemoradiotherapy can significantly improve both overall survival and progression-free survival rates in patients with locally advanced unresectable non-small cell lung cancer. While the latest NCCN guidelines recommend this combination regimen, they do not specify the optimal timing for administering durvalumab after completing radiotherapy. The PACIFIC study suggested initiating durvalumab within 42 days of completing radiotherapy, but early administration of the drug may increase the incidence of pneumonitis. Therefore, we conducted this study to investigate whether the time interval between completion of radiotherapy and initiation of durvalumab treatment is associated with the risk of pneumonitis (Grade ≥ 3), which is the primary endpoint, as well as progression-free survival, which is the secondary endpoint.MethodsA comprehensive search of clinical trials in PubMed and EMBASE was conducted up to March 2023 to identify clinical trials involving locally advanced unresectable non-small cell lung cancer patients who were treated with durvalumab following chemoradiotherapy. Meta-analysis was performed on single-arm studies to estimate the incidence of pneumonitis (Grade ≥ 3) and progression-free survival in all studies, as well as in studies that administered durvalumab within 42 days after completion of radiotherapy.ResultsThis meta-analysis consisted of nine studies with a total of 2560 patients. The analysis showed that the incidence of pneumonitis (Grade ≥ 3) was 5.36% [95%CI (0.03, 0.08), I2 = 18.41%, p = 0.29], while the 1-year progression-free survival rate was 57.91% [95%CI (0.53, 0.63), I2 = 10.57%, p = 0.35]. Furthermore, when the duration between completion of radiotherapy and initiation of durvalumab treatment was shorter than 42 days, the incidence of pneumonitis (Grade ≥ 3) was 4.12% [95%CI (0.02, 0.06), I2 = 0.00%, p = 0.56], with a 1-year progression-free survival rate of 61.03% [95%CI (0.51, 0.71), I2 = 59.06%, p = 0.09].ConclusionOverall, based on the available evidence, it appears that there is no significant increase in pneumonitis or decrease in progression-free survival (PFS) when the time interval is less than 42 days and a shorter interval between treatment sessions does not necessarily have a detrimental effect on the rate of pneumonitis. We recommend that clinicians carefully evaluate the specific circumstances of each patient to determine the optimal timing for initiating immunotherapy.

Pre-treatment metastatic growth rate is associated with clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab

BackgroundImmune checkpoint inhibitors (ICIs) have been approved for the treatment of metastatic renal cell carcinoma (mRCC). However, the response rate is still limited, and it is urgent to pursue novel and concise markers of responses to ICIs that allow the determination of clinical benefits. Recently, it was reported that the metastatic growth rate (MGR) is an independent factor associated with clinical outcome for anticancer therapy in some types of cancer.MethodsWe investigated pre-treatment MGR before starting nivolumab for mRCC patients between September 2016 to October 2019. In addition, we examined clinicopathological factors including MGR and analyzed the correlation between pre-treatment MGR and clinical efficacy of nivolumab.ResultsOf all patients, the median age was 63 years (range, 42–81), and the median observation period was 13.6 months (range, 1.7–40.3). Twenty-three patients and sixteen patients were classified as the low and the high MGR group, respectively, with the cutoff value of 2.2 mm/month. Progression-free survival (PFS) and overall survival (OS) were significantly better in patients in the low MGR group (p = 0.005 and p = 0.01). Importantly, in multivariate analysis, only the high MGR was significantly associated with a decrease of PFS (Hazard ratio (HR): 2.69, p = 0.03) and OS (HR: 5.27, p = 0.02).ConclusionsPre-treatment MGR may serve as the simple and valid indicator obtained from imaging studies, and the prominent surrogate marker associated with OS and PFS in mRCC patients treated with nivolumab.

Clonal hematopoiesis of indeterminate potential (CHIP) and association with response to bipolar androgen therapy (BAT).

e17048 Background: CHIP, the expansion of hematopoietic cells carrying acquired somatic alterations associated with hematologic malignancies, is associated with increased inflammation, risk of heart disease, and poor outcomes. BAT, where testosterone levels are therapeutically manipulated between castrate levels to supraphysiologic levels, has been shown to be an effective therapy for some men with castration resistant prostate cancer. Clinical predictors of response are not established. We hypothesized that CHIP, would be negatively associated with clinical outcomes. Methods: Baseline peripheral blood from participants on the RESTORE Cohort C (NCT02090114) were analyzed for the presence of CHIP. Patients in this cohort had castration resistant prostate cancer with progressive disease after treatment with ADT alone. All participants were treated with 400mg of intramuscular testosterone cypionate every 28 days. Peripheral blood mononuclear cells were analyzed for the presence of CHIP using targeted next generation sequencing focused on 49 genes most commonly mutated in CHIP and myeloid malignancies. Given patients had metastatic and non-metastatic CRPC, progression free survival was determined based on the time to the start of the next therapy. Results: CHIP was present in 6 of 29 patients at baseline (21%) with one patient having 2 clones (Table). Median age of patients CHIP+ was 73 compared to age of 68 in the CHIP- group (p = 0.16). Median PSA was higher in the CHIP+ group (median 15, IQR 1-56) compared to the CHIP- group (median 3.5, IQR 1-57). 67% of the CHIP+ group and 57% of the CHIP- group had baseline Gleason scores of &gt; = 8. The CHIP+ group had a median PFS of 8.8 months compared to 13.3 months in the CHIP- group (HR 3.3 95%CI 1.2, 9.1; p = 0.02). This remained significant after adjusting for age. There was no difference in overall survival (HR = 2.5 95% CI 0.5,2.9; p = 0.3). Conclusions: Among men treated with BAT as first line treatment for CRPC after ADT alone, CHIP was associated with a decreased progression free survival. Larger studies are needed to understand the impact of CHIP in larger cohorts of men treated with BAT and other therapies for prostate cancer.[Table: see text]

Significance of bone marrow immunohistochemical analysis in patients with plasma cell neoplasms

Background. The group of plasma cell neoplasms includes benign and malignant diseases. Sometimes there are difficulties in making a diagnosis. The study of the diagnostic and prognostic significance of immunohistochemical (IHC) markers is of current interest.Aim. To study the significance of IHC markers and histological features of the bone marrow in primary diagnosis in patients with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).Materials and methods. The study included 287 patients with plasma cell neoplasms: MGUS (n = 148), MM (n = 139). The observation period was 50 months. All patients have performed an aspiration biopsy and histological examination of the bone marrow with IHC analysis of CD138+, CD56+, CD34+, κ- and λ-chains expression.Results. During the observation period the progression of MGUS to MM was recorded in 8.8 % (n = 13) of cases, the progression of MM was determined in 38.1 % (n = 53) of cases.In patients with MGUS and MM the determined percentage of plasma cells at aspiration biopsy was somewhat lower than at histological examination (p &gt;0.001). Statistically significant differences were determined between the groups MGUS and MM by the type of infiltration (р &lt;0.001). With an increase in the percentage of bone marrow lesions by IHC (&lt;20 % vs. 20–50 % and 20–50 % vs. &gt;50 %), in our study interstitial and diffuse type of lesion with large accumulations was more common compared to the nodular type (p = 0.001).The CD138+ expression (IHC) more than 10 % was associated with a decrease of progression-free survival in patients with MGUS.In MM patients with an interstitial type of bone marrow infiltration and CD138+ over 10 % osteodestructive syndrome was detected by X-ray methods in 82.9 % of cases.Determination of CD56+ and immunoglobulin light chains expression in patients with MM and MGUS indicated an unfavorable prognosis.Resistance to chemotherapy or disease progression in MM patients most often occurred with a combination of IgG and immunoglobulin light chains secretion, with CD138+ plasma cells more than 50 % according to IHC, with a diffuse type of bone marrow lesion with accumulations of plasma cells. MGUS patients progressed more frequently with more than 20 % CD138+ plasma cells according to IHC, interstitial type and diffuse plasma cells accumulation type of bone marrow lesion, secretion of IgG or two immunoglobulins.Conclusion. The significance of the IHC study in the diagnosis of plasma cell neoplasms was confirmed. Markers associated with the disease progression and chemotherapy resistance in patients with MGUS and MM were identified.

Analysis of the epidemiological characteristics of multiple myeloma and clinical factors affecting the course of the disease

Multiple myeloma (MM) is the second most common malignant neoplasm of the hematopoietic system. Survival rate has improved significantly in patients over the past decade with the use of new therapeutic strategies. The absence of adverse factors at the time of diagnosis does not always determine a positive course of the disease. Therefore, the search for prognostic factors is relevant. The article presents data based on the epidemiological characteristics and clinical factors of MM that affected the progression-free survival. We have shown that a significant excess of the levels of IL2, IL6, TNF, the level of clonal CD138+ &gt;20% at the time of diagnosis is associated with an increase in the frequency of disease progression.A decrease in progression-free survival was detected at kidney damage, anemic syndrome, infectious complications, multiple skeletal bone lesions, genetic changes at the time of diagnosis and did not depend on the type of immunoglobulin secretion.

Abstract P5-02-50: Do thymidine kinase 1 (TK1) plasma concentration and activity play a role in therapy management of metastatic breast cancer patients treated with CDK4/6 inhibitors?

Abstract Introduction: CDK4/6 is a checkpoint kinase, regulating the transition of the S into the G2 phase of the cell cycle. As a cell transverses through the cell cycle, thymidine kinase 1 (TK1) is expressed and represents a direct marker of proliferative activity.which might indicate therapy efficiency of CDK4/6 inhibitors (CDK4/6i), the first choice of therapy in case no sign of visceral crisis is detected in hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) patients. We here determined whether the activity and/or concentration of TK1 in plasma samples of MBC patients treated with CDK4/6i harbours predictive, monitoring or prognostic value. Methods: Blood of 90 HR+/HER2-MBC patients drawn at baseline of CDK4/6i (Ribociclib/Palbociclib) plus endocrine treatment and 18 HR+/HER2-MBC patients drawn before initiation of endocrine monotherapy (control), as well as available matched blood samples of these patients after six months under TX (n=90), 12/24 months before progression (n=72/24) and at the time of progression (n=52) are available. TK1 concentration in plasma samples was measured by competitive ELISA (ABIN809094, Shanghai BlueGene Biotech Co., LTD, China) and TK1 activity of matched plasma samples by competitive, two-step chemiluminescence immunoassay (REF 310960, Diasorin, Stillwater, US). Statistical analysis was conducted via log-rank test and univariate or multivariate Cox regression. Results: Currently, baseline samples were evaluated for TK1 concentration (n=106) and activity (n=90). The mean value for TK1 activity was 12.69 U/L and the median value was 8.37 U/L in the entire cohort. Values ranged from 0.89 to 79.50 U/L and the standard deviation was determined to be 12.64 U/L, which is similar to the mean value. In contrast to the control group, high TK1 activity (Cut-off: mean or determined by ROC analysis and maximal Youden’s Index for PFS &amp;lt; six months) was significantly correlated with decreased progression free survival (PFS) in the CDK4/6i cohort (p-value &amp;lt; 0.05 in log rank test and univariate Cox regression). In addition, using multivariate Cox regression analysis including clinical parameters (e.g. therapy line, prior chemo- or endocrine therapies, type of CDK4/6i accompanying endocrine therapy, number of sites of metastases, visceral metastases, menopausal status), TK1 activity was found to be an independent marker for PFS.High TK1 activity (Cut-off: mean or determined by ROC analysis and maximal Youden’s Index for PFS &amp;lt; six months or already deceased patients) at baseline was significantly correlated with shorter time from baseline to death in the CDK4/6i cohort (p-value &amp;lt; 0.05 in log rank test and univariate Cox regression) but not in the control cohort. For TK1 concentration analysis, the mean value was 21.76 ng/ml and the median value was 18.57 ng/ml in the entire cohort. Values ranged from 7.35 ng/ml to 46.66 ng/ml and the standard deviation was determined to be 11.16 ng/ml, which is half of the mean value. In contrast to TK1 activity measurements, no significant association of TK1 concentration with PFS or overall survival (OS) was detected in the CDK4/6i cohort. Currently, all remaining samples during the course of treatment are evaluated for TK1 activity and concentration and final statistical analysis of the complete data set will be available at the meeting. Conclusion: Our preliminary results indicate that TK1 activity, in contrast to TK1 concentration, determined before starting CDK4/6 inhibtion could be a suitable predictive and prognostic biomarker for estimating response to treatment. Our final analysis will clarify, whether TK1 could also serve as a monitoring marker during treatment. Citation Format: Stefanos Moukas, Merle Dohn, Rainer Kimmig, Mitra Tewes, Hans-Christian Kolberg, Sabine Kasimir-Bauer, Corinna Keup. Do thymidine kinase 1 (TK1) plasma concentration and activity play a role in therapy management of metastatic breast cancer patients treated with CDK4/6 inhibitors? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-50.

High-volume mCRPC is associated with decreased cancer specific survival in patients on second-generation hormone therapy in the post docetaxel setting.

192 Background: In the setting of disease progression of metastatic castrate resistant prostate cancer (mCRPC) on docetaxel, abiraterone acetate (AA) and enzalutamide are two commonly used second line therapies with data demonstrating survival benefits. Less is known about patient specific factors that contribute to success with these therapies. The objective of this study is to improve patient selection for post-docetaxel second generation hormone therapy (AA or enzalutamide) by evaluating whether overall metastatic burden is associated with treatment response in this setting. Methods: By retrospective chart review, patients with mCRPC treated with AA or enzalutamide following docetaxel failure (defined as PSA rise and radiographic progression) were identified. Patients were categorized into low volume and high volume metastatic disease based on the number of pre-treatment metastatic lesions; where low volume disease describes patients with ≤ 5 metastatic lesions (e.g. oligometastatic disease), and high volume disease represents patients with &gt; 5 individual lesions. The primary endpoint was cancer-specific mortality and the secondary endpoint was radiographic progression free survival. Median follow-up time was 29.5 months. Results: 75 patients were identified and included in our analysis: 39 with high volume metastatic disease, and 36 with low volume metastatic disease. Baseline characteristics of age and pre-treatment ECOG were not statistically different between these groups. Pre-treatment high-volume disease burden was significantly associated with increased risk of radiographic disease progression (HR 4.21, 95%CI 1.97-8.99, p &lt; 0.0001) and cancer specific mortality (HR 5.84, 95% CI 1.58-21.53, p = 0.0026) during treatment with second generation androgen deprivation therapy. Conclusions: High volume metastatic disease burden is associated with significantly increased cancer specific mortality and decreased progression free survival for patients on second line therapy with AA or enzalutamide following docetaxel treatment failure.

Optimal number of neoadjuvant chemotherapy cycles prior to interval debulking surgery in advanced epithelial ovarian cancer: a systematic review and meta-analysis of progression-free survival and overall survival.

Neoadjuvant chemotherapy (NACT) represents a treatment option in patients with advanced epithelial ovarian cancer (AEOC) who are not good candidates for primary debulking surgery. Usually, 3 cycles of chemotherapy before surgery have been considered the best option for patient survival, although quite often some patients receive more than 3 cycles. The aim of this systematic review and meta-analysis was to identify the optimal number of NACT cycles reporting better survival in AEOC patients. PubMed, Cochrane Library, and Scopus were searched for original articles that analyzed the relationship between the number of chemotherapy cycles and clinical outcomes in AEOC patients before interval debulking surgery (IDS). The main outcomes were progression-free survival (PFS) and overall survival (OS). A total of 22 studies comprising 7,005 patients diagnosed with AEOC were included in our analysis. In terms of survival, the reviewed studies dividing the patients in ≤3 NACT cycles vs. >3, showed a trend for a decrease in PFS and a significant reduction in OS with an increasing number of cycles, while a difference in both PFS and OS was revealed if early IDS included patients with 4 NACT cycles. These results should be interpreted with caution due to the complex characteristics of AEOC patients. In conclusion, our review and meta-analysis revealed that there is not enough evidence to determine the optimal number of NACT treatments before surgery. Further research in the form of well-designed randomized controlled trials is necessary to address this issue. PROSPERO Identifier: CRD42022334959.

SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma.

SET domain-containing protein 2 (SETD2) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins. Initially, we sought to explore SETD2-dependent changes in lysine methylation of proteins in proximal renal tubule cells. Subsequently, we focused on changes in lysine methylation of the translation elongation factor eEF1A1. To accomplish these objectives, we initially performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) and SETD2-knock out (KO) kidney cells and later focused our studies on eEF1A1 as well as the expression of lysine methyltransferases that regulate its lysine methylation. We observed decreased lysine methylation of the translation elongation factor eEF1A1. EEF1AKMT2 and EEF1AKMT3 are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function of SETD2. Globally, we observe differential expression of hundreds of proteins in WT versus SETD2-KO cells, including increased expression of many involved in protein translation. Finally, we observe decreased progression free survival and loss of EEF1AKMT2 gene expression in SETD2-mutated tumors predicted to have loss of function of the SET domain. Overall, these data suggest that SETD2-mutated ccRCC, via loss of enzymatic function of the SET domain, displays dysregulation of protein translation as a potentially important component of the transformed phenotype.

B7-H3 Trike Enhances Killing of Myeloid Derived Suppressor Cells in Multiple Myeloma

Multiple myeloma (MM) is sensitive to Natural Killer (NK) cell-mediated killing but develops methods to attenuate NK cell function. One method to enhance NK cell specificity against myeloma is antibody dependent cellular cytotoxicity through the CD16 receptor. We developed a tri-specific killer engager (TriKE®) with a camelid single-domain antibody (sdAb) fragment against CD16 (on NK cells) as well as a linker region containing IL-15, to enhance NK cell survival. Delivery of IL-15 by TriKE supports NK cell proliferation while avoiding off-target effects on T cells. The second sdAb targets B7-H3 (CD276), a tumor antigen that is expressed on myeloma and is associated with decreased progression free survival. B7-H3 is differentially expressed on myeloma tumor lines MM1S, RPMI-8226, U266, and H929 but all four MM lines are significantly killed by peripheral blood NK cells in the presence of 3nM B7-H3 TriKE compared to NK cells alone. Bone marrow aspirates from 5 MM patients (3 newly diagnosed and 2 relapsed) were analyzed by flow cytometry and showed 58-96% expression of B7-H3 on CD138+ plasma cells. The bone marrow biopsy aspirates also showed monocytic myeloid derived suppressor cells (Mo-MDSC, CD14+, CD11b+) that expressed B7-H3 (38-87%) as well as the damage associated molecular pattern (DAMP) S100A8/9. In comparison, CD14+ cells from the peripheral blood of healthy donors expressed very low levels of B7-H3 or S100A8/9 (<5%). Mo-MDSC are important to the pathogenesis of MM because they support MM growth and contribute to suppression of NK in the tumor microenvironment. B7-H3 is highly expressed on mature osteoclasts and MDSC can develop into osteoclasts in mouse models of MM and breast cancer. We saw that Mo-MDSC expressing B7-H3 also co-expressed RANK, a receptor necessary for signaling osteoclastic development. We developed Mo-MDSC from CD33+ myeloid cells from healthy donors using IL-6 and GM-CSF or co-culture with MM cell lines at 1:1000 ratio. Both types of MDSC suppressed NK proliferation. Peripheral blood derived MDSC expressed >80% B7-H3 and RANK. We separated B7-H3 positive and negative populations by flow cytometry and attempted to develop osteoclasts with M-CSF and RANK-L over 14 days. Tartrate resistant acid phosphatase (TRAP) staining was performed but both groups were negative and exhibited no phenotypic changes by light microscopy. We then isolated CD14+ cells from the bone marrow of an MM patient who was in complete remission (CR) after autologous stem cell transplant but had a distinct population of B7-H3+, RANK+, S100A8/9+ Mo-MDSC in her surveillance bone marrow aspirate. After fourteen days of culture with M-CSF and RANK-L, TRAP staining was positive, and cells had grown larger, consistent with osteoclastic differentiation (Figure 1A). We tested the ability of B7-H3 TriKE to eliminate MDSC by NK cells, therefore diminishing there immune suppression. Cytotoxicity assays were conducted over 48 hours with NK cells with or without B7-H3 TriKE. Killing was significantly enhanced by B7-H3 TriKE (Figure 1B). Since MDSC are known to suppress NK cell function, we assessed metabolic fitness in NK cells with MDSC at 1:1 ratio for 48 hours with or without 3nM B7-H3 TriKE and found that B7-H3 TriKE improved both the oxygen consumption and extracellular acidification rates. These data show that B7-H3 TriKE enhances NK cell killing of MM through direct targeting and eliminates suppressive Mo-MDSC. B7-H3+ Mo-MDSC can differentiate into osteoclasts and persist even in patients who are in CR, possibly contributing to relapse. B7-H3 TriKE may be particularly useful for patients with bone lesions or as consolidative therapy. Commercial manufacturing of B7-H3 TriKE (GTB-5550) has begun, and a phase I trial is expected in late 2023. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

SURG-10. Pediatric PF-A ependymoma: a case series of cytogenetics and progression-free survival

Abstract Ultra-high risk PF-A ependymoma, defined as 6q chromosome deletion in the setting of 1q gain, represents a biologically unique entity. These tumors are associated with significantly worse progression-free survival and 6q loss is an independent predictor of overall survival. Here, we present cytogenetics and progression-free survival from all PF-A ependymomas diagnosed at Lurie Children’s Hospital of Chicago over a 10-year period (2011 and 2021). Twelve patients were identified with the diagnosis of PF-A ependymoma (42% males, average age at diagnosis 5.75 years) during the study period. Four patients demonstrated gain of 1q on methylation profiling. Two patients with a gain of 1q also had a deletion of 6q, carrying the ultra high-risk designation. All patients underwent surgical resection and post-operative radiation therapy. Patients who received chemotherapy had a significant increase in overall number of surgical resections (p-value &amp;lt; 0.0001). Patients without 1q gain had an average of 2.1 surgeries, while patients with 1q gain had an average 2.75 surgeries. Patients with 1q gain and 6q deletion had an average of 3.5 surgeries. All patients with 1q gain had recurrence of their tumor, compared to 38% of patients without 1q gain. In this series, progression-free survival for the PF-A without 1q gain, 1q gain, and 1q gain with 6q deletion cohort was 27.9, 18.4, and 19.5 months, respectively. The most common complications were radiation toxicity and cerebellar dysfunction (ataxia, dysmetria, and gait imbalance). Not surprisingly, complications were more common in those patients undergoing a greater number of subsequent resections. All PF-A ependymomas should be evaluated for 1q gain and 6q deletion, which can be reliably ascertained using cytogenetic markers in routine clinical use. In this series, 1q gain was associated with a decrease in progression-free survival. Only 2 patients were designated ultra high-risk based on cytogenetic analysis.

Abstract PD1-07: Mutant ESR1 receptors antagonize the tumor suppressor function of androgen receptors

Abstract Background: Acquired ESR1 mutations are a dominant driver of distant metastasis in metastatic breast cancer, inducing a basal-like phenotype that is relatively resistant to ER antagonists with decreased progression free survival. The majority of ER+ patients also express the androgen receptor (AR), and although AR expression is associated with better outcomes, high AR expression has also been associated with resistance to endocrine therapy (ET). Thus, there is currently a conundrum on how best to target AR, and to define when it is participating as a proliferative/metastatic driver, or when it may be a potential tumor suppressor associated with good prognosis. Methods: We generated ESR1 Y537S or D538G homozygous mutations in MCF-7 cells using CRISPR Cas-9 technology. ChIP-Seq, transcriptome analyses, and quantitative analysis of ER ChIP-Seq profiles from patient biopsies were integrated. Nuclear fractionation and immunoblot analyses were performed. Results: Correlation and gene set enrichment analyses demonstrated that the androgen response pathway was significantly reduced in ESR1 mutant, compared to wild-type (WT) ER cells. A dramatic redistribution in AR binding sites to heterochromatin was observed in ESR1 mutant cells. AR and ER co-occupied DNA binding sites were redistributed only to ERE motifs present in a restricted set of gene enhancer regions. Quantitative analysis of ER DNA binding profiles from ER+ patients showed that the highest recruitment of ER to AR/ER binding sites were in patients with metastatic breast cancer. Integration of AR/ER co-bound sites with the differentially-expressed mutant transcriptome identified a gene signature that predicted poor disease-free and overall survival in ER+ primary breast cancer patients from the METABRIC database. Elevated gene expression of these AR/ER co-regulated genes, including NCOA3, BMP7, N4BP3, and FOXA1, were validated in a cohort of metastatic tumors (N=97), compared to primary tumors (N=276). AR protein levels were elevated in ESR1 mutant tumors. Mechanistic studies demonstrated that elevated AR phosphorylation at specific sites (pS515, pS650) and decreased phosphorylation (pS308) occurs in mutant cells. These sites are known to affect AR transcriptional activity, protein stability, and nuclear export. Decreased K48-AR ubiquitination was observed, suggesting that elevated AR protein levels result from altered post-transcriptional modification of AR in mutant cells. Conclusions: We propose a two-prong genomic activation mechanism in ESR1 mutant tumors with AR redistribution to heterochromatin, and genomic co-activation of AR and ER. We hypothesize that the loss of AR tumor suppressor function may help drive metastasis in ESR1 mutant tumors via AR’s collaboration with ESR1 mutant oncogenic activity. Efficacious targeting of AR may require disruption of this driver AR/ER-regulated transcriptional program. Citation Format: Sandra L. Grimm, Guowei Gu, Sarah K. Herzog, Thomas L. Gonzalez, Hangqing Lin, Amanda R. Beyer, Yassine Rechoum, Tasneem Bawa-Khalfe, Ashfia F. Khan, Lili Du, W. Fraser Symmans, Ralf Kittler, Cristian Coarfa, Suzanne A.W. Fuqua. Mutant ESR1 receptors antagonize the tumor suppressor function of androgen receptors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD1-07.