Molecular Risk Profile Research Articles

Escalation and De-Escalation of Adjuvant Radiotherapy in Early Breast Cancer: Strategies for Risk-Adapted Optimization.

Postoperative radiotherapy (RT) is recommended after breast-conserving surgery and mastectomy (with risk factors). Consideration of pros and cons, including potential side effects, demands the optimization of adjuvant RT and a risk-adapted approach. There is clear de-escalation in fractionation-hypofractionation should be considered standard. For selected low-risk situations, PBI only or even the omission of RT might be appropriate. In contrast, tendencies toward escalating RT are obvious. Preoperative RT seems attractive for patients in whom breast reconstruction is planned or for defining the tumor location more precisely with the potential of giving ablative doses. Dose escalation by a (simultaneous integrated) boost or the combination with new compounds/systemic treatments may increase antitumor efficacy but also toxicity. Despite low evidence, RT for oligometastatic disease is becoming increasingly popular. The omission of axillary dissection in node-positive disease led to an escalation of regional RT. Studies are ongoing to test if any axillary treatment can be omitted and which oligometastatic patients do really benefit from RT. Besides technical improvements, the incorporation of molecular risk profiles and also the response to neoadjuvant systemic therapy have the potential to optimize the decision-making concerning if and how local and/or regional RT should be administered.

Identification of prognostic models for glycosylation-related subtypes and tumor microenvironment infiltration characteristics in clear cell renal cell cancer

One of the most fatal forms of cancer of the urinary system, renal cell carcinoma (RCC), significantly negatively impacts human health. Recent research reveals that abnormal glycosylation contributes to the growth and spread of tumors. However, there is no information on the function of genes related to glycosylation in RCC. In this study, we created a technique that can be used to guide the choice of immunotherapy and chemotherapy regimens for RCC patients while predicting their survival prognosis. The Cancer Genome Atlas (TCGA) provided us with patient information, while the GeneCards database allowed us to collect genes involved in glycosylation. GSE29609 was used as external validation to assess the accuracy of prognostic models. The "ConsensusClusterPlus" program created molecular subtypes based on genes relevant to glycosylation discovered using differential expression analysis and univariate Cox analysis. We examined immune cell infiltration as measured by estimate, CIBERSORT, TIMER, and ssGSEA algorithms, Tumor Immune Dysfunction and Exclusion (TIDE) and exclusion of tumour stemness indices (TSIs) based on glycosylation-related molecular subtypes and risk profiles. Stratification, somatic mutation, nomogram creation, and chemotherapy response prediction were carried out based on risk factors. We built and verified 16 gene signatures associated with the prognosis of ccRCC patients, which are independent prognostic variables, and identified glycosylation-related genes by bioinformatics research. Cluster 2 is associated with lower human leukocyte antigen expression, worse overall survival, higher immunological checkpoints, and higher immune escape scores. In addition, cluster 2 had significantly better angiogenic activity, mesenchymal EMT, and stem ability scores. Higher immune checkpoint genes and human leukocyte antigens are associated with lower overall survival and a higher risk score. Higher estimated and immune scores, lesser tumor purity, lower mesenchymal EMT, and higher stem scores were all characteristics of the high-risk group. High amounts of tumor-infiltrating lymphocytes, a high mutation load, and a high copy number alteration frequency were present in the high-risk group.Discussion.According to our research, the 16-gene prognostic signature may be helpful in predicting prognosis and developing individualized treatments for patients with renal clear cell carcinoma, which may result in new personalized management options for these patients.

The Absolute Monocyte Count at Diagnosis Affects Prognosis in Myelodysplastic Syndromes Independently of the IPSS-R Risk Score.

The absolute monocyte count (AMC) is associated with mortality in a variety of medical conditions. Its prognostic impact in myelodysplastic syndromes (MDSs) is less well studied. Therefore, we investigated its potential prognostic value in a cohort from the Düsseldorf MDS registry in relationship to the revised international prognostic scoring system (IPSS-R). An AMC below the population's median (<0.2 × 109/L) was associated with several adverse disease features such as lower haemoglobin levels, lower count of neutrophils and platelets, and a higher percentage of blasts in the bone marrow. MDS patients with an AMC < 0.2 × 109/L had a significantly higher risk of progression into acute myeloid leukemia (AML). In a univariate, proportional hazards model the effect of the AMC as a continuous variable was modelled via p-splines. We found a U-shaped effect with the lowest hazard around 0.3 × 109/L. Accordingly, an AMC within the last quartile of the population (0.4 × 109/L) was associated with a reduced overall survival independently of IPSS-R, but not with the risk of secondary AML. Considering monocytopenia as a risk factor for AML progression in MDS may provide an additional argument for allogeneic transplantation or the use of hypomethylating agents in patients who are not clear candidates for those treatments according to current prognostic scoring systems and/or recommendations. Further studies are needed to assess the prognostic impact of the AMC in the context of prognostic scoring systems, considering the molecular risk profile, and to identify the mechanisms responsible for the higher mortality in MDS patients with a subtle monocytosis.

Retrospective Review of Outcomes of Multiple Myeloma (MM) Patients With COVID-19 Infection (Two-Center Study).

COVID-19 has profound effects on patients with multiple myeloma (MM) mainly due to underlying immune dysfunction and associated therapies leading to increased susceptibility to infections. The overall risk of morbidity and mortality (M&M) in MM patients due to COVID-19 infection is unclear with various studies suggesting case fatality rate of 22% to 29%. Additionally, most of these studies did not stratify patients by their molecular risk profile. Here, we aim to investigate the effects of COVID-19 infection with associated risk factors in MM patients and the effectiveness of newly implemented screening and treatment protocols on outcomes. After obtaining institutional review board approvals from each participating institution, we collected data from MM patients diagnosed with SARS-CoV-2 infection from March 1, 2020, to October 30, 2020, at 2 myeloma centers (Levine Cancer Institute & University of Kansas medical center). We identified a total of 162 MM patients who had COVID-19 infection. The majority of patients were males (57%) with a median age of 64 years. Most patients had an associated comorbid condition. Their myeloma disease status and prior autologous stem cell transplant at the time of infection had no impact on hospitalization or mortality. In univariate analysis, chronic kidney disease, hepatic dysfunction, diabetes, and hypertension were associated with an increased risk of hospitalization. In multivariate analysis regarding survival, increased age and lymphopenia were associated with increased COVID-19-related mortality. Our study supports the use of infection mitigation measures in all MM patients, and adjustment of treatment pathways in MM patients diagnosed with COVID-19.

PP01.02 Molecular Recurrence Risk Profiles in Patients with Early-Stage NSCLC: Current Standard of Care Compared to a Prognostic and Predictive 14-gene Expression Assay

PP01.02 Molecular Recurrence Risk Profiles in Patients with Early-Stage NSCLC: Current Standard of Care Compared to a Prognostic and Predictive 14-gene Expression Assay

Outcomes Following Hypomethylating Agent / Venetoclax Combination-Therapy for MDS or AML Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the consolidation therapy with the highest chance of sustained remission for most patients (pts) with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, relapse occurs in up to 40% of pts and adversely affects prognosis. Currently, post-HSCT relapse strategies include intensive chemotherapy, hypomethylating agents (HMA), as well as targeted therapy, e.g. FLT3-inhibitors frequently combined with donor lymphocyte infusions (DLIs). Here we investigated combinations of HMA and venetoclax (VEN) as salvage options for relapse after alloHSCT. Methods: 2 MDS and 24 AML pts (median age 60 [range 38-73] years) relapsed after a median of 6.2 (range 1.6-55.5) months (mo) after 1st (n=22) or 2nd (n=4) HSCT. Conditioning regimens were myeloablative (n=5) or non-myeloablative (n=21). Remission status at HSCT was composite complete remission (CRc; including CR, CR with incomplete recovery [CRi] and morphologic leukemia free state [MLFS]; 50%), partial remission or stable disease (12%), and refractory (38%). While 22 pts had hematological relapse, 4 pts showed either combined (n=3) or sole (n=1) extramedullary disease. All pts subsequently received HMA/VEN-based therapies (azacitidine/venetoclax [n=22], azacitidne/venetoclax/gilteritinib [n=3] or decitabine/venetoclax [n=1]) with concomitant DLI in 13 pts. Prior to HMA/VEN, 13 pts received a different relapse therapy including azacitidine [n=7], gilteritinib [n=2], radiation [n=1], an investigational therapy with an IRAK4 inhibitor [n=1], or a combination therapy with azacitidine and pevonedistat [n=1] or tagraxofusp [n=1]. European LeukemiaNET 2022 risk at the timepoint of relapse was favorable (n=2), intermediate (n=4) or adverse (n=20). Median follow-up since HMA/VEN start was 6.4 mo. Results: HMA/VEN was well tolerated and administered in an outpatient setting in 20/26 pts (77%). The most common adverse effects were expected and included neutropenia CTCAE 3/4° in 25/26 pts (96%) and thrombocytopenia CTCAE 3/4° in 22/26 pts (85%). Eight pts (31%) developed at least one episode of febrile neutropenia. Four pts (15%) showed signs of afebrile infections and were hospitalized. Thirteen pts (50%) achieved a CRc (CR [n=3], CRi [n=8], MLFS [n=2]) under HMA/VEN therapy (Figure 1A), with a median time to 1st and best morphological response of 1.0 and 2.1 mo, respectively. Later relapse (>12 mo after HSCT) and a lower number of prior therapies before HMA/VEN (≤2 vs. >2 lines) associated with improved outcomes (cumulative incidence of achieving a CRc: P=.004 and P=.04, and OS: P=.02 and P=.02, respectively). Six of 13 pts (46%), who received a prior non-HMA/VEN therapy for the current relapse achieved a CRc after switching to HMA/VEN. Pts achieving a CRc had a significantly longer OS compared to pts with no CRc (P=.002; Figure 1B). Of the pts with CRc, 7 continued HMA/VEN with a median response duration of 7.2 mo (6/7 pts are still on treatment at last follow-up), 5 received a 2nd HSCT and 1 an experimental CART-therapy. For those that could be bridged to a 2nd HSCT outcomes were beneficial with 4/5 pts (80%) alive and disease-free (median follow-up since 2nd HSCT: 4.3 months). One patient with CART-therapy suffered from a 2nd relapse 1.7 months after treatment and is currently again salvaged with HMA/VEN. Two of 13 pts (15%) died after initial CRc, 1 due to non-relapse mortality of a 2nd HSCT and 1 by losing treatment response. Of the 13 pts who did not achieve a CRc, 1 patient could be bridged to 2nd HSCT with a post-HSCT relapse free survival of 12 mo. In the remaining 12 non-CRc pts median OS since start of HMA/VEN was 2.9 mo (range 0.7-6.5 mo) and 9/12 pts (75%) died due to progressive disease. Regarding the molecular risk profile, none of the TP53 mutated pts (n=3) responded, whereas pts with IDH1/2, NPM1, or myelodysplasia-related gene mutations, i.e.ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2, had mixed responses (2/5 pts [40%], 1/3 pts [33%], and 8/15 pts [53%], respectively). Conclusion: HMA/VEN is a promising and well tolerated treatment strategy for MDS and AML pts relapsing after HSCT with a CRc of 50% and potential long-term survival. Especially pts that could be bridged to a 2nd HSCT benefited from the treatment. However, in pts with a disease resistant to HMA/VEN, outcome was very poor with a median OS of only 2.9 mo. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sentinel lymph node mapping in patients with endometrial hyperplasia: A practice to preserve or abandon?

ObjectivesTo compare outcomes of patients with premalignant endometrial pathology undergoing hysterectomy with or without sentinel lymph node (SLN) removal. Outcomes of interest included surgical adverse events (AEs), cancer status on final pathology, postoperative treatment, and The Cancer Genome Atlas (TCGA) molecular risk profiles. MethodsWe retrospectively identified patients with premalignant pathology on preoperative endometrial biopsy who underwent hysterectomy with or without SLN mapping/excision at our institution from 01/01/2017–12/31/2021. Clinical, pathologic, surgical, and TCGA profiling data were abstracted. Appropriate statistical tests were used. ResultsOf 221 patients identified, 161 (73%) underwent hysterectomy with SLN excision and 60 (27%) underwent hysterectomy without SLN excision. Median age and body mass index were similar between groups. Median operative time was 130 min for those who underwent SLN mapping/excision versus 136 min for those who did not (p = 0.6). Thirty-day postoperative AE rates were 9% (n = 15/161) and 13% (n = 8/60), respectively (p = 0.9). Ninety-eight (44%) of 221 patients had grade 1–2 endometrioid endometrial cancer on final pathology (4 [4%] were stage IB or higher). Ten (10%) of 98 patients, all within the SLN group, received adjuvant treatment. Among all patients, of 33 (15%) with TCGA molecular classification data, 27 (82%) had copy number-low, 3 (9%) microsatellite instability-high, 2 (6%) POLE-ultramutated, and 1 (3%) copy number-high disease. ConclusionsSLN assessment appears safe, detects a small number of occult nodal metastases for those upstaged, and provides additional staging information that can guide adjuvant treatment. SLN mapping should be discussed in preoperative counseling and offered using a shared decision-making approach.

Abstract P3-02-02: FES-dedicated breast PET uptake in early-stage ER+ breast cancers

Abstract BACKGROUND: Patients with ER+ breast cancer may have a recurrence risk of aggressive disease. While clinical evidence suggests that ER+ tumors are responsive to endocrine therapy, up to one-third of patients with early-stage ER+ disease may not respond to endocrine therapy. Tumor biologic factors such as ER functionality, cell proliferation, and molecular traits may influence endocrine treatment responsiveness and long-term recurrence risk. More comprehensive tools are needed to depict the primary breast tumor. [18F]fluoroestradiol (FES) is a radiotracer developed for positron emission tomography (PET) imaging of ER status. We used FES with a high-resolution dedicated breast PET (dbPET) to quantify ER expression in primary ER+ tumors and assessed the relationship between FES uptake and tumor characteristics. METHODS: With IRB approval, patients with biopsy-proven ER+/HER2- breast cancer were imaged using dbPET with 5 mCi of FES before treatment. FES uptake (SUVmax, SUVmean, and SUVpeak), background parenchymal uptake (BPU), tumor uptake volume (TUV), and tumor to background ratio (TBR) were calculated. Background values (SUVbkg) were obtained from the normal region of the ipsilateral breast. Lesions with background-corrected SUVmax 2 times higher than SUVbkg were considered FES avid. Tumor size (longest diameter) was measured by MRI. The histologic subtype, ER expression, tumor grade, and Ki67 were obtained from core biopsies before treatment. Ki67 was dichotomized to low and high using a 20% cutoff. Spearman’s rank correlation was used to assess the correlation between FES uptake and tumor size. Differences between FES uptake, histologic subtype, and Ki67 were compared using a Wilcoxon rank-sum test. RESULTS: 19 treatment-naïve patients were included in this analysis as part of an ongoing study. Patient and tumor characteristics are listed in Table 1. While all patients had ER positivity &amp;gt;90% by immunohistochemistry (IHC), we observed varying FES avidity in ER+ breast cancers, with 14 FES avid and 5 non-FES avid lesions. There was a statistically significant difference between FES avid vs. non-avid lesions measured by all uptake metrics except BPU. FES uptake in invasive ductal carcinoma was similar to invasive lobular carcinoma. FES uptake correlated with tumor size, with the highest correlation ρ = 0.58, 95% CI (0.17, 0.84), p=0.012, detected in TUV. FES uptake was associated with Ki67, with all uptake metrics except BPU showing a statistically significant difference between high and low Ki67 expression (Table 2). CONCLUSION: We found that not all lesions that were highly ER+ by IHC were FES avid. FES-dbPET captures information from the entire tumor, providing a more comprehensive assessment of functional ER status than IHC of a limited tumor sample. Moreover, FES uptake correlates with tumor size and cell proliferation. This is an ongoing study; additional data may help to guide endocrine therapy decisions. Future studies with a larger cohort are planned to assess the relationship between FES uptake and tumor grade and molecular risk profiles. Table 1.Patient and tumor characteristicsCharacteristicsNo. of patientsTotal N=19Age (median (IQR))56.0 (21.5)Pre-menopausal7Post-menopausal12Histologic subtypeInvasive ductal carcinoma (IDC)6Invasive lobular carcinoma (ILC)13Tumor size (N=18) (MRI LD (cm), median (IQR))3.2 (4.1)Tumor grade1421332Ki67Low12High6Unknown1FESNon-avid5Avid14 Table 2.Summary of baseline FES uptake valuesTumor Size (cm)FES AvidityHistologic SubtypeKi67Spearman CorrelationAvid vs. Non-avidILC vs. IDCHigh vs. Lowρ (95%CI)P-valueMedian Diff (95%CI)P-valueMedian Diff (95%CI)P-valueMedian Diff (95%CI)P-valueSUVmax0.51 (0.054, 0.79)0.0318.02 (3.55, 11.9)0.0010.187 (-8.04, 6.32)0.976.38 (2.36, 11.6)0.017SUVmean0.31 (-0.18, 0.68)0.2042.42 (1.47, 3.49)0.001-0.477 (-1.96, 1.37)0.571.61 (0.81, 2.77)0.028SUVpeak0.46 (-0.0053, 0.76)0.0533.16 (1.42, 5.2)0.003-0.583 (-3.76, 2.61)0.633.16 (1.32, 4.66)0.013BPU-0.09 (-0.53, 0.39)0.723-0.33 (-1.25, 0.46)0.3790.226 (-0.58, 1.19)0.40-0.49 (-1.49, 0.28)0.122TUV (cm3)0.58 (0.15, 0.82)0.0125.45 (1.09, 12.5)0.005-2.82 (-12.5, 4.06)0.405.9 (0.98, 12.66)0.021TBR0.5 (0.047, 0.79)0.0333.48 (2.2, 13.5)0.001-0.295 (-11.9, 7.42)0.9010.2 (1.47, 13.49)0.028 Citation Format: Ella F. Jones, Deep K. Hathi, Julissa Molina-Vega, David C. Newitt, Courtney Lawhn-Heath, Kimberly M. Ray, Bonnie N. Joe, Diane Heditsian, Susie Brain, Rita A. Mukhtar, A. Jo Chien, Hope S. Rugo, I-SPY 2 TRIAL Consortium, I-SPY 2 TRIAL Imaging Working Group, Laura J. Esserman, Nola M. Hylton. FES-dedicated breast PET uptake in early-stage ER+ breast cancers [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 P3-02-02.

Abstract P3-02-01: Initial experience of FES-dedicated breast PET imaging of early-stage ER+ invasive lobular carcinoma

Abstract BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer, representing 15% of all invasive breast cancers. Most ILC tumors are estrogen receptor-positive (ER+) and may respond to endocrine therapy. However, tumor biologic factors such as ER functionality, cell proliferation, and molecular traits may influence endocrine treatment response and long-term recurrence risk, thus necessitating a comprehensive approach to characterize the primary breast tumor. [18F]fluoroestradiol (FES) is a radiotracer developed for positron emission tomography (PET) imaging of ER status. For this work, we studied the utility of imaging FES uptake in early-stage primary ER+ ILC lesions, using high-resolution dedicated breast PET (dbPET) to assess the relationship between FES uptake and tumor characteristics. METHODS: With institutional review board approval, patients with biopsy-proven ER+/HER2- ILC were prospectively imaged using dbPET with 5 mCi of FES before treatment. FES uptake (SUVmax, SUVmean, and SUVpeak), tumor uptake volume (TUV), and background parenchymal uptake (BPU) values were calculated. Background values (SUVbkg) were obtained from the normal region of the ipsilateral breast. Lesions with background-corrected SUVmax 2 times higher than SUVbkg were considered FES-avid. Tumor grade, Ki67 cell proliferation index, and ER expression were obtained from core biopsies before treatment. Ki67 was dichotomized to low and high using a 20% cutoff1. Tumor size (longest diameter) was measured by magnetic resonance imaging (MRI). Spearman rank correlation was used to assess the relationship between FES uptake and tumor size. Differences between FES uptake at high and low Ki67 were compared using a Wilcoxon rank-sum test. RESULTS: 13 treatment-naïve ILC patients aged 32-82 years were included in this analysis (Table 1). Despite all lesions exhibiting strongly positive ER expression &amp;gt;90% by immunohistochemistry (IHC), we observed varying FES avidity with 9 FES avid and 4 FES non-avid ILC lesions. SUVmax, TUV, and TBR had substantial median differences between Ki67 high and low lesions (5.9, 4.3, and 9.6, respectively), but the difference did not achieve statistical significance. FES tumor uptake also correlated with tumor size, with the highest correlation observed for SUVpeak (ρ = 0.71 (95% CI: 0.22, 0.91), p=0.010) (Table 2). CONCLUSION: We found that not all highly ER expressing ILC by IHC were FES-avid. As FES-dbPET captures information from the entire tumor, it provides a more comprehensive assessment of functional ER status than IHC of a limited tumor sample. FES uptake in ILC also relates to tumor size and Ki67. This is an ongoing study; additional data may help to guide endocrine therapy decisions. Future studies with a larger cohort are planned to assess the relationship between FES uptake and tumor grade and molecular risk profiles. 1. Acs, B. et al. Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy. Diagn Pathol 12, 20, doi:10.1186/s13000-017-0608-5 (2017). Patient and tumor characteristicsCharacteristicsNumber of patients (Total N=13)Age (median (range))56.0 (32-80)Pre-menopausal3Post-menopausal10MRI tumor size (median (interquartile range)4.1 (2.4-6.8)Tumor grade132931Ki6712Low/High3/9FES13Avid/Non-avid9/4 Summary of FES uptake values and correlation coefficients.FES avidity (N=13)Ki67 (N=12)MRI tumor size (N=12)Avid vs Non-avidHigh vs LowSpearman rank correlationMedian Difference (95% CI)P-valueMedian Difference (95% CI)P-valueSpearman ρ (95% CI)P-valueSUVmax8.68 (2.86, 12)0.0075.9 (-19.5, 11.6)0.140.67 (0.16, 0.9)0.017SUVmean2.56 (1.43, 4.86)0.0071.34 (-4.14, 3.1)0.200.6 (0.042, 0.87)0.039SUVpeak2.86 (1.14, 4.59)0.0112.15 (-14.4, 3.72)0.190.71 (0.22, 0.91)0.01BPU-0.31 (-1.89, 1.02)0.82-0.73 (-2.34, 0.28)0.0960.01 (-0.57, 0.58)0.98TUV (cm3)5.45 (1.04, 10)0.014.3 (-185, 10)0.190.70 (0.21, 0.91)0.011TBR3.61 (2.2, 13)0.0079.57 (-19.6, 12.4)0.0640.66 (0.13, 0.89)0.02 Citation Format: Ella F Jones, Deep K Hathi, Natalia Konovalova, Julissa Molina-Vega, David C Newitt, Courtney Lawhn-Heath, Kimberly M Ray, Bonnie N Joe, Diane Heditsian, Susie Brain, I-SPY 2 TRIAL Imaging Working Group, I-SPY 2 TRIAL Consortium, A. Jo Chien, Laura J Esserman, Nola M Hylton, Rita A Mukhtar. Initial experience of FES-dedicated breast PET imaging of early-stage ER+ invasive lobular carcinoma [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 P3-02-01.

Maintenance Treatment Post-transplant

Disease recurrence is the most common cause of HCT failure in patients with AML,ALL and SMD and factors such as the presence of measurable residual disease before and after transplantation, stage of the disease before transplantation and the cytogenetic and molecular risk profile are factors associated with increased risk of recurrence.

P07.05 Characterization of Clinicopathologic Features and Molecular Recurrence Risk Profiles in Patients with Early-Stage NSCLC

P07.05 Characterization of Clinicopathologic Features and Molecular Recurrence Risk Profiles in Patients with Early-Stage NSCLC

Soluble PD-1 but Not PD-L1 Levels Predict Poor Outcome in Patients with High-Risk Diffuse Large B-Cell Lymphoma.

Simple SummarySoluble forms of checkpoint protein PD-1 and its ligand PD-L1 can be measured from circulation, but their source, function, and clinical impact in cancer remain incompletely understood. In this study, we used serum samples collected during a conduction of a prospective immunochemotherapy trial in patients with high-risk diffuse large B-cell lymphoma (DLBCL) and assessed their clinical significance. Our results demonstrate that sPD-1 levels in the peripheral blood at the time of diagnosis correlate with the quantities of tumor infiltrating PD1+ T cells and translate to inferior survival. To our knowledge, this is the first study to identify sPD-1 as a prognostic factor, providing interesting perspectives on future clinical trials in DLBCL, including patients’ stratification associated with checkpoint blockade.Interaction of checkpoint receptor programmed death 1 (PD-1) with its ligand 1 (PD-L1) downregulates T cell effector functions and thereby leads to tumor immune escape. Here, we aimed to determine the clinical significance of soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) in patients with diffuse large B-cell lymphoma (DLBCL). We included 121 high-risk DLBCL patients treated in the Nordic NLG-LBC-05 trial with dose-dense immunochemotherapy. sPD-1 and sPD-L1 levels were measured from serum samples collected prior to treatment, after three immunochemotherapy courses, and at the end of therapy. sPD-1 and sPD-L1 levels were the highest in pretreatment samples, declining after three courses, and remaining low post-treatment. Pretreatment sPD-1 levels correlated with the quantities of PD1+ T cells in tumor tissue and translated to inferior survival, while no correlation was observed between sPD-L1 levels and outcome. The relative risk of death was 2.9-fold (95% CI 1.12–7.75, p = 0.028) and the risk of progression was 2.8-fold (95% CI 1.16–6.56, p = 0.021) in patients with high pretreatment sPD-1 levels compared to those with low levels. In conclusion, pretreatment sPD-1 level is a predictor of poor outcome after dose-dense immunochemotherapy and may be helpful in further improving molecular risk profiles in DLBCL.

Poor Treatment Outcomes of Young (

Poor Treatment Outcomes of Young (<60 Years) African American Patients (Pts) Diagnosed with Acute Myeloid Leukemia (AML) (Alliance)

Evaluation of Tagraxofusp (SL-401) Alone and in Combination with Ruxolitinib for the Treatment of Myeloproliferative Neoplasms

Background: The introduction of the JAK1/2 inhibitor Ruxolitinib has resulted in significant benefits for patients with Myelofibrosis (MF) and Polycythemia Vera, including reduction of splenomegaly and improvement in symptom burden. However, Ruxolitinib has limited ability to alter the natural history and biology of disease in myeloproliferative neoplasms (MPNs). More importantly, patients often lose response to ruxolitinib or suffer disease progression despite therapy with ruxolitinib. These observations have prompted efforts to introduce novel therapeutic approaches and devise novel combinatorial treatment strategies to improve the outcomes of patients with MPNs. CD123 (interleukin-3 receptor-a; IL-3R-a) has been identified as a therapeutic target in several myeloid malignancies. CD123 is expressed in a variety of myeloid malignancies, including AML, myelodysplastic syndrome (MDS) and CMML. Further, Tagraxofusp (ELZONRIS®, SL-401), a targeted therapy directed to CD123 comprised of recombinant IL-3 fused to a truncated diphtheria toxin payload, was recently FDA approved for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). In an ongoing Phase 1/2 trial, Tagraxofusp has demonstrated single agent clinical activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF. Thus, Tagraxofusp appears to have activity in MF. However, the utility of Tagraxofusp in more advanced forms of MPN (such as accelerated phase MPN), as well as the utility of combination Ruxolitinib and Tagraxofusp, have not been evaluated to date. To address these questions, we first evaluated CD123 expression using flow cytometry analysis of peripheral blood samples from patients with MF with progression to accelerated-phase (&gt;10%) or blast-phase (&gt;20%) disease. CD123 expression was generally noted to be higher than that observed in normal control samples, by mean florescence intensity (Figure 1A). We next sought to determine the effect of treatment with Tagraxofusp alone and in combination with Ruxolitinib in leukemia cell lines and primary patient samples. We performed cell viability assays using the JAK2V617F mutant cell line UKE1. We first determined the IC50 of Tagraxofusp in UKE1 cells (range 2.95-3.57nM). Using this data, we then tested the impact of the addition of Tagraxofusp to Ruxolitinib on UKE1 cell viability using a fixed concentration of Tagraxofusp (5nM). The IC50 of range of single agent Ruxolitinib was 44.42-70.93nM. However, the addition of Tagraxofusp to Ruxolitinib resulted in a decrease of the IC50 range to 11.72-21.6nM, indicating an effect of combination therapy (Figure 1B). We then determined the impact of Tagraxofusp both alone and in combination with Ruxolitinib using primary patient MPN peripheral blood mononuclear cells in methylcellulose. Patient characteristics are described in Table 1. In most samples, CD123 expression was confirmed. In all samples studied, Tagraxofusp was able to significantly reduce colony formation when compared to vehicle, at a dose range of 2.5nM to 20nM. Notably, this includes two samples (151, 455) from patients with accelerated-phase disease. As well, Tagraxofusp demonstrated activity across genotypes, including in cases with TP53 and ASXL1 mutations. A reduction in colony formation in samples treated with combination Ruxolitinib and Tagraxofusp beyond that observed with either agent alone was observed in several cases (Figure 1C). Conclusions: Current therapeutic options for patients with MF beyond Ruxolitinib are limited. This is particularly the case for patients with progression to accelerated and blast-phase MPN. Here, we demonstrate that CD123 expression is evident in many such cases. Further, therapeutic targeting of CD123 using Tagraxofusp either alone or in combination with Ruxolitinib has activity in primary patient samples, including those in accelerated-phase and with high molecular risk profiles. These data thus support further testing of Tagraxofusp in MPNs, and in advanced MPNs in particular. Disclosures Roshal: Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents &amp; Royalties. Levine:Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Prelude Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Amgen: Honoraria; Roche: Consultancy, Research Funding. Rampal:Constellation, Incyte, and Stemline Therapeutics: Research Funding; Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy.

Disparities in survival by insurance status in chronic lymphocytic leukemia.

e18134 Background: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in western world. It is the disease of older adults with a median age at diagnosis of approximately 70 years. However, significant proportion of younger adults are diagnosed with CLL and they usually have an adverse clinical and molecular risk profile necessitating early interventional strategies compared to older patients. Socioeconomic disparities may affect survival for some patient populations. This study examined survival by insurance status for younger patients with CLL. Methods: The Surveillance, Epidemiology, and End Results database was used to identify patients, aged 15 - 64 years, who were diagnosed with CLL between 2007 and 2014 and whose insurance status (no insurance, Medicaid, and other insurance) was documented at diagnosis. Unadjusted associations between insurance status and overall survival (OS) were plotted using Kaplan-Meier curves. The association between insurance status and CLL-specific mortality was assessed using multivariate Cox proportional hazards regression models, adjusting for sociodemographic covariates. Results: A total of 10,913 patients with CLL were included with a median follow up of 44 months. Five-year survival estimates were 87.3%, 87.2%, and 94.0% for patients with no insurance, Medicaid, and other insurance, respectively. In multivariate analysis, compared to patients with other insurance, patients with no insurance (hazard ratio [HR] = 2.33, 95% confidence interval [CI] = 1.73 – 3.140) and Medicaid (HR = 1.95, 95% CI = 1.49 – 2.54) had significantly worse OS survival after adjusting for sociodemographic factors. Conclusions: Younger patients with no insurance or Medicaid have lower survival outcomes after diagnosis with CLL compared to patients with other insurance. Addressing barriers to care, providing resources, and expanding access to care is paramount to reducing the gap in survival for the uninsured patients and those with lower socioeconomic status. Further studies are needed to address poor survival outcomes among Medicaid patients.

Molecular characterization of endometrial cancer and therapeutic implications.

The present article reviews genomic subtyping of endometrial carcinoma and new molecular markers with therapeutic and prognostic implications. Endometrial cancer has historically been classified through histology into endometrioid (type 1) and nonendometrioid (type II, mainly serous) subtypes. Molecular classification through genomic analysis now allows for a major advance in characterization; four distinct subgroups have been identified: polymerase ε (POLE) ultramutated, microsatellite unstable, copy number low/microsatellite stable, and copy number high/'serous-like'. These subtypes have prognostic implications and may aid in the identification of early-stage patients who are at high risk for recurrence. Through analysis of surrogate markers (POLE, MSI, and p53) and other validated molecular alterations (L1CAM), it may be possible to obtain an integrated molecular risk profile. Ongoing studies are utilizing this risk profile in order to identify patients who may benefit from additional treatment for early-stage disease. Molecular characterization of endometrial cancer into subgroups has prognostic and therapeutic implications. Further development of an integrated molecular risk profile may identify patients who could benefit from additional treatment because of a higher risk of recurrence.

L1CAM further stratifies endometrial carcinoma patients with no specific molecular risk profile

BackgroundThe newly developed Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) has consistently been shown to be prognostically significant in endometrial carcinomas (EC). Recently, we and others have demonstrated L1 cell-adhesion molecule (L1CAM) to be a significant indicator of high-risk disease in EC. In the current study, it was our aim to determine the prognostic significance of aberrant L1CAM expression in ProMisE subgroups in a large, single centre, population-based EC cohort.MethodsProMisE (POLE; MMR-D; p53 wt/NSMP; p53 abn) classification results from a cohort of 452 EC were available for analysis. L1CAM expression was studied by immunohistochemistry on whole slides. Correlations between clinicopathological data and survival were calculated.ResultsExpression of L1CAM was most frequent in p53 abnormal tumours (80%). L1CAM status was predictive of worse outcome among tumours with no specific molecular profile (p53 wt/NSMP) (p < 0.0001). Among p53 wt/NSMP EC, L1CAM remained a significant prognosticator for disease-specific survival after multivariate analysis (p = 0.035).ConclusionL1CAM status was able to significantly stratify risk among tumours of the large p53 wt/NSMP ProMisE subgroup of EC. Furthermore, our study confirms a highly significant correlation between mutation-type p53 immunostaining and abnormal L1CAM expression in EC.

Risk of high-grade serous ovarian cancer associated with pelvic inflammatory disease, parity and breast cancer

BackgroundOvarian carcinoma is not a single disease, but rather a collection of subtypes with differing molecular properties and risk profiles. The most common of these, and the subject of this work, is high-grade serous ovarian carcinoma (HGSC). MethodsIn this population-based study we identified a cohort of 441,382 women resident in Western Australia who had ever been admitted to hospital in the State. Of these, 454 were diagnosed with HGSC. We used Cox regression to derive hazard ratios (HRs) comparing the risk of disease in women who had each of a range of medical diagnoses and surgical procedures with women who did not. ResultsWe found an increased risk of HGSC associated with a diagnosis of pelvic inflammatory disease (PID) (HR 1.47, 95% CI 1.04–2.07) but not with a diagnosis of infertility or endometriosis with HRs of 1.12 (95% CI 0.73–1.71) and 0.82 (95% CI 0.55–1.22) respectively. A personal history of breast cancer was associated with a three-fold increase in the rate of HGSC. Increased parity was associated with a reduced risk of HGSC in women without a personal history of breast cancer (HR 0.57; 95% CI 0.44-0.73), but not in women with a personal history of breast cancer (HR 1.48; 95% CI 0.74–2.95). ConclusionsOur finding of an increased risk of HGSC associated with PID lends support to the hypothesis that inflammatory processes may be involved in the etiology of HGSC.

Using omics to explore complications of kidney transplantation.

The importance of genetic and biochemical variation in renal transplant outcomes has been clear since the discovery of the HLA in the 1950s. Since that time, there have been huge advancements in both transplantation and omics. In recent years, there has seen an increased number of genome-, proteome- and transcriptome-wide studies in the field of transplantation moving away from the earlier candidate gene/protein approaches. These areas have the potential to lead to the development of personalized treatment depending on individual molecular risk profiles. Here, we discuss recent progress and the current literature surrounding omics and renal transplant complications.

Abstract 5722: Serum Sonic hedgehog (Shh) and interleukin-(IL-6) as dual prognostic biomarkers in progressive metastatic breast cancer

Abstract Objectives: Breast cancer (BC) still remains the leading cause of mortality in women worldwide despite substantial developments in diagnosis and therapeutic interventions. Several factors, i.e. different molecular subtypes, biological behaviors, and risk profiles still pose a challenge for prognostication and clinical management. Traditional prognostic and treatment options for BC patients are largely based on careful histological analysis of tumor size, tumor grade, lymph node metastasis and tumor subtypes. Molecular mechanisms play critical roles in developing tumors as well as early and late stage tumor progression of metastatic disease. It is not surprising that many genes are shared amongst the various gene signatures and may have a similar performance in survival risk assessment of the BC patients. Given the production of Shh and IL-6 in the breast tumor microenvironment, we hypothesized that Shh and IL-6 might be detectable in the general circulation. If positive, then it would be clinically useful to identify whether robust expression of serum Shh and IL-6 is correlated with BC prognosis, distant metastasis, lymph node positivity, multidrug resistance as well as self-renewal and maintenance of BC stem cells. We evaluated relative clinical outcome of Shh and IL-6 in the serum from a cohort of patients with untreated early operable and progressive metastatic BC. Patients and Methods: One hundred and ten breast cancer patients and 30 healthy female volunteers, enrolled in this study and, were evaluated for serum levels of Shh and IL-6 using human ShhN and IL-6 specific enzyme-linked immunoassays. All patients were regularly monitored for event free survival (EFS) and overall survival (OS). Results: Overall outcome analysis was based on serum Shh and IL-6 levels from 45 early operable and 65 progressive metastatic BC patients. In patients with progressive metastatic BC, serum Shh was elevated in 44% (29 of 65) and IL-6 in 63% (41 of 65). Serum Shh (p=0.0001) and IL-6 (p=0.0001) levels were significantly elevated in BC patients compared to low levels in healthy volunteers, and tended to increase with metastatic progression and lymph node positivity. High serum Shh and IL-6 levels were associated with inferior EFS and OS opposite to negative or lower levels of serum Shh and IL-6. Elevated levels of both serum Shh and IL-6 were mainly observed in hormone refractory BC patients, who had a significantly higher risk of early recurrence, bone metastasis and death. Conclusion: Elevated levels of serum Shh and IL-6 are associated with increased risk of recurrence and a worse survival for patients with progressive metastatic BC. Further studies are warranted for validating these biomarkers as prognostic and predictive therapeutic tools in a larger patients cohort. Citation Format: Sonam Akther, Abu Shadat M. Noman, Junayed Nayeem, Zaheer Raihan, Irfanur Rashid, Lutfur Rahman, David Barua, Afrin Sultana, Afsana Shirin, Jannatul Ferdous, Rashed Parag, Mizanur Rahman, Reaz Mahmud, Chandsultana Jerin, Nusrat Jahan, Ayesha Siddiqua, Emran Sabur, Sabrina Alam, Sunanda Baidya, Saiful M. Islam, Syed S. Islam. Serum Sonic hedgehog (Shh) and interleukin-(IL-6) as dual prognostic biomarkers in progressive metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5722. doi:10.1158/1538-7445.AM2017-5722