Predictor Of Shorter Progression-free Survival Research Articles

Abstract PO3-13-05: PD-L1 and PD-L2 Protein Expression is Frequently Discordant in Breast Cancer

Abstract Background: In neoadjuvant setting, PD-1 inhibitors have shown significantly higher pathological responses in patients (pts) with early-stage triple-negative breast cancer (TNBC) irrespective of PD-L1 status. However, durable responses are less common in estrogen receptor-positive (ER+) pts. Most breast cancer (BC) clinical trials of PD-1 inhibitors have thus far focused on PD-L1 expression for patient eligibility. The alternative PD-1 ligand, PD-L2, with reported ~4-fold greater affinity for PD-1, has been largely understudied. We recently reported that high cancer cell protein levels of PD-L2 in pts with treatment-naïve ER+ BC was an independent predictor of shorter progression-free survival. PD-L2 expression was significantly high in ER- group as well, however, given the low numbers of ER- pts, the study was not powered enough to determine the correlation of PD-L2 with PFS in the ER- subgroup. These findings suggest that PD-L2 has an important role in BC and combined PD-L1/PD-L2 status may help improve BC pt selection for PD-1 inhibitors. We therefore initiated efforts to determine baseline expression patterns of PD-L1 and PD-L2 in BC. Methods: PD-L1 and PD-L2 protein levels in cancer cells and tumor-infiltrating immune cells were prospectively analyzed by immunohistochemistry (IHC) using validated antibodies in diagnostic core biopsies of 31 consecutive pts diagnosed with localized or locoregional ER+/HER2- BC or TNBC. Percent positivity of PD-L1 and PD-L2 in cancer cells and immune cells was determined by our breast pathologist. Detectable PD-L1 or PD-L2 expression in ≥1% of cancer cells or stromal immune cells was considered positive. Spearman correlation and Wilcoxon paired analyses were used to measure and correlate PD-L1 and PD-L2 protein expression in cancer and immune cells. Results: There was no significant correlation between PD-L1 and PD-L2 expression, neither across all cases (N=31), nor within ER+ (N=22) or TNBC (N=9) cases. However, PD-L1 and PD-L2 expression patterns in BC differed in several ways. PD-L1-positivity in immune cells was higher than in cancer cells (median=5.0% vs. 0.0%; p=0.001), whereas PD-L2-positivity was higher in cancer cells than in immune cells (median=30% vs. 5.0%; p< 0.001). PD-L1 positivity in cancer cells and immune cells were positively correlated in TNBC (rho=0.69, p=0.04) but not in ER+ BC. Conversely, PD-L2 positivity in cancer cells and immune cells were positively correlated in ER+ BC (rho=0.68, p=0.001) but not in TNBC. TNBC diverged from ER+ BC by displaying higher PD-L1 positivity in immune cells (median=20.0% vs. 1.0%; p=0.004). By the conventional cut point for positivity of ≥1% for PD-L1 and PD-L2 in cancer cells or immune cells, all TNBC tumors were PD-L1-positive (9/9), with 8 also being PD-L2-positive. Of the 22 ER+ cases, 16 were PD-L2-positive, of which only 9 were also PD-L1-positive. Table 1. shows cross tabulation data for PD-L1 and PD-L2 status by BC subtype. Conclusions: PD-L1 and PD-L2 proteins show divergent expression and are not correlated in BC. Discordant PD-L2 and PD-L1 expression may be more common in ER+ BC than in TNBC. This finding justifies efforts to explore PD-L2 as a complementary marker to PD-L1 for improved prediction of response to PD-1 inhibitors, which may benefit patients with aggressive ER+ BC that are eligible for chemotherapy. Table 1. PD-L1 vs. PD-L2 Status by Breast Cancer Subtype Citation Format: Lubna Chaudhary, Julie Jorns, Yunguang Sun, Sailaja Kamaraju, Yee Chung Cheng, Amanda Kong, Tina Yen, Caitlin Patten, Chandler Cortina, Inna Chervoneva, Christopher Chitambar, Hallgeir Rui. PD-L1 and PD-L2 Protein Expression is Frequently Discordant in Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-05.

Impact of Genomic Alterations on Efficacy of Trastuzumab Deruxtecan Against Human Epidermal Growth Factor Receptor-2-Positive Advanced Gastric Cancer.

The impact of genomic alterations on response and resistance to trastuzumab deruxtecan (T-DXd) has not been elucidated. Thus, we sought to identify factors predicting sensitivity to T-DXd in gastric or gastroesophageal junction (G/GEJ) cancer. We conducted a retrospective study using real-world clinical data and next-generation sequencing-based comprehensive genomic profiling (CGP) data from patients with advanced G/GEJ cancers, collected by the nationwide database in Japan. We analyzed the associations between genomic alterations and the patients' survivals after T-DXd treatment. In 114 patients with human epidermal growth factor receptor-2 (HER2)-positive G/GEJ cancer treated with T-DXd, the most frequently altered genes were TP53 (82%), ERBB2 (80%), and CCNE1 (36%). Multivariate Cox regression analysis revealed CCNE1 amplification to be a significant predictor of shorter progression-free survival (PFS) after T-DXd treatment among 91 patients whose CGP samples were obtained before T-DXd (median PFS, 131 days v 189 days; hazard ratio [HR], 1.90 [95% CI, 1.02 to 3.53]; P = .044). Analyses of 1,450 G/GEJ cancers revealed significant CCNE1/ERBB2 coamplification (41% relative to 11% CCNE1 amplification in ERBB2-nonamplified tumors; P < .0001). ERBB2-activating mutations were also detected in 3.7% of G/GEJ cancers and in 8.8% of HER2-positive G/GEJ cancers treated with T-DXd. Patients with ERBB2-mutated tumors showed shorter PFS than those without ERBB2 mutations after T-DXd treatment (mPFS, 105 v 180 days; P = .046). CCNE1 amplification may confer primary resistance to T-DXd in HER2-positive G/GEJ cancer, suggesting that the cell cycle could be a potential therapeutic target in CCNE1/ERBB2 coamplified tumors. ERBB2-activating mutation may also attenuate T-DXd efficacy in HER2-positive G/GEJ cancer.

B-cell receptor signaling activity identifies patients with mantle cell lymphoma at higher risk of progression

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy characterized by a high clinical variability. Therefore, there is a critical need to define parameters that identify high-risk patients for aggressive disease and therapy resistance. B-cell receptor (BCR) signaling is crucial for MCL initiation and progression and is a target for therapeutic intervention. We interrogated BCR signaling proteins (SYK, LCK, BTK, PLCγ2, p38, AKT, NF-κB p65, and STAT5) in 30 primary MCL samples using phospho-specific flow cytometry. Anti-IgM modulation induced heterogeneous BCR signaling responses among samples allowing the identification of two clusters with differential responses. The cluster with higher response was associated with shorter progression free survival (PFS) and overall survival (OS). Moreover, higher constitutive AKT activity was predictive of inferior response to the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib. Time-to-event analyses showed that MCL international prognostic index (MIPI) high-risk category and higher STAT5 response were predictors of shorter PFS and OS whilst MIPI high-risk category and high SYK response predicted shorter OS. In conclusion, we identified BCR signaling properties associated with poor clinical outcome and resistance to ibrutinib, thus highlighting the prognostic and predictive significance of BCR activity and advancing our understanding of signaling heterogeneity underlying clinical behavior of MCL.

Intramedullary Spinal Cord Tumors: Whole-Genome Sequencing to Assist Management and Prognosis.

Intramedullary spinal cord tumors (IMSCTs) harbor unique genetic mutations which may play a role in prognostication and management. To this end, we present the largest cohort of IMSCTs with genetic characterization in the literature from our multi-site institutional registry. A total of 93 IMSCT patient records were reviewed from the years 1999 to 2020. Out of these, 61 complied with all inclusion criteria, 14 of these patients had undergone genetic studies with 8 undergoing whole-genomic sequencing. Univariate analyses were used to assess any factors associated with progression-free survival (PFS) using the Cox proportional hazards model. Firth's penalized likelihood approach was used to account for the low event rates. Fisher's exact test was performed to compare whole-genome analyses and specific gene mutations with progression. PFS (months) was given as a hazard ratio. Only the absence of copy neutral loss of heterozygosity (LOH) was shown to be significant (0.05, p = 0.008). Additionally, higher risk of recurrence/progression was associated with LOH (p = 0.0179). Our results suggest LOH as a genetic predictor of shorter progression-free survival, particularly within ependymoma and glioblastoma tumor types. Further genomic research with larger multi-institutional datasets should focus on these mutations as possible prognostic factors.

Prognostic impact of pretreatment cell-free DNA concentration in newly diagnosed peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) have a poor prognosis and, to date, there are no reliable predictive biomarkers of response. In this work we explored the prognostic impact of cell-free DNA (cfDNA) concentration in 75 newly diagnosed patients enrolled in a prospective multicenter study. Pre-treatment cfDNA was strongly associated with clinical risk factors and was identified as a superior predictor for shorter progression-free survival in multivariable analysis, outweighing canonical risk parameters. Furthermore, we identified a cfDNA value above which survival worsens. In conclusion, pre-treatment cfDNA concentration represents an easily usable predictive biomarker that is highly associated with survival of PTCL patients.

Comprehensive ctDNA Measurements Improve Prediction of Clinical Outcomes and Enable Dynamic Tracking of Disease Progression in Advanced Pancreatic Cancer.

Circulating tumor DNA (ctDNA) has emerged as a promising tumor-specific biomarker in pancreatic cancer, but current evidence of the clinical potential of ctDNA is limited. In this study, we used comprehensive detection methodology to explore the utility of longitudinal ctDNA measurements in patients with advanced pancreatic cancer. A targeted eight-gene next-generation sequencing panel was used to detect point mutations and copy-number aberrations (CNA) in ctDNA from 324 pre-treatment and longitudinal plasma samples obtained from 56 patients with advanced pancreatic cancer. The benefit of ctDNA measurements to predict clinical outcome and track disease progression was assessed. We detected ctDNA in 35/56 (63%) patients at baseline and found that it was an independent predictor of shorter progression-free survival (PFS) and overall survival (OS). After initiation of treatment, ctDNA levels decreased significantly before significantly increasing by the time of progression. In some patients, ctDNA persistence was observed after the first chemotherapy cycles, and it was associated with rapid disease progression and shorter OS. Longitudinal monitoring of ctDNA levels in 27 patients for whom multiple samples were available detected progression in 19 (70%) patients. The median lead time of ctDNA measurements on radiologically determined progression/time of death was 19 days (P = 0.002), compared with 6 days (P = 0.007) using carbohydrate antigen 19-9. ctDNA is an independent prognostic marker that can be used to detect treatment failure and disease progression in patients with advanced pancreatic cancer.

Immunological markers for predicting the response to immunotherapy in non-small cell lung cancer

Itroduction. Immune checkpoint inhibitors have become the standard of care for patients with advanced non-small cell lung cancer. However, despite the determination of programmed death-ligand 1 expression in clinical practice, which determines the effectiveness of therapy, up to 80 % of patients with non-small cell lung cancer do not respond to treatment.The study objective – investigation of the prognostic role of clinical and immunological markers during immune checkpoint inhibitor monotherapy in ≥2 lines in patients with advanced non-small cell lung cancer.Materials and methods. The study included 45 patients with advanced non-small cell lung cancer receiving programmed cell death 1 / programmed death-ligand 1 inhibitors in monotherapy in 2 and subsequent lines (Group 1), as well as 30 patients with advanced non-small cell lung cancer receiving first-line chemotherapy (Group 2). All patients from 2 groups did not have autoimmune diseases before starting treatment. The determination of autoantibodies, β-2-microglobulin, neopterin, interleukin 6, interleukin 18 and the allelic variant of HLA-DRB1 in patients in the Group 1 was carried out 2 months after the start of therapy, and in the Group 2 – before the start of the next chemotherapy cycle.Results. In Group 1, the presence of EGFR / ALK mutations is an independent predictor of shorter progression-free survival (p = 0.018). Also, in the univariate analysis, neutrophil-lymphocyte ratio &lt;5 before immune checkpoint inhibitors (p = 0.009) and the appearance of immune-related adverse events (p = 0.038) are associated with long-term progressionfree survival. In Group 1, β-2-microglobulin was lower in patients with a response duration of ≥6 months than with a progression &lt;6 months: 1.7 mg / L and 2.9 mg / L, respectively (p &lt;0.0001). Patients receiving immune checkpoint inhibitors with a β-2-microglobulin level ≥2.5 mg / L have a shorter progression-free survival than patients with a marker value &lt;2.5 mg / L: 168 days and the value is not reached, respectively (p = 0.017). In response duration ≥6 months neopterin value was lower than in disease progression: 8.6 nmol / l and 13.4 nmol / L, respectively (p &lt;0,0001). Progression-free survival was lower in patients with neopterin ≥12 nmol / L than patients with neopterin &lt;12 nmol / L: median was 164 days and the value was not reached, respectively (p = 0.0007). Based on the results of multivariate analysis, β-2-microglobulin ≥2.5 mg / L (p = 0.006) and neopterin ≥12 nmol / L (p = 0.027) were independent predictors of shorter progression-free survival. Low levels of interleukin 6 and interleukin 18, as well as antibodies to thyroperoxidase, are associated with a response of ≥6 months. HLA-DRB1*03 was associated with a duration of response of ≥6 months, as well as a longer progression-free survival compared with other allelic variants. The levels of β-2-microglobulin, neopterin, interleukin 6, interleukin 18 were higher in patients in Group 1 than in patients in Group 2 (p &lt;0.0001).Conclusion. Immunological markers can serve as promising prognosis markers in patients with advanced non-small cell lung cancer during immunotherapy.

Expression and Prognostic Value of B7 Family Immune Checkpoints in Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare malignancies with heterogeneous clinical courses requiring novel prognosticators and therapies. B7 family molecules have an important role in various cancers; however, these have not been distinguished in PanNETs. To investigate the expression and clinical significance of programmed death ligand-1 (PD-L1), programmed death ligand-2 (PD-L2), B7 homolog 3 (B7-H3), B7 homolog 4 (B7-H4), and V-domain immunoglobulin suppressor of T-cell activation (VISTA) in 182 PanNETs (with a high proportion of functioning versus nonfunctioning PanNETs: 51% versus 49%). Molecules were immunostained by using tissue microarrays from 182 patients with grade 1/2 PanNETs. VISTA-positive microvessel density (VISTA+ MVD) was evaluated in 4 high-power fields (HPFs) (×200) and mean count was calculated; immune cells with 1% or greater VISTA staining were considered positive. PD-L1 tumoral expression was considered positive in samples with 5% or more membranous staining. Tumoral VISTA, stromal PD-L1, PD-L2, B7-H3, and B7-H4 expression were deemed positive if any staining was observed. VISTA+ MVD was high (≥10.8/HPF) in 45 patients (25%), while VISTA stained positively on immune and tumor cells in 121 (66%) and 0 patients, respectively. Positive PD-L1 tumoral and stromal expression was observed in 23 (13%) and 0 patients, with positive B7-H3 expression in 76 (42%) and 98 (54%) patients, respectively, in these cells; PD-L2 and B7-H4 were not detected. PD-L1 positivity rate was high in functioning PanNETs. Stromal B7-H3 and high VISTA+ MVD correlated with unfavorable clinicopathologic features. Moreover, high VISTA+ MVD was an independent predictor of shorter progression-free survival. VISTA may serve as a prognosticator and immunotherapeutic target for patients with pancreatic neuroendocrine tumor (PanNET).

Clinical factors and conventional MRI may independently predict progression-free survival and overall survival in adult pilocytic astrocytomas.

Pilocytic astrocytoma (PA) is rare in adults, and only limited knowledge on the clinical course and prognosis has been available. The combination of clinical information and comprehensive imaging parameters could be used for accurate prognostic stratification in adult PA patients. This study was conducted to predict the prognostic factors from clinical information and conventional magnetic resonance imaging (MRI) features in adult PAs. A total of 56 adult PA patients were enrolled in the institutional cohort. Clinical characteristics including age, sex, anaplastic PA, presence of neurofibromatosis type 1, Karnofsky performance status, extent of resection, and postoperative treatment were collected. MRI characteristics including major axis length, tumor location, presence of the typical 'cystic mass with enhancing mural nodule appearance', proportion of enhancing tumor, the proportion of edema, conspicuity of the nonenhancing margin, and presence of a cyst were evaluated. Univariable and multivariable Cox proportional hazard modeling were performed. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 83.9% and 91.l%, respectively. On univariable analysis, older age, larger proportion of edema, and poor definition of nonenhancing margin were predictors of shorter PFS and OS, respectively (all Ps < .05). On multivariable analysis, older age (hazard ratio [HR] = 1.04, P = .014; HR = 1.14, P = .030) and poor definition of nonenhancing margin (HR = 3.66, P = .027; HR = 24.30, P = .024) were independent variables for shorter PFS and OS, respectively. Age and the margin of the nonenhancing part of the tumor may be useful biomarkers for predicting the outcome in adultPAs.

The impact of increasing karyotypic complexity and evolution on survival in patients with CLL treated with ibrutinib

AbstractComplex karyotype, defined as ≥3 cytogenetic abnormalities, is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (ie, ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti–CD20 antibody at our institution. We included 456 patients with both treatment-naive and RR disease. Median number of prior therapies was 2 (range, 0-13), 30% of patients had presence of del(17p), and 75% expressed unmutated IGHV. Fifty percent had ≥3 cytogenetic abnormalities, including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (hazard ratio, 1.07; 95% confidence interval, 1.04-1.10; P < .0001) and overall survival (hazard ratio, 1.09; 95% confidence interval, 1.05-1.12; P < .0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (P = .02). This solidifies karyotypic complexity as an important prognostic factor for patients with CLL treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.

Progression-free survival in patients with 68Ga-PSMA-PET-directed SBRT for lymph node oligometastases

Background Prostate cancer oligometastatic disease can be treated using stereotactic body radiotherapy (SBRT) in order to postpone start of systemic treatments such as androgen deprivation therapy (ADT). 68Ga-PSMA-PET/CT imaging allows for diagnosis of oligometastases at lower PSA values. We analysed a cohort of patients with prostate cancer lymph node oligometastases detected on PSMA-PET/CT. Materials and methods Ninety patients with metachronous oligometastatic prostate cancer received SBRT for 1–3 lymph node metastases diagnosed on 68Ga-PSMA-PET/CT. The primary end point was progression free survival (PFS), with disease progression defined as occurrence of either target lesion progression, new metastatic lesion or biochemical progression. Secondary outcomes were biochemical PFS (BPFS), ADT-free survival (ADT-FS), toxicity and quality of life (QoL). Baseline patient characteristics were tested for association with PFS and a preliminary risk score was created. Results Median follow-up was 21 months (interquartile range 10–31 months). Median PFS and BPFS were 16 and 21 months, respectively. Median ADT-FS was not reached (73% (95%-CI 62–86%) at 24 months). In multivariable analysis, younger age, higher PSA prior to SBRT and extrapelvic location were associated with shorter PFS. Grade 1 fatigue was the most predominant acute toxicity (34%). Highest grade toxicity was grade 2 for acute and late events. QoL analysis showed mild, transient increase in fatigue at 1–4 weeks after SBRT. Conclusion A median PFS of 16 months was attained after SBRT for patients with PSMA-PET positive oligometastatic lymph nodes from prostate cancer. Higher pre-SBRT PSA, younger age and extrapelvic location were found to be predictors of shorter PFS.

Endometrial endometrioid carcinoma, grade 1, is more aggressive in the elderly than in the young

The aim of this study was to characterize endometrioid carcinoma, G1, in the elderly, using clinicopathological features and immunohistochemical features of surrogate markers of molecular subtypes. We retrospectively analyzed tumour samples from 268 patients with endometrioid carcinoma, G1 (<40 years: n=24, 40-59 years: n=169, ≥60 years: n=75), for whom long-term clinical follow-up data were available. Endometrioid carcinoma, G1, in the elderly (≥60 years) was characterized by frequent deep myometrial invasion, less frequent endometrioid intraepithelial neoplasia (EIN), lack of benign hyperplasia (BH), less frequent squamous differentiation and occasional aberrant p53 expression. In contrast, this condition in the young (<40 years) was characterized by frequent EIN, BH, and squamous differentiation. Univariate analysis revealed that an elderly status (≥60 years), International Federation of Obstetrics and Gynecology (FIGO) 2009 stage, and aberrant p53 expression were significantly associated with shorter progression-free survival, while multivariate analysis revealed that an elderly status and FIGO 2009 stage were independent poor prognostic factors. Endometrioid carcinoma, G1, in the elderly is more aggressive than that in the young, and an elderly status is an independent predictor of shorter progression-free survival in this condition. We propose that type 1 tumours can be subdivided into types 1a (young onset and indolent) and 1b (old onset and relatively aggressive).

Antibiotic use reduces efficacy of tyrosine kinase inhibitors in patients with advanced melanoma and non-small cell lung cancer.

3100 Background: Antibiotic (ABX) use and disruption of the gut microbiome has been demonstrated to reduce the efficacy of immune checkpoint inhibitors and chemotherapeutics in cancer patients. Little is known about the impact of ABX use in patients treated with targeted therapies, such as tyrosine kinase inhibitors (TKI). Methods: Retrospective data analysis was performed on advanced melanoma and non-small cell lung cancer (NSCLC) patients treated with TKIs between January 2015 and April 2017 at The Christie NHS Foundation Trust, UK. Demographics, prior systemic treatment, extent of disease, lactate dehydrogenase level (LDH), presence of brain metastases, performance status, comorbidities, TKI agent and the use of ABX (class, route, duration) were collected. Progression free survival (PFS) and overall survival (OS) were compared between the ABX+ group (defined as patients treated with ABX within 2 weeks of TKI initiation or 6 weeks after) and the ABX – group (patients with no ABX during specified period). Statistical analyses were performed with univariate and multivariable models. Results: In total, 168 patients were included; 89 patients (53%) with advanced NSCLC and 79 patients (47%) with melanoma. Over a third of patients, (57/168, 34%) received ABX in the specified period (ABX+). On univariable analysis, ABX use was associated with shorter PFS (208 days vs 357 days, p = 0.008) and OS (294 days vs 438 days, p = 0.024). Increased age, poorer performance status, and higher LDH were also associated with shorter PFS and OS. On multivariable analysis, ABX use was independently associated with shorter PFS (HR 1.57, 95% CI 1.05-2.34, p = 0.028) and OS (HR 2.19, 95% CI 1.44-3.32, p = 0.0002). The negative impact of ABX on OS was particularly pronounced for patients with worse performance status (HR 3.82, 95% CI 1.18-12.36, p = 0.025). Conclusions: To our knowledge, this is the largest multivariable analysis showing ABX use independently reduces PFS and OS in patients treated with TKIs. It is the first analysis to demonstrate this phenomenon across two distinct tumour sites. The data suggests that ABX use could be an independent predictor of shorter PFS and OS in cancer patients treated with TKIs, and warrants further validation in a larger cohort.

Somatic Copy-Number Alterations in Plasma Circulating Tumor DNA from Advanced EGFR-Mutated Lung Adenocarcinoma Patients.

Background: To assess the clinical relevance of genome-wide somatic copy-number alterations (SCNAs) in plasma circulating tumor DNA (ctDNA) from advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma patients. Methods: We included 43 patients with advanced EGFR T790M-positive lung adenocarcinoma who were treated with osimertinib after progression under previous EGFR-TKI therapy. We performed genomic profiling of ctDNA in plasma samples from each patient obtained pre-osimertinib and after patients developed resistance to osimertinib. SCNAs were detected by shallow whole-genome plasma sequencing and EGFR mutations were assessed by droplet digital PCR. Results: SCNAs in resistance-related genes (rrSCNAs) were detected in 10 out of 31 (32%) evaluable patients before start of osimertinib. The presence of rrSCNAs in plasma before the initiation of osimertinib therapy was associated with a lower response rate to osimertinib (50% versus 81%, p = 0.08) and was an independent predictor for shorter progression-free survival (adjusted HR 3.33, 95% CI 1.37–8.10, p = 0.008) and overall survival (adjusted HR 2.54, 95% CI 1.09–5.92, p = 0.03). Conclusions: Genomic profiling of plasma ctDNA is clinically relevant and affects the efficacy and clinical outcome of osimertinib. Our approach enables the comprehensive assessment of SCNAs in plasma samples of lung adenocarcinoma patients and may help to guide genotype-specific therapeutic strategies in the future.

Predictive value of integrated 18F-FDG PET/MRI in the early response to nivolumab in patients with previously treated non-small cell lung cancer

BackgroundThe early response to treatment with immune-checkpoint inhibitors is difficult to evaluate. We determined whether changes in integrated [18F]-fluoro-2-deoxy-D-glucose positron emission tomography/MRI (18F-FDG PET/MRI) parameters after the first 2 weeks...

Association between metastatic sites and first-line pembrolizumab treatment outcome for advanced non-small cell lung cancer with high PD-L1 expression: a retrospective multicenter cohort study.

Associations between treatment outcomes of immune checkpoint inhibitors and metastatic sites in advanced non-small cell lung cancer (NSCLC) are not well known. Therefore, this multicenter retrospective study aimed to investigate the predictive factors of metastatic sites after first-line pembrolizumab treatment for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. We retrospectively analyzed advanced NSCLC patients with a PD-L1 TPS ≥50% who underwent first-line pembrolizumab therapy at 11 institutions between February 2017 and April 2018. Clinical data collected from medical records included metastatic sites at the time of pembrolizumab treatment. Treatment outcomes of pembrolizumab were assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 213 patients were included in the study. The median age was 71years (range 39-91years). Of the 213 patients, 176 (83%) were men and 172 (81%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0-1. The most common metastases were thoracic lymph node metastasis (77%), intrapulmonary metastasis (31%), bone metastasis (28%), and malignant pleural effusion (26%). On multivariate analysis, a poor ECOG-PS score (hazard ratio: 1.95, 95.0% confidence interval: 1.25-3.04; P = 0.003) and malignant pleural effusion (hazard ratio: 1.52, 95.0% confidence interval: 1.01-2.29; P = 0.043) were independent predictors of shorter progression-free survival in patients treated with pembrolizumab. For NSCLC patients with malignant pleural effusion, pembrolizumab monotherapy is not a suitable first-line treatment because of its insufficient effectiveness, even though their PD-L1 TPS was high.

Neutrophil to lymphocyte ratio (NLR) as a predictor of outcomes in patients with urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICI)

Neutrophil to lymphocyte ratio (NLR) as a predictor of outcomes in patients with urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICI)

Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

Prognostic significance of total metabolic tumor volume on 18F-fluorodeoxyglucose positron emission tomography/ computed tomography in patients with diffuse large B-cell lymphoma receiving rituximab-containing chemotherapy.

PurposeThe purpose of this study was to determine the prognostic significance of metabolic parameters on pre-treatment 18F-fluorodeoxyglucose positron emission tomography/ computed tomography (FDG PET/CT), in patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab-containing therapy.Materials and MethodsFrom September 2009 to December 2014, DLBCL patients who had received FDG PET/CT scans for staging were enrolled. The maximal standardized uptake value of tumor (SUVt) was recorded. The metabolic tumor volume (MTV) was the volume of lesion with an elevated SUV greater than 2.5. The total lesion glycolysis (TLG) was the sum of the products of MTV and mean SUV in all measured lesions. Univariate and multivariate analyses were used to assess the prognostic significance of maximal SUVt, total MTV, TLG and other clinical parameters.ResultsThere were 118 patients enrolled in this study. The median follow-up time was 28.7 months. The 5-year progression-free survival (PFS) for patients with higher and lower total MTV was 32.3% and 66.0% respectively (p = 0.0001). The 5-year overall survival (OS) for patients with higher and lower total MTV was 34.3% and 69.9% respectively (p < 0.0001). Multivariate analysis revealed, besides IPI, that total MTV was independently predictive for PFS (HR: 2.31, 95% CI: 1.16 – 4.60, p = 0.0180) and OS (HR: 2.38, 95% CI: 1.12 – 5.04, p = 0.024). TLG and maximal SUV of tumor were not independent prognostic factors.ConclusionsAn elevated total MTV was a predictor for shorter PFS and OS in patients with DLBCL receiving rituximab-containing therapy, independent of IPI.

Neutrophil lymphocyte ratio (NLR) as a predictor of outcomes with immune checkpoint inhibitor (ICI) therapy in genitourinary cancer and melanoma.

37 Background: Immunotherapy, such as PD-1 and PD L1, has been recently approved in melanoma and genitourinary cancers (GU) such as renal cell carcinoma and urothelial carcinoma. There is an unmet need to determine factors predictive of response, to guide therapeutic selection in these cancers. We evaluated NLR (ratio of absolute values of neutrophils to lymphocytes) as predictors of response, progression free survival (PFS) and overall survival (OS) in patients treated with PD1 or PD L1 inhibitors. We extrapolated from renal cell data with NLR and used a value of 4 as cutoff. Other known prognostic clinical factors assessed were age, race, and smoking status. Methods: Regulatory approval was obtained. A retrospective chart review of melanoma and genitourinary cancer patients at Karmanos Cancer Institute, treated with ICI was conducted. Data were collected on demographics, smoking status, pretherapy NLR, and post 4 doses of ICI. Association with clinical outcomes (response rate, PFS and OS) was conducted by univariable and multivariable analyses. A log-rank test was used to compare PFS and OS. Results: 143 pts, (59 GU and 84 Melanoma) were evaluated with median age of 61yrs (range, 24-87). 11 pts (19%) and 5 (6%) were African American (AA) in GU and melanoma respectively. 61 pts (43%) were smokers in total. Pretherapy NLR&lt;4 and ≥4 was seen in 97(68%) and 46 (32%) pts. The table summarizes the results of the analysis. Conclusions: Pretherapy NLR ≥4 was a statistically significant predictor of shorter PFS and OS with ICI therapy in GU and melanoma cancers. NLR is an easily applicable predictive factor, however validation of this observation is required in a larger sample size. [Table: see text]