Independent Prognostic Impact Research Articles

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictors of outcomes in inflammatory breast cancer.

Background: Inflammatory breast cancer (IBC) is uncommon, aggressive and associated with poor survival outcomes. The lack of prognostic biomarkers and therapeutic targets specific to IBC is an added challenge for clinical practice and research. Inflammatory biomarkers such as neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios (NLR and PLR) demonstrated independent prognostic impact for survival in breast cancer. In our study, these biomarkers were investigated in a cohort of patients with nonmetastatic IBC. Methods: A retrospective cohort of 102 IBC patients with nonmetastatic disease was conducted at the Mohammed VI University Hospital (Oujda, Morocco) between January 2010 and December 2014. NLR and PLR were obtained from blood cell count at baseline before neoadjuvant chemotherapy (NACT) from patients' medical records. The receiver operating characteristic was used to find the optimal cut-off. Correlation between these blood-based biomarkers and response to NACT was analyzed by Chi-squared and Fisher's exact test. Their prognostic value for predicting disease-free survival (DFS) and overall survival (OS) was performed based on Cox regression models. Results: Totally, 102 patients with IBC were included in the analysis. Pathologic complete response (pCR) after NACT, defined by the absence of an invasive tumor in the breast tissues and nodes after surgery (ypT0 ypN0), was observed in eight patients (7.8%). NACT response was found to be associated with menopausal status (p=0.039) and nodal status (p<0.001). Patients with a low NLR had a higher pCR rate as compared with the high-NLR group (p=0.043). However, the pCR rate was not significantly associated with age (p=0.122), tumor side (p=0.403), BMI (p=0.615), histological grade (p=0.059), hormone receptors status(p=0.206), HER2 (p=0.491) and PLR (p=0.096). Pre-treatment blood-based NLR of 2.28 was used as the cut-off value to discriminate between high and low NLR according to the receiver operating characteristic curves. Similarly, a value of 178 was used as the cut off for PLR. Patients with low-NLR had a significantly better 5-year DFS (p<0.001) and OS (p<0.001) than the high-NLR group. Moreover, low-PLR was significantly associated with higher DFS (p=0.001) and OS (p=0.003). The NLR showed a significant prognostic impact for DFS (HR: 2.57; 95% CI: 1.43-4.61; p=0.01) and for OS (HR: 2.92; 95% CI: 1.70-5.02; p<0.001). Similarly, a meaningful association between PLR and 5-year DFS (HR: 1.95; 95% CI: 1.10-3.46; p=0.021) and OS (HR: 1.82; 95% CI: 1.06-3.14; p=0.03) was noticed. Conclusions: High NLR and PLR were found associated with reduced DFS and OS in nonmetastatic IBC. Further studies are awaited to confirm these findings.

AML-291: Treatment Response and Outcome in DNMT3A-mutated Acute Myeloblastic Leukemia

<h3>Introduction:</h3> Mutations in DNMT3A have been associated with clonal hematopoiesis. Among patients with DNMT3A-mutated AML, prior reports of the prognostic impact of mutations at the R882 residue versus non-R822 mutations have been conflicting. <h3>Objective:</h3> To identify the prognostic impact of DNMT3A mutations and whether mutations at codon R882 (DNMT3A-R882) <i>versus</i> mutations at codons other than R882 (non-R882) have clinically relevant differences. <h3>Design:</h3> We retrospectively reviewed the clinical records of 236 patients with newly diagnosed AML with DNMT3A mutations who presented to our institution from 2012 to 2020. The study population was classified into two age groups (<65 years <i>vs</i> >65 years). We analyzed the disease-related characteristics, response rates (CR/CRi), and survival of those with DNMT3A-R882 versus non-R882 mutations. <h3>Results:</h3> Patients <65 years with DNMT3A-R882 had a median age of 55 years compared to 58 years in the non-R882 group (p=0.04). There were no additional significant differences in this group. Similarly, among patients >65 years, those with DNMT3A-R882 showed a median age of 70 years versus 74 years in those with non-R882 (p=0.01). Moreover, DNMT3A-R882 presented with a diploid karyotype (69%) and complex karyotype (11%, p=0.06). The presence of concomitant mutations was not significantly different, and the most frequently co-occurring mutations were NPM1, FLT3-ITD, IDH2, and IDH1. TP53-mutated was overrepresented in the non-R882 group (21% <i>vs</i> 8% in DNMT3A-R882; p=0.009). There was a trend for a higher CR/CRi rate among those with DNMT3A-R882 treated with cladribine plus low-dose cytarabine (93%; p=0.08) or hypomethylating agents with venetoclax (87%; p=0.21). Finally, concomitant TP53 mutation significantly increased the risk of death (HR; 4; 95% CI: 0.47–2.27, p<0.01). Among patients >65 years, DNMT3A non-R822 was associated with worse survival, although it was not statistically significant. Secondary or therapy-related AML had a two-fold increased risk of death (p=0.01 and p=0.04, respectively). HMA-Ven or Clad-LDAC-Ven showed a survival advantage. <h3>Conclusions:</h3> DNMT3A mutations do not have an independent prognostic impact in patients diagnosed with AML across age groups. Patients >65 years with DNMT3A-R882 had a trend toward longer OS. Clad-LDAC-Ven and HMA-Ven provided better CR/CRi and survival advantage. Co-occurrence of TP53 mutations was associated with a negative prognostic impact in all patients.

How to Improve Prognostication in Acute Myeloid Leukemia with CBFB-MYH11 Fusion Transcript: Focus on the Role of Molecular Measurable Residual Disease (MRD) Monitoring.

Acute myeloid leukemia (AML) carrying inv(16)/t(16;16), resulting in fusion transcript CBFB-MYH11, belongs to the favorable-risk category. However, even if most patients obtain morphological complete remission after induction, approximately 30% of cases eventually relapse. While well-established clinical features and concomitant cytogenetic/molecular lesions have been recognized to be relevant to predict prognosis at disease onset, the independent prognostic impact of measurable residual disease (MRD) monitoring by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), mainly in predicting relapse, actually supersedes other prognostic factors. Although the ELN Working Party recently indicated that patients affected with CBFB-MYH11 AML should have MRD assessment at informative clinical timepoints, at least after two cycles of intensive chemotherapy and after the end of treatment, several controversies could be raised, especially on the frequency of subsequent serial monitoring, the most significant MRD thresholds (most commonly 0.1%) and on the best source to be analyzed, namely, bone marrow or peripheral blood samples. Moreover, persisting low-level MRD positivity at the end of treatment is relatively common and not predictive of relapse, provided that transcript levels remain stably below specific thresholds. Rising MRD levels suggestive of molecular relapse/progression should thus be confirmed in subsequent samples. Further prospective studies would be required to optimize post-remission monitoring and to define effective MRD-based therapeutic strategies.

Independent prognostic impact of plasma NCOA2 alterations in metastatic castration-resistant prostate cancer.

The androgen receptor (AR) pathway-associated gene nuclear receptor coactivator 2(NCOA2) has an established oncogenic role in early prostate cancer and likewise is a driver of metastatic disease and castration-resistant prostate cancer. However, its significance as a biomarker in metastatic castration-resistant prostate cancer (mCRPC), both alone and in conjunction with co-occurring AR alterations using a liquid biopsy approach has not been investigated. Ninety-one patients were included in this study, (n = 68 receiving an androgen receptor pathway inhibitorand n = 23 receiving taxane chemotherapy). Up to 30 ml of peripheral blood was collected before commencing treatment from each patient. Plasma cell-free DNA, along with a matched germline sample, underwent targeted next-generation sequencing using a validated, highly sensitive in-house prostate cancer panel. Variants in AR and NCOA2 were identified and correlated with clinical outcomes. Plasma AR and NCOA2 aberrations were identified in 35% and 13% of the cohort, respectively, whilst 8% had concurrent AR and NCOA2 alterations. NCOA2 copy number gain and any NCOA2 aberration predicted for lower prostate-specific antigen (PSA) response rates. Likewise, median overall survival was shorter for NCOA2 gain (10.1vs. 18.3 months; p = .004), remaining significant after adjusting for covariates including circulating tumor DNA fraction and tumor suppressor gene alterations. Importantly, dual AR and NCOA2 aberrations were also associated with inferior outcomes, including no PSA responses in patients treated with AR pathway inhibitors (0% vs. 64%; p = .02). These data highlight the importance of identifying multiple markers of AR pathway modulation in mCRPC and represent the first instance of the assessment of plasma NCOA2 status as a prognostic biomarker for standard-of-care therapies. Further assessment is warranted to determine if NCOA2 aberrations are a marker of primary resistance to AR pathway inhibitors.

At least two high-risk cytogenetic abnormalities indicate the inferior outcomes for newly diagnosed multiple myeloma patients: a real-world study in China

We retrospectively studied the impact of cytogenetic abnormalities in 328 consecutive newly diagnosed multiple myeloma (MM) patients. High-risk cytogenetic abnormalities (HRCAs) included del (17p), amp/gain (1q21), t(4;14), and t(14;16). We defined a standard-risk group by the absence of HRCA, an intermediate-risk group with one HRCA, and a high-risk (HiR) group with at least two HRCAs. The HiR group constituted 14.3% of patients and was associated with a median overall survival (OS) of 28.6 months and progression-free survival (PFS) of 14.0 months. Moreover, the HiR group predicted poor outcomes for OS and PFS in multivariate analyses, and bortezomib prolongation to nine cycles could not bring additional benefit to this entity, suggesting the necessity of more effective therapies for these patients. Furthermore, we confirmed the independent prognostic impact of amp 1q21 in this real-world study.

P-131 External validation of prognostic ALAN score in patients with inoperable bile duct cancer treated with second-line chemotherapy

The prognosis of patients affected by cholangiocarcinoma is extremely variable, owing to different symptoms, sites of disease involvement, and unpredictable chemotherapy response rates. Different scores have been suggested for survival estimation: baseline neutrophil count combined with serum albumin and neutrophil/lymphocyte ratio (NLR) and lymphocyte/monocyte ratio (LMR) is one of the latest additions (ALAN score). Even though durable responses to chemotherapy are rarely seen in this setting, second-line treatment has proven to be effective in some patients. The aim of this analysis is to assess whether ALAN score might be used to estimate survival in patients with bile duct cancer treated with second-line chemotherapy. Patients with unresectable bile duct cancer treated with second-line chemotherapy with FOLFOX or FOLFIRI were enrolled. The primary objective of the analysis was to assess differences in overall survival in patients stratified by each of the different components of ALAN score (neutrophil count 8000/mmc, serum albumin 3.5 g/dl, NLR 3, LMR 2.1) and the complete ALAN score (0 vs 1-2 vs 3-4). Survival was calculated by Kaplan-Meier method and differences in survival among stratification factors were assessed by Log-rank test. Cox-proportional-hazard regression was used for multivariate analysis. Level of statistical significance p was set at 0.05 for all tests. 45 patients were eligible. mOS of the entire cohort was 8.68 months (95%CI:6.75-14.59) while mean OS was 18.107 months (standard error: 4.007). At the time of the present analysis, 26/45 patients have died already. 13/45 (29%) patients had albumin levels lower than 3.5 g/dl, 9/45 (20%) had neutrophil count greater than 8000/mmc, 17/45 (38%) had LMR lower than 2.1 and 27/45 (60%) had NLR higher than 3. Low albumin was associated with shorter OS (mOS: 5.96 vs 9.24 months, HR:2.86, 95%CI:0.99-8.18, p=0.05). High neutrophil count was associated with shorter OS (mOS: 1.73 vs 9.24, HR:10.91, 95%CI:2.71-43.89, p=0.008). High NLR was associated with shorter OS (mOS:7.44 vs 12.13 months, HR:2.50, 95%CI: 1.09-5.72, p=0.0289). Low LMR was not associated with significantly different overall survival (mOS: 7.44 vs 9.24 months, HR:1.96, 95%CI:0.80-4.80, p=0.138). Multivariate analysis confirmed an independent prognostic impact only for albumin levels (p=0.0313) and neutrophil count (p=0.0012). Stratifying patients by ALAN score, OS was significantly different (mOS 27.57 vs 8.19 vs 1.73 months for 0 vs 1-2 vs 3-4 respectively, p=0.0072). Using only neutrophil count and albumin levels to stratify patients, a statistically significant difference was also proven (mOS 12.31 vs 8.19 vs 1.31 months for 0 vs 1 vs 2 respectively, p < 0.0001). Second-line treatment can be a potentially useful option for a few patients with bile duct cancer; our analysis suggests that ALAN score might be used in this setting for patient survival estimates, helping treatment decisions. In addition, a simplified version of ALAN score, comprised only of serum albumin levels and neutrophil count, might be used instead as it was able to define patient prognosis more accurately compared to the standard ALAN score.

Clinical Effect of Genetic Alterations in Pediatric Patients with B-Progenitor Acute Lymphoblastic Leukemia

▪BackgroundRecent genetic studies using high-throughput sequencing have substantially revealed genetic alterations in pediatric patients with B-progenitor acute lymphoblastic leukemia (B-ALL). However, their clinical relevance of these alterations has not been fully investigated.MethodsWe performed targeted-capture sequencing of 149 known or putative driver genes for B-ALL in 525 pediatric patients who were uniformly treated according to the Japan Association of Childhood Leukemia Study ALL-02 protocol. In addition, we performed whole transcriptome sequencing in 63 of 118 patients who were not categorized into any genetic subgroup defined by RT-PCR status or targeted-capture sequencing results.ResultsIn total, 647 focal deletions (median 1 per patient; range, 0-7) and 993 mutations (median 2 per patient; range, 0-10) were detected in 491 (94%) cases. Some of these alterations were closely associated with disease subtypes. We identified recurrent PHF6 mutations, which were almost exclusively detected in the TCF3 - PBX1- positive ALL genotype. Furthermore, frequent involvement of PAX5 and KMT2D (mutations) and IKZF3 (deletions) were characteristic of TCF3 - PBX1 -positive ALL genotype. To identify genetic alterations associated with a poor prognosis, we analyzed 20 genes that were mutated in at least 20 patients in our study cohort. Univariate analyses revealed genetic alterations in TP53 , KMT2D , and IKZF1 to be associated with a significantly shorter overall survival. Mutations and deletions in IKZF1 were also strongly associated with induction failure (Odds ratio, 12; 95% CI, 2.7-55). This led to death in 80% (n = 4/5) of the patients with IKZF1 alterations. Most patients with TP53 and KMT2D mutations and with disease relapse had fatal disease progression [94% mortality rate (n = 17/18)]. Multivariate analysis, together with the NCI criteria, revealed that two genetic lesions, TP53 and KMT2D , retained prognostic impacts for overall survival. Prediction of 5-year OS improved in each NCI-risk group when patients in each risk group were stratified according to the presence or absence of mutations in TP53 or KMT2D lesions: 69% [with alteration (n = 26)] vs. 85% [without alteration (n = 138)] for the NCI-HR group (P = 0.03) and 85% [with alteration (n = 42)] vs. 97% [without alteration (n = 319)] for the NCI-SR group (P = 0.004). Additionally, the four less frequently mutated genes also had an independent prognostic impact before and after adjustment for risk factors: IKZF2 (n = 6; HR for death, 7.4; 95% CI, 2.3-24), SH2B3 (n = 4; HR for death, 7.0; 95% CI, 1.7-29), JAK2 (n = 7; HR for events, 4.6; 95% CI, 1.7-12), and PTEN (n = 9; HR for death, 3.8; 95% CI, 1.2-12). Notably, mutations in three genes present potentially druggable targets: ruxolitinib for mutations in JAK2 or SH2B3 and poly (ADP-ribose) polymerase inhibitor formutations in PTEN . Finally, based on a gene expression profile, 20 of 63 patients were categorized into discrete subgroups characterized by Ph-like profiles (n = 7), ZNF384 (n = 7), and MEF2D (n = 6) fusions. Ph-like and MEF2D fusion-positive ALLs were associated with a dismal prognosis, whereas all patients with a ZNF384 fusion survived with complete remission. No mutations were associated with a poor prognosis in the 43 remaining patients. Further analysis, such as whole genome sequencing, is warranted for these patients.ConclusionsTargeted-capture sequencing improves the prediction of clinical outcomes and helps detect prognostic and druggable biomarkers. Our results can facilitate the clinical applications of next-generation sequencing to select optimal therapy for pediatric patients with B-ALL. DisclosuresMakishima:Yasuda Medical Foundation: Research Funding.

Molecular Characterisation of TP53 Aberrations in 1,777 Myeloma Trial Patients

Molecular Characterisation of TP53 Aberrations in 1,777 Myeloma Trial Patients

Analysis of Risk Factors Regarding Short- and Long-Term Mortality of Critically Ill Patients with Hematologic Malignancies or Following Stem Cell Transplantation Requiring Treatment on the Intensive Care Unit

▪Introduction: Patients with hematologic malignancies or following hematopoietic stem cell transplantation (HSCT) are at an increased risk of suffering from severe complications requiring intensive care treatment. Despite improvement in antimicrobial therapy and supportive care, prognosis of these patients after transferal to the intensive care unit (ICU) is still often considered dismal and strategies to identify patients who might best benefit from ICU treatment are a matter of debate.Methods: We retrospectively analyzed clinical characteristics of patients with hematologic malignancies or following HSCT who were admitted to the ICU at Heidelberg University Hospital, a tertiary referral hospital and HSCT center, between 01/2009 and 12/2016. The impact of possible risk factors on ICU mortality as well as 1-year mortality was assessed by univariate Chi square tests and multivariate logistic regression.Results: In total, 346 patients were identified, 204 (59%) were male. Median age was 55.7 years (range 19-80). Regarding transplant status, 42 patients (12.5%) had received a prior autologous HSCT, 111 (32.1%) an allogeneic HSCT. Of the latter, 55.0% suffered from acute or chronic graft-versus-host disease (GVHD). Overall ICU mortality was 50.3% with a median time to death of 11.6 days (range 0-113), 1-year mortality of patients discharged from ICU was 47.6%.The main reason for ICU transferal was respiratory failure with 309 (89.3%) patients requiring mechanical ventilation. In univariate analysis, status post allogeneic HSCT (p<0.0001) and presence of GVHD (p<0.001) were significantly associated with higher ICU mortality, as was hospital stay prior to ICU admission > 4 days (p=0.04). Neither prior autologous HSCT nor prior conventional chemotherapy showed a negative impact on survival.Pneumonia at transferal or during ICU stay was diagnosed in 293 patients (84.7%). Microbiologically confirmed invasive pulmonary aspergillosis was associated with higher ICU mortality (p=0.02) in univariate analysis as was influenza-associated pneumonia (p=0.04). Regarding 1-year survival, this negative effect was no longer significantly discernible. Colonization by multi-resistant bacteria did not exert a significant impact on ICU mortality or 1-year survival.Regarding organ complications, use of mechanical ventilation (p<0.0001), especially requirement of nitric oxide ventilation (p<0.0001), requirement of vasopressors within the first hour of transferal (p=0.02) and requirement of hemodialysis (p=0.001) were significant risk factors for ICU mortality in univariate analysis. With the exception of vasopressor therapy, all these remained significant risk factors regarding 1-year survival. Regarding laboratory assessments, an initial pH value < 7.25 (p=0.004), serum creatinine > 1.1 mg/dL (p=0.004), serum bilirubin > 2mg/dL (p<0.001), and serum lactate > 2.2 mg/dL (p=0.02) as indicators of multi-organ failure were significantly associated with inferior ICU survival, a trend was seen for leukocytes < 1/nL (p=0.05). Elevated serum creatinine, bilirubin and lactate levels remained significant risk factors with respect to 1-year survival.Next we performed a multivariate analysis in 309 patients requiring mechanical ventilation evaluating parameters easily assessable by the treating physician at the time of ICU transferal. This revealed that presence of GHVD (p=0.009, OR 2.5), pH < 7.25 (p=0.03, OR 2.3), and bilirubin > 2 mg/dL (p=0.047, OR 1.8) exerted an independent negative prognostic impact on ICU mortality, a trend was seen for elevated serum creatinine (p=0.098, OR 1.5). Of interest, neither prior autologous HSCT nor prior allogeneic HSCT in the absence of GVHD showed an independent adverse influence.Conclusions: In this cohort of critically ill patients with hematologic malignancies, ICU survival of 49.7% could be achieved despite the high rate of requirement of mechanical ventilation. Severe ongoing immunosuppression in the setting of GVHD, and signs of organ failure such acidosis or hyperbilirubinemia at time of ICU transferal were significantly associated with an increased risk of ICU mortality. Early identification of patients at risk and implementation of counter-measures to avoid organ complications are therefore of the utmost importance. DisclosuresNo relevant conflicts of interest to declare.

Extramedullary Manifestations in World Health Organization-Defined Chronic Myelomonocytic Leukemia: Clinical, Molecular and Prognostic Correlates

Background:Chronic myelomonocytic leukemia (CMML) is an aggressive myeloid neoplasm with overlapping myeloproliferative and myelodysplastic features. Extramedullary manifestations (EMM) include splenomegaly, hepatomegaly, lymphadenopathy, leukemia cutis, gingival infiltrates, central nervous system (CNS) and testicular involvement and myeloid sarcomas. We carried out this study to i) define clinical and laboratory correlates of EMM in CMML, ii) to assess the prognostic impact of EMM, and iii) to document survival outcomes.Methods:Four hundred and fifty-two patients with WHO-defined CMML were included in the study. All morphological and cytogenetic assessments at baseline were performed at the Mayo Clinic, MN. Bone marrow (BM) DNA at diagnosis was available in 229 (50%) patients and was subjected to a 29 gene panel next generation sequencing analysis. EMM for the purpose of this study were defined as: palpable splenomegaly, palpable hepatomegaly, palpable lymphadenopathy, clinical/radiological or biopsy proven leukemia cutis, gingival infiltrates, testicular involvement, CNS involvement, and myeloid sarcomas. EMM were included if present either at the time of CMML diagnosis, or within six months of stable disease following diagnosis. Standard statistical tests and measures were utilized.Results:Three hundred and seventy-three (82%) patients had an exam documented at the time of diagnosis, or within six months of diagnosis, and were included in the analysis. The median age was 69 years (range, 18-95), 66% were male and 176 (47%) had a “proliferative CMML phenotype.”1. Clinical correlates:One hundred and nineteen (32%) patients had at least one EMM at diagnosis. This included; palpable splenomegaly 91 (76%), hepatomegaly 48 (40%), lymphadenopathy 19 (15%), leukemia cutis 7 (6%), gingival infiltrates 4 (3%), myeloid sarcomas 2 (2%), and 1 each with testicular and CNS involvement (1%). Thirty two (27%) had non hepatosplenic EMM, 102 (86%) had palpable hepato and/or splenomegaly, whereas 54 (45%) and 11 (9%) had isolated palpable splenomegaly and hepatomegaly. In comparison to CMML patients without EMM, those with, were more likely to be younger (p <0.0001), have a higher leukocyte count (WBC, p <0.0001), higher absolute neutrophil count (ANC, p <0.0001), higher absolute monocyte count (AMC, p <0.0001), have circulating immature myeloid cells (IMC, p <0.0001), have mutations involving ASXL1 (p 0.03), CBL (p 0.04), and CSF3R (p 0.02), lack SF3B1 (p 0.009) and ZRSR2 (p 0.03) mutations and have a higher risk stratification by the Mayo Molecular Model (MMM, p<0.0001) and the GFM model (p=0.004).2. Prognostic impact:At last follow up (median 14 months), 249 (67%) deaths and 69 (18%) leukemic transformations were documented. Median survival (OS) was 13 months for patients with non hepatosplenic EMM, 13.2 months for those with palpable hepatosplenomegaly, and 25 months for those without EMM (Figure 1). On univariate analysis, survival was adversely affected by, male sex (p 0.03), low hemoglobin (p <0.0001), high WBC (p 0.0005), high AMC (p <0.0001), presence of IMC (p 0.002), circulating blast % (p <0.0001), high LDH (p 0.0004), presence of EMM (p <0.0001), palpable hepatosplenomegaly (p=0.0008), leukemia cutis (p=0.02), proliferative CMML phenotype (p <0.0001), adverse cytogenetics (p 0.003), absence of TET2 (p 0.0004) and the presence of DNMT3A (p 0.002), IDH1 (p 0.013), ASXL1 (p 0.03), and Tp53 (p 0.014) mutations. Non-hepatosplenic EMM, palpable lymphadenopathy, CNS, testicular involvement and the presence of myeloid sarcomas did not impact OS. On multivariate analysis, only male sex (p= 0.009, HR 1.6, 95% CI 1.1-2.3), low hemoglobin (p <0.0001, HR 1.74, 95% CI 1.3-2.3), palpable hepatosplenomegaly (p 0.0005, HR 1.8, 95% CI 1.04-2.2), absence of TET2 mutations (p 0.023, HR 0.7, 95% CI 0.5-0.95), and the presence of DNMT3A mutations (p 0.013, HR 2.3, 95% CI 1.2-4.3) retained an independent negative prognostic impact. Palpable hepatosplenomegaly retained prognostic significance when assessed in the context of the MMM (p=0.03) and the GFM (p=0.04) models. EMM had no impact on leukemia-free survival.Conclusion:The current study demonstrates a prognostically-relevant frequent occurrence of hepatosplenomegaly in CMML; the study also provides the spectrum and frequency of extramedullary manifestations and correlations with mutations. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Salvage Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma

IntroductionPrimary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin lymphoma. This unique disease shows unsatisfactory outcomes comparing to other types of non-Hodgkin lymphoma and limited treatment options are available with relapsed or refractory disease. The purpose of this study is to evaluate outcomes of relapsed or refractory PCNSL patients treated with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT).MethodsThe registry data set of PCNSL, collected from March 1993 to May 2017 at a single institute, Asan Medical Center, was retrospectively reviewed and patients with refractory disease to first-line therapy and who relapsed were sorted. Among selected patients, patients who showed complete response (CR) or partial response (PR) to salvage therapy were enrolled in analyses and divided into two groups with whether high-dose chemotherapy followed-by ASCT was done or not as consolidation therapy. Overall survival (OS) was defined as the time from the day response was evaluated after salvage therapy to any cause of death, and progression free survival (PFS) was defined as the time from the day response was evaluated after salvage therapy to disease progression or any cause of death. Chi square test and Fisher's exact test was done to compare variables in two groups. Survival curves were estimated by Kaplan-Meier methods with log-rank tests and multivariate analysis with Cox-proportional hazards regression analyses was done to evaluate potential confounding effects of known prognostic factors. All statistical analyses were performed using IBM SPSS version 21.0.ResultsTotal 241 patients with diagnosis of PCNSL were identified and 83 patients who had relapsed or refractory to induction chemotherapy were sorted. Among these patients, 39 patients who had CR or PR to salvage chemotherapy were enrolled in analyses. Median follow-up duration was 2.1 years (IQR 0.1-15.49), median OS was 1.5 years (95% CI 0.3-2.7), and median PFS was 1.4 years (95% CI 0.2-2.7). Median age was 63 years (range, 29-77), 69.2% of patients were 60 years or older and 59.0% of patients was male. Thirty patients (76.9%) had high-dose methotrexate based chemotherapy as first-line therapy and 71.8% had overall response (CR or PR). Twenty patients (48.7%) had ICE (ifosfamide, carboplatin, etoposide) + dexamethasone regimen, 22.9% had high-dose methotrexate based regimen. Thirty-one patients (79.5%) showed good performance (ECOG performance status < 2). Among these patients, 16 patients had high-dose chemotherapy followed-by ASCT as consolidation therapy and 23 patients did not. Proportion of patients with good performance status, salvage chemotherapy regimen, response to salvage therapy showed no statistically significant difference between two groups who had salvage ASCT or not. The median age was 55 years old (range 29-64) in salvage ASCT group, and 68 years old (range, 36-77) in non-ASCT. Median OS was 2.5 years [95% CI 0.3-4.6] in salvage ASCT group, and 1.0 years [95% CI 0.4-1.7] in group without salvage ASCT (p = 0.032). Median PFS was 1.5 years in salvage ASCT group, and 0.4 years [95% CI 0.4-0.5] in non-ASCT group (p = 0.027). In multivariate analyses with age, ECOG performance status, CSF protein level, and serum LD level, salvage ASCT revealed its independent prognostic impact for OS with HR of 0.11 [95% CI 0.01-0.96, p = 0.046], and for PFS with HR of 0.13 [95% CI 0.02-0.78, p = 0.025].ConclusionConsolidation therapy with high-dose chemotherapy followed-by ASCT could be a good treatment option in relapsed or refractory PCNSL patients who had response to salvage therapy. Prospective studies are needed to validate our results. DisclosuresNo relevant conflicts of interest to declare.

Recurrent Gene Mutations and Clinical Outcome in the Context of Lenalidomide Treatment of Relapsed/Refractory CLL — Results from Multicenter Phase II Trial CLL-009

Abstract INTRODUCTION Mutations in genes such as TP53, SF3B1 and NOTCH1 are frequent in CLL and have been associated with outcome in previous studies. Whereas NOTCH1mut appeared to be a negative predictive factor in the context of chemotherapy combined with Rituximab, other mutations, e.g. SF3B1mut, TP53mut and BIRC3mut, were adverse prognostic factors in patient cohorts with different therapies. However, the impact on outcome among patients treated with non-chemotherapeutic agents is less clear. METHODS We assessed the incidence and impact of gene mutations in the CLL-009 trial (relapsed/refractory CLL, single-agent lenalidomide, Wendtner et al., Leuk Lymphoma 2016). Samples from study entry were available from 96 of 103 patients (93%). Analysis was performed via liquid chromatography (dHPLC) and sanger sequencing for TP53 and a customized targeted Next Generation Sequencing (tNGS) panel for ATM, BIRC3, EGR2, FBXW7, MYD88, TP53 (all exons), NOTCH1 (exon 34), SF3B1 (exon 14-16, 18) and XPO1 (exon 14, 15). All mutations with a variant allelic fraction > 5% were considered. RESULTS In total we identified 162 mutations across 11 genes in 79 of 96 patients with incidences of TP53mut 37.5%, SF3B1mut 33.3%, NOTCH1mut 21.9%, ATMmut 15.6%, XPO1mut 9.4%, FBXW7mut 7.3%, NFKBIEmut 6.3%, POT1mut 5.2%, BIRC3mut 3.1%, EGR2mut 2.0% and MYD88mut 2.0%. Twelve of 36 (33.3%) TP53mut patients had additional mutations within the same gene in contrast to only 2 of 32 (6.3%) SF3B1mut patients and 1 of 20 (5.0) NOTCH1mut patients. tNGS as compared to dHPLC and Sanger revealed 2 additional mutations in TP53 resulting in identification of 2 more TP53mut patients. We identified a variety of associations of subgroups defined by mutations with clinical and laboratory parameters, such as TP53mut with del17p (p 65 years more commonly had mutations in POT1 (p=0.02) and TP53 (p=0.02). Patients with NOTCH1mut (p Regarding response, OS and PFS, only the presence of NOTCH1mut showed a trend for reduced OS (HR=1.66, p=0.08). All other mutational subgroups, in particular TP53mut and SF3B1mut, had no significant association with PFS and OS. Three or more prior lines of therapy had the strongest impact on OS (HR 1.4, p To identify factors of independent prognostic impact, we performed multivariable Cox regressions for PFS and OS including number of prior lines of therapy, del17p, del11q, IGHV status and gene mutations. Only del17p (HR=2.81, p=0.01) was associated with decreased PFS, while for OS unmutated IGHV (HR 2.36 p=0.04), NOTCH1mut (HR 2.74 p =3 therapy lines (HR 3.3, p SUMMARY In this cohort, only del17p was associated with decreased PFS, while for OS unmutated IGHV, NOTCH1mut and >=3 therapy lines were identified as independent prognostic factors. The specific characteristics of the population under study and the treatment modality could explain not only the high incidence of recurrent mutations, but also uncommon associations of mutations to other characteristics or outcomes. Therefore, the associations of genetic prognostic factors may depend on the context of the particular trial population and the treatments administered, making a reassessment of prognostic markers and models mandatory in the era of novel treatments. Download : Download high-res image (358KB) Download : Download full-size image Figure . Disclosures Fraser: Lundbeck: Speakers Bureau; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy. Hillmen: Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Durig: Lead Discovery Center: Research Funding. Gribben: Pharmacyclics: Honoraria; TG Therapeutics: Honoraria; Celgene: Honoraria; Acerta: Honoraria; Karyopharm: Honoraria; Kite: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Genentech/Roche: Honoraria. Kipps: Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Oncternal: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Speakers Bureau; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Purse: Celgene: Employment. Zhang: Celgene: Employment. De Bedout: Celgene: Employment. Hallek: AbbVie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Wendtner: Servier: Other: Grant, Personal Fees; Celgene: Consultancy, Research Funding; Mundipharma: Other: Grant, Personal Fees; Abbvie: Other: Personal Fees; Morphosys: Other: Personal Fees; Gilead: Other: Personal Fees; Novartis: Other: Personal Fees; Janssen-Cilag: Other: Personal Fees; Hoffmann La Roche: Other: Grant, Personal Fees. Stilgenbauer: Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding.

Genomic Analyses of Pediatric Acute Lymphoblastic Leukemia Ph+ and Ph-Like-Recent Progress in Treatment.

Pediatric acute lymphoblastic leukemia (ALL) with t(9;22)(q34;q11.2) is a very rare malignancy in children. Approximately 3–5% of pediatric ALL patients present with the Philadelphia chromosome. Previously, children with Ph+ had a poor prognosis, and were considered for allogeneic stem cell transplantation (allo-HSCT) in their first remission (CR1). Over the last few years, the treatment of childhood ALL has significantly improved due to standardized research protocols. Hematopoietic stem cell transplantation (HSCT) has been the gold standard therapy in ALL Ph+ patients, but recently first-generation tyrosine kinase inhibitor (TKI)-imatinib became a major milestone in increasing overall survival. Genomic analyses give the opportunity for the investigation of new fusions or mutations, which can be used to establish effective targeted therapies. Alterations of the IKZF1 gene are present in a large proportion of pediatric and adult ALL Ph+ cases. IKZF1 deletions are present in ~15% of patients without BCR-ABL1 rearrangements. In BCR-ABL1-negative cases, IKZF1 deletions have been shown to have an independent prognostic impact, carrying a three-fold increased risk of treatment failure. The prognostic significance of IKZF1 gene aberrations in pediatric ALL Ph+ is still under investigation. More research should focus on targeted therapies and immunotherapy, which is not associated with serious toxicity in the same way as classic chemotherapy, and on the improvement of patient outcomes. In this review, we provide a molecular analysis of childhood ALL with t(9;22)(q34;q11.2), including the Ph-like subtype, and of treatment strategies.

Characteristics and outcomes of patients diagnosed with DNMT3A mutated acute myeloblastic leukemia.

e19018 Background: Advances in molecular profiling have identified recurring gene mutations in acute myeloid leukemia (AML) that have independent prognostic significance with several being targets for the development of new small molecule inhibitors. DNMT3A mutations have been reported in up to 34% of patients with AML. Mutations of this gene are associated with silencing of tumor suppressor genes, thereby leading to leukemogenesis. Several prior reports have suggested an association with worse outcomes. Methods: We retrospectively reviewed records of 258 patients with ND AML with DNMT3A mutations who presented to our institution from 2002 to 2020. We analyzed their clinical and laboratory characteristics. We estimated their overall survival (OS) and disease-free survival (DFS) through the Kaplan-Meier method. P-value was 2-tailed, ≤ 0.05 was considered statistically significant with a confidence interval of 95%. Univariate and multivariate analyses were also applied. Results: Our cohort had a median age of 66 years, 56% were female. The majority of the patients (77%) had de novo AML and the M0 FAB subtype was predominantly observed in 70%. Diploid karyotype was detected in 60% while complex karyotype in 14% of patients. DNMT3A was most frequently mutated at codon 882 (64%). NPM1 was the most frequent concomitant mutation followed by FLT3-ITD and IDH2. Age &gt; 65 years (p = 0.001) and presence of concomitant TP53 mutation (p &lt; 0.001) were associated with worse survival and concomitant NPM1 was associated with a 40% reduction of death, p = 0.003. Secondary AML and concurrent TP53 mutation were associated with a higher risk of relapse, (p &lt; 0.001 for both). Intensive chemotherapy (ICT) was administered to 82 patients of which 68 achieved a complete response or CR with incomplete count recovery (CRi). Nineteen patients were treated with Cladribine plus low dose Ara-C (Clad-LDAC) and CR or CRi was achieved in 16 patients. Eleven treated with Clad-LDAC-Ven and all achieved CR/CRi. Hypomethylating agents (HMA) were given to 22 patients of which 10 achieved CR/CRi. Twenty-five received HMA-Ven, of these, CR/CRi was achieved in 20 patients (p = 0.02). There was an 80% and 90% reduction of death with ICT, p &lt; 0.001 and Clad-LDAC-Ven, p = 0.04 respectively. Moreover, the risk for relapse was reduced by 70% and 90% with ICT and Clad-LDAC-Ven respectively. Ninety-seven patients were treated with immunotherapy, FLT3 inhibitors, and IDH inhibitors, which were not included in this analysis. Conclusions: DNMT3A mutations have an independent prognostic impact in patients diagnosed with AML. Among these patients, older age, secondary AML, a concomitant mutation in TP53 showed a significant negative impact in terms of OS and DFS. Concomitant mutations in NPM1 and IDH2 were associated with better outcomes. Treatment with intensive chemotherapy or clad-LDAC-Ven was associated with the highest response rates.

Prognosis impact of serous metastases (SMs) in clear cell renal cell carcinoma patients in the GETUG-AFU-26 NIVOREN phase II trial.

e16566 Background: Nivolumab monotherapy (N) is a standard of care for patients with metastatic clear cell renal cell carcinoma (ccRCC) after failure of antiangiogenic therapies. IMDC criteria is the established prognostic model in anyline of systemic treatment including with N. While liver, bone and brain have been reported to convey a dismal prognosis, little is known about the pejorative prognostic impact of serous metastatic sites (pleura, peritoneum, pericardium) in patients receiving anti-PD (L) -1 treatment. Methods: We aimed to assess survival, and activity of N in patients included in the GETUG-AFU 26 NIVOREN phase II prospective trial ( NCT03013335 ), according to serous metastases (SMs). Results: Overall, 720 patients with metastatic ccRCC, and treated with N. Baseline RECIST metastases data were available for 708 patients included in this analysis. Among them, 142 (20%) had SMs (pleura, n=91 ; peritoneum, n=50 ; pericardium, n=1). Median PFS (4.5 vs 2.6 mo ; HR :1.31 ; p=0.0079), and OS (26.1 vs 15 mo ; HR :1.67 ; p&lt;0.0001) were significantly lower in patients with SMs. The dismal prognostic impact was observed both with pleura and peritoneum SMs. These 2 sites were not significantly associated. Using multivariate Cox models, SMs remained significantly associated with poor survival, independently of IMDC category, gender, age, and number of previous lines of therapy. Objective response rate in patients with SMs was not significantly different from others patients (16.4 vs 22.1%; p=0.147). SMs were not statistically associated with known poor prognosis metastatic sites (cerebral, bone, and liver.) Conclusions: SMs are a strong independent prognostic impact in patients receiving N for metastatic ccRCC Poor prognostic metastatic sites should be considered when assessing the prognosis of patients with metastatic ccRCC

The Pan-Immune-Inflammation Value in microsatellite instability–high metastatic colorectal cancer patients treated with immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) yielded unprecedented efficacy in patients with microsatellite instability (MSI)–high metastatic colorectal cancer (mCRC). Since the Pan-Immune-Inflammation Value (PIV) is a blood-based biomarker with prognostic usefulness in mCRC, it might predict clinical outcomes and primary resistance to ICIs. MethodsWe retrospectively analysed the association of PIV and its early modulation at 3/4 weeks after treatment initiation with the outcomes of MSI-high mCRC patients receiving anti-programmed death-(ligand)1 (PD-[L]1) +/− anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) agents. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. PIV cut-offs were determined using the maximally selected rank statistics. ResultsA total of 163 patients were included. In the multivariable models for overall survival (OS) and progression-free survival (PFS), both high (>492) baseline PIV (OS: adjusted [a] HR, 3.00; 95% CI, 1.49–6.04, p = 0.002; PFS: aHR, 1.91; 95% CI, 1.06–3.44, p = 0.031) and early PIV increase ≥+30% (OS: aHR, 3.21; 95% CI, 1.65–6.23, p < 0.001; PFS: aHR, 2.25; 95% CI, 1.30–3.89, p = 0.003) confirmed an independent prognostic impact. After stratifying patients according to baseline PIV and ICI regimen, OS and PFS were significantly worse in subjects with high PIV receiving anti-PD-1/PD-L1 monotherapy. Early PIV increase was an independent predictor of clinical benefit (aOR, 0.23; 95% CI, 0.08–0.66; p = 0.007), whereas a trend was observed for baseline PIV (aOR, 0.33; 95% CI, 0.10–1.07; p = 0.065). ConclusionPIV is a strong predictor of outcomes in MSI-high mCRC patients receiving ICIs. Prospective validation of these results is required to establish its role as a stratification factor for personalised combination strategies.

Integrative prognostic models predict long-term survival after immunochemotherapy in chronic lymphocytic leukemia patients.

Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) can induce long-term remissions in patients with chronic lymphocytic leukemia. Treatment efficacy with Bruton's tyrosine kinase inhibitors was found similar to FCR in untreated chronic lymphocytic leukemia patients with a mutated immunoglobulin heavy chain variable (IGHV) gene. In order to identify patients who specifically benefit from FCR, we developed integrative models including established prognostic parameters and gene expression profiling (GEP). GEP was conducted on n=337 CLL8 trial samples, “core” probe sets were summarized on gene levels and RMA normalized. Prognostic models were built using penalized Cox proportional hazards models with the smoothly clipped absolute deviation penalty. We identified a prognostic signature of less than a dozen genes, which substituted for established prognostic factors, including TP53 and IGHV gene mutation status. Independent prognostic impact was confirmed for treatment, β2-microglobulin and del(17p) regarding overall survival and for treatment, del(11q), del(17p) and SF3B1 mutation for progression-free survival. The combination of independent prognostic and GEP variables performed equal to models including only established non-GEP variables. GEP variables showed higher prognostic accuracy for patients with long progression-free survival compared to categorical variables like the IGHV gene mutation status and reliably predicted overall survival in CLL8 and an independent cohort. GEP-based prognostic models can help to identify patients who specifically benefit from FCR treatment. The CLL8 trial is registered under EUDRACT-2004-004938-14 and clinicaltrials gov. Identifier: NCT00281918.

Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients.

Simple SummaryThe use of BRD4 inhibitors has emerged as a novel therapeutic approach in a wide variety of tumors including the triple negative breast cancer. Moreover, PP2A has been proposed as the phosphatase involved in regulating BRD4 phosphorylation and stabilization. Our aim was to evaluate for the first time the clinical impact of BRD4 phosphorylation in triple negative breast cancer patients and as well as its potential linking with the PP2A activation status in this disease. Our findings are special relevant since they suggest the prognostic value of BRD4 phosphorylation levels, and the potential clinical usefulness of PP2A inhibition markers to anticipate response to BRD4 inhibitors. The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences (p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall (p < 0.001) and event-free survival (p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition.

The prognostic impact of circulating homeobox A9 methylated DNA in advanced non-small cell lung cancer.

BackgroundThe homeobox A9 gene encodes a transcription factor, and aberrantly methylated homeobox A9 in the circulation has been suggested as a prognostic marker in early stage non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the prognostic impact of methylated homeobox A9 in plasma from patients with advanced NSCLC.MethodsBlood samples were prospectively collected from patients with NSCLC stage III and IV receiving standard first line chemotherapy. Sampling took place before treatment initiation and subsequently before each treatment cycle. Plasma was stored at −80 °C until analysis. DNA was extracted, and following bisulfite conversion methylated homeobox A9 was analyzed by methylation specific droplet digital polymerase chain reaction. Detection of methylated homeobox A9 was assessed as a binary variable. The primary endpoint was overall survival (OS).ResultsA total of 231 patients were included. At baseline methylated homeobox A9 was detected in 78.5% of the patients with a clear correlation to survival. The median OS for patients with and without detectable methylated homeobox A9 was 7.4 and 11.1 months, respectively [hazard ratio (HR) 1.79, 95% confidence interval (CI): 1.35–2.38, P<0.001]. The difference increased after the first cycle of treatment. At this time point the median OS was 6.2 and 15.6 months for patients with and without detectable methylated homeobox A9, respectively (HR 2.07, 95% CI: 1.58–2.73, P<0.001). The independent prognostic impact of detectable methylated homeobox A9 after one treatment cycle assessed by multiple Cox regression including known prognostic factors resulted in a HR of 3.79 (2.19–6.54, P<0.001) compared to undetectable methylated homeobox A9.ConclusionsMeasurable methylated homeobox A9 after the first treatment cycle may serve as a valuable prognostic marker in patients with advanced NSCLC. Routine clinical application with treatment reconsideration calls for further studies, preferably in prospective clinical trials.

Secretome of Activated Fibroblasts Induced by Exosomes for the Discovery of Biomarkers in Non-Small Cell Lung Cancer.

Molecules involved in crosstalk between tumor cells and fibroblasts play vital roles in tumor progression. Extracellular matrix proteins, whose abundance is altered after being affected by tumor-derived exosomes, possess considerable promise as biomarkers for diagnosis or prognosis. In this study, quantitative proteomics is employed to determine the abundance of proteins secreted by normal fibroblasts and exosome-activated fibroblasts, which first identify differentially secreted proteins affected by lung cancer cell-derived exosomes. Based on the differentially secreted proteins and multiple independent datasets comprising 1897 patient samples with non-small cell lung carcinoma or other lung diseases, a diagnostic marker is identified that can effectively distinguish tumor tissues from normal tissue, as well as tumor-associated stroma from normal stroma, and a five-gene prognostic signature is presented with independent prognostic impact to identify patients who may require further adjuvant therapy after surgical resection. In addition, the secretome provides novel potential targets for clinical treatment.