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Purpose:Follicular lymphoma (FL) is the most frequent indolent non-Hodgkin lymphoma. Around 20% of patients suffer early disease progression within 24 months (POD24) of diagnosis. This study examined the significance of circulating tumor DNA (ctDNA) in predicting response to therapy and POD24 in patients with FL.Experimental Design:We collected 100 plasma samples, before and during the treatment, from 36 patients with FL prospectively enrolled in 8 Spanish hospitals. They were treated with a chemotherapy-rituximab regimen and followed up for a median of 3.43 years. We performed targeted deep sequencing in cell-free DNA (cfDNA) and tumor genomic DNA from 31 diagnostic biopsy samples.Results:Of the alterations detected in the diagnostic tissue samples, 73% (300/411) were also identified in basal cfDNA. The mean numbers of alterations per basal cfDNA sample in patients who suffered progression of disease within 24 months (POD24-pos) or did not achieve complete response (non-CR) were significantly higher than in POD24-neg or CR patients (unpaired samples t test, P = 0.0001 and 0.001, respectively). Pretreatment ctDNA levels, as haploid genome equivalents per milliliter of plasma, were higher in patients without CR (P = 0.02) and in POD24-pos patients compared with POD24-neg patients (P < 0.001). Dynamic analysis showed that ctDNA levels decreased dramatically after treatment, although the reduction was more significant in patients with CR and POD24-neg patients.Conclusions:Basal ctDNA levels are associated with the risk of early progression and response to treatment in FL. cfDNA monitoring and genotyping during treatment and follow-up predict response to treatment and early progression.

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Supplementary Data 1

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment—panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA

Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort (C) 1), G1/2 gastrointestinal (C2), G1/2 pancreatic (C3) and G3 gastroenteropancreatic (GEP) (C4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month (m) disease control rate (DCR) for C1-3 and 9-m overall survival (OS) rate for C4. Median follow-up was 16.5 m; 9-m DCR was 25.9%/35.5%/25% for C1, 2, and 3 respectively. The 9-m OS rate for C4 was 36.1%. Benefit in C4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab was safe in NENs and showed modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.

Purpose: Follicular lymphoma (FL) is the most frequent indolent non-Hodgkin lymphoma. Around 20% of patients suffer early disease progression within 24 months (POD24) of diagnosis. This study examined the significance of circulating tumor DNA (ctDNA) in predicting response to therapy and POD24 in patients with FL. Experimental Design: We collected 100 plasma samples, before and during the treatment, from 36 patients with FL prospectively enrolled in 8 Spanish hospitals. They were treated with a chemotherapy-rituximab regimen and followed up for a median of 3.43 years. We performed targeted deep sequencing in cell-free DNA (cfDNA) and tumor genomic DNA from 31 diagnostic biopsy samples. Results: Of the alterations detected in the diagnostic tissue samples, 73% (300/411) were also identified in basal cfDNA. The mean numbers of alterations per basal cfDNA sample in patients who suffered progression of disease within 24 months (POD24-pos) or did not achieve complete response (non-CR) were significantly higher than in POD24-neg or CR patients (unpaired samples t test, P = 0.0001 and 0.001, respectively). Pretreatment ctDNA levels, as haploid genome equivalents per milliliter of plasma, were higher in patients without CR (P = 0.02) and in POD24-pos patients compared with POD24-neg patients (P < 0.001). Dynamic analysis showed that ctDNA levels decreased dramatically after treatment, although the reduction was more significant in patients with CR and POD24-neg patients. Conclusions: Basal ctDNA levels are associated with the risk of early progression and response to treatment in FL. cfDNA monitoring and genotyping during treatment and follow-up predict response to treatment and early progression.

[Introduction] Somatostatin analogs (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NENs., [Methods] We identified patients with well-differentiated (Ki-67% ≤20%), metastatic GEP-NENs treated in first line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real-world clinical practice versus RCTs., [Results] The dataset contained 535 patients with a median age of 62 years (range: 26–89). The median Ki-67% was 4 (range: 0–20). The most common primary tumor sites were as follows: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n = 266) and half, lanreotide autogel (n = 269). The median PFS was 28.0 months (95% CI: 22.1–32.0) for octreotide versus 30.1 months (95% CI: 23.1–38.0) for lanreotide. The overall hazard ratio for lanreotide versus octreotide was 0.90 (95% credible interval: 0.71–1.12). The probability of effect sizes >30% with lanreotide versus octreotide was 2 and 6% for midgut and foregut NENs, respectively., [Conclusion] Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data). Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs., The study has been funded by a restricted grant from Novartis Farmacéutica, S.A. RGETNE and the GETNE group is partially funded by Ipsen, Novartis, Pfizer and AAA. Dr Angela Lamarca received funding from ASCO Conquer Cancer Foundation Young Investigator Award and The Christie Charity. Dr Jorge Barriuso received funding from the received funding from the ENETS Centre of Excellence Fellowship Grant Award.

7569 Background: Follicular lymphoma (FL) is the most frequently occurring indolent non-Hodgkin lymphoma, with generally favorable outcomes but a variable clinical course. Around 20% of patients suffer progression of disease within 24 months (POD24) of chemoimmunotherapy. In this prospective study, we examined the prognostic value of circulating tumor DNA (ctDNA), before and during treatment, to predict response and POD24 in FL patients. Methods: We collected 110 plasma samples from 39 patients diagnosed with FL, prospectively enrolled in 8 Spanish hospitals and treated with Chemotherapy-Rituximab regimen from April 2017 to November 2020 with a median follow-up of 41 months (m). Samples were collected before treatment (basal), mid-treatment (3m), at the end of treatment (EOT) (6m) and relapse or follow-up. We performed targeted deep sequencing in cell-free DNA and paired genomic DNA from 30 formalin-fixed paraffin-embedded tumoral (FFPET) samples with the same gene panel. Results: Before treatment, ctDNA levels, measured as haploid genome equivalents per milliliter of plasma (hGE/mL), were detected in 17/30 patients. Basal ctDNA levels were higher in patients without complete response (CR) than in CR patients [18 vs 14 log2(hGE/mL); Mann-Whitney P = 0.007] and in patients with POD24 compared to those not-POD24 [18 vs 13 log2(hGE/mL); P = 0.005]. None of the 13 patients with zero basal ctDNA levels, experienced POD24. Patients with at least one mutation detected in basal ctDNA had an inferior 24-months PFS than patients without alterations (64 vs 100%, log-rank test P = 0.027). In addition, basal ctDNA levels were detected in one patient with low FLIPI, but partial response and POD24, and by contrast, no ctDNA was detected in another patient with CR and no progression event but high FLIPI. From the alterations detected in FFPET samples, 66% were also identified in basal ctDNA. No alterations were detected in basal ctDNA from 7 patients with CR and 3 patients with watch-and-wait strategy. Dynamic analysis showed that ctDNA levels decreased after treatment for every patient (3 mo), but the reduction at EOT was higher in patients achieving CR than in non-CR patients (12 vs 3 log-reduction) and in not-POD24 patients compared to those with POD24 (10 vs 8). Furthermore, patients with at least one mutation detected in ctDNA at EOT had a shorter 24-months PFS than those without alterations (50 vs 90%). The sensitivity to detect alterations in ctDNA at EOT was 94% in patients not achieving a CR and no mutation was detected in patients with CR. Conclusions: In a real-life, prospective-based population, we showed that pre-treatment and dynamic molecular response measured by ctDNA, could be useful to stratify patients and predict response to treatment and early relapse in FL patients.