BACKGROUND Using mobile health (mHealth) interventions such as smartphone apps to deliver health ... more BACKGROUND Using mobile health (mHealth) interventions such as smartphone apps to deliver health services is an opportunity to engage patients more actively in their own treatment. Usability tests allow for the evaluation of a service by testing it out on the relevant users before implementation in clinical practice. OBJECTIVE The objective of this study was to design, develop, and evaluate the user interface of an app that would aid patients with cancer in reporting a more comprehensive summary of their side effects. METHODS The usability test was conducted by exposing patients with cancer to a prototype of an mHealth app that allowed for reporting of side effects from a chemotherapy regimen. After solving a set of 13 tasks, the test participants completed a system usability scale questionnaire and were interviewed using a semistructured interview guide. The interviews were later transcribed and analyzed. RESULTS The 10 test participants had a mean age of 56.5 (SD 7.11) years. The ...
BACKGROUND: We evaluated first-line treatment of metastatic microsatellite-stable colorectal canc... more BACKGROUND: We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatinbased chemotherapy alternating with immune checkpoint blockade. METHODS: Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. RESULTS: Eighty patients were randomised and 38 in each group received treatment. PFS was comparable-control group: median 9.2 months (95% confidence interval (CI), 6.3-12.7); experimental group: median 9.2 months (95% CI, 4.5-15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04-0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8-23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. CONCLUSIONS: The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03388190 (02/01/2018).
PURPOSE Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor progn... more PURPOSE Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor prognosis. Most GEP-NEC are diagnosed with metastatic disease, with only minor biopsies available for molecular diagnostics. We assessed the applicability of liquid biopsies for molecular profiling of GEP-NEC. MATERIALS AND METHODS We performed massive parallel sequencing of 76 cancer-related genes in circulating tumor DNA from 50 patients with advanced GEP-NEC and compared findings to previous analyses of solid tumor biopsies from the same patients. Plasma samples were collected before therapy, and the median time span between blood and tissue sampling was 25 days. RESULTS We detected 178 somatic mutations in the liquid biopsies, 127 (71%) were also detected in the solid biopsies, whereas 51 (29%) were unique to the liquid biopsies. In the same 76 genes, we previously detected 199 somatic mutations (single nucleotide variants) in solid biopsies, of which 127 (64%) were also now detected in l...
PURPOSE Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor progn... more PURPOSE Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor prognosis. Most GEP-NEC are diagnosed with metastatic disease, with only minor biopsies available for molecular diagnostics. We assessed the applicability of liquid biopsies for molecular profiling of GEP-NEC. MATERIALS AND METHODS We performed massive parallel sequencing of 76 cancer-related genes in circulating tumor DNA from 50 patients with advanced GEP-NEC and compared findings to previous analyses of solid tumor biopsies from the same patients. Plasma samples were collected before therapy, and the median time span between blood and tissue sampling was 25 days. RESULTS We detected 178 somatic mutations in the liquid biopsies, 127 (71%) were also detected in the solid biopsies, whereas 51 (29%) were unique to the liquid biopsies. In the same 76 genes, we previously detected 199 somatic mutations (single nucleotide variants) in solid biopsies, of which 127 (64%) were also now detected in liquid biopsies. In exploratory subgroup assessments, concordance was higher in patients with liver metastases (P = 1.5 × 10-5) and increasing with level of liver involvement (P = 1.2 × 10-4). The concordance was similar between GEP-NEC with different primary sites, except being lower in esophageal cases (P = .001). Concordance was not associated with tumor mutation burden. Tumor tissue mutations also detected in liquid biopsies was lower for MSI (40%) versus MSS tumors (70%; P = 7.8 × 10-4). We identified potentially targetable mutations in plasma of 26 (52%) of patients with GEP-NEC; nine patients (18%) had potentially targetable mutation detected only in liquid biopsies. CONCLUSION Liquid biopsy analyses may be an applicable alternative to solid biopsies in GEP-NEC. Liquid biopsies may add additional mutations compared with tumor biopsies alone and could be useful for biomarker assessment in clinical trials for these patients.
BACKGROUND: Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mut... more BACKGROUND: Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mutation (mutKRAS) have an inferior prognosis after liver or lung surgery, whereas the prognostic role in the context of peritoneal metastasis (PM) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been less investigated. METHODS: In total, 257 patients with non-appendiceal PM-CRC were included from the Norwegian National Unit for CRS-HIPEC. RESULTS: In total, 180 patients received CRS-HIPEC with Mitomycin C, 77 patients received palliative surgery only. In the CRS-HIPEC group, mutBRAF was found in 24.7%, mutKRAS 33.9% and double wild-type 41.4% without differences in survival. MSI was found in 29.3% of mutBRAF cases. Patients with mutBRAF/MSI had superior 5-year survival compared to mutBRAF with MSS (58.3% vs 25.2%, P = 0.022), and better 3-year disease-free survival (DFS) compared to mutKRAS (48.6% vs 17.2%, P = 0.049). Peritoneal Cancer Index and the number of lymph node metastasis were prognostic for OS, and the same two, location and gender prognostic for DFS in multivariate analysis. CONCLUSIONS: PM-CRC with CRS-HIPEC patients has a surprisingly high proportion of mutBRAF (24.7%). Survival was similar comparing mutBRAF, mutKRAS and double wild-type cases, whereas a small subgroup with mutBRAF and MSI had better survival. Patients with mutBRAF tumours and limited PM should be considered for CRS-HIPEC.
High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive ... more High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive cancers. The molecular etiology of these tumors remains unclear, and the prevalence of pathogenic germline variants in patients with HG-GEP NENs is unknown. We assessed sequencing data of 360 cancer genes in normal tissue from 240 patients with HG-GEP NENs; 198 patients with neuroendocrine carcinomas (NECs) and 42 with grade 3 neuroendocrine tumors (NET G3). Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in three patients and a recurrent MUTYH variant in two patients, indicating that these genes may be important underlying risk factors for HG-GEP NENs when mutated. Further, germline variants were found in canonical tumor-suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0–17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP NECs. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG-GEP NENs with germline pathogenic variants is relatively high, but still &lt;10%, meaning that that germline mutations cannot be the major underlying cause of HG-GEP NENs.
Purpose: Immune checkpoint inhibition (ICI) may result in tumor response patterns that differ fro... more Purpose: Immune checkpoint inhibition (ICI) may result in tumor response patterns that differ from efficacy measures of directly cytotoxic chemotherapies. Hence, the selection of patients for experimental ICI schedules, for instance in MSS-mCRC, calls for applicable and reliable signals of activity or early failure that enable treatment adaptation and maintain patient safety. Experimental procedures: In the ongoing METIMMOX phase 2 study, we hypothesize that patients with previously untreated unresectable MSS-mCRC can obtain durable disease control to ICI when given short-course oxaliplatin-based chemotherapy (2 cycles of FLOX Q2W) before 2 cycles of nivolumab (240 mg Q2W) in a repeat sequential schedule to a total of 8 cycles. Patients have been randomly assigned to either this experimental study arm or a control arm of 8 FLOX cycles Q2W (standard-of-care; SoC), in both cases before treatment break until disease progression and reintroduction of a new treatment sequence. Radiologic response assessment is performed every 8 weeks with progression-free survival (PFS) as the primary end point. Results: At analysis 10 November 2021, median PFS was 9.3 months (95% CI, 8.3-10.3) for SoC (n = 34) and 11.4 months (95% CI, 7.4-15.5) for the experimental therapy (n = 39) (p = 0.335; log-rank test). In the latter group, 37 patients had available response evaluation at minimum 8 weeks of study treatment, as 2 patients (compared to 4 in the control group) had discontinued treatment due to intolerable toxicity before the first post-baseline assessment. The control arm patients had deeper responses with mean 23% (SD, 19%) target lesion reduction compared to mean 8%(SD, 33%) reduction for the experimental schedule (p = 0.028; Student’s t-test). We categorized the experimental arm patients into those with ≥10% (n = 20) or &lt;10% (n = 17) target lesion reduction at 8 weeks. Median PFS for the ≥10% group was 15.2 months (95% CI, 11.4-19.0) and for the &lt;10% group 4.5 months (95% CI, 3.2-5.7), which was clearly superior and inferior to the control arm PFS (p = 0.007 for the ≥10% group and p = 0.019 for the &lt;10% group; log-rank test). Categorisation of experimental arm patients set at higher than 10% target lesion change at the first radiologic response assessment did not identify patients with longer PFS. Conclusions: While the SoC first-line chemotherapy resulted in deeper early responses, target lesion reduction of ≥10% at 8 weeks identified MSS-mCRC patients who held ICI responsiveness evoked by short-course oxaliplatin-based chemotherapy, with significantly improved PFS compared to the SoC. An early radiologic signal of clinical activity may guide the selection of patients to the safe continuation of investigational ICI schedules; however, we do not know if adopting it may compromise prognosis for patients with early ICI failure who can proceed with SoC. Citation Format: Sebastian Meltzer, Anne Negård, Hanne Mari Hamre, Christian Kersten, Eva Hofsli, Marianne Grønlie Guren, Halfdan Sørbye, Kjersti Flatmark, Anne Hansen Ree. Early radiologic signal of nivolumab responsiveness after short-course oxaliplatin-based chemotherapy in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1279.
MicroRNAs (miRNAs) are promising prognostic and diagnostic biomarkers due to their high stability... more MicroRNAs (miRNAs) are promising prognostic and diagnostic biomarkers due to their high stability in blood. Here we investigate the expression of miRNAs and other noncoding (nc) RNAs in serum of rectal cancer patients. Serum from 96 rectal cancer patients was profiled using small RNA sequencing and expression of small RNAs was correlated with the clinicopathological characteristics of the patients. Multiple classes of RNAs were detected, including miRNAs and fragments of tRNAs, snoRNAs, long ncRNAs, and other classes of RNAs. Several miRNAs, miRNA variants (isomiRs) and other ncRNAs were differentially expressed between Stage IV and Stage I-III rectal cancer patients, including several members of the miR-320 family. Furthermore, we show that high expression of miR-320d as well as one tRNA fragment is associated with poor survival. We also show that several miRNAs and isomiRs are differentially expressed between patients receiving preoperative chemoradiotherapy and patients who did not receive any treatment before serum collection. In summary, our study shows that the expression of miRNAs and other small ncRNAs in serum may be used to predict distant metastasis and survival in rectal cancer.
3552 Background: The CRC incidence increases sharply from the age of 60. Most patients harbor pri... more 3552 Background: The CRC incidence increases sharply from the age of 60. Most patients harbor primarily non-immunogenic MSS disease and abdominal metastases are in particular considered unresponsive to immune checkpoint blockade (ICB). The METIMMOX trial explored if MSS-CRC can be transformed into an immunogenic malignancy by short-course oxaliplatin-based therapy and if followed by ICB (without concomitant chemotherapy that might compromise an invoked tumor-defeating immunity) may result in durable clinical response for patients with abdominal metastases. Methods: Patients had MSS-CRC with infradiaphragmatic metastases deemed unresectable, ECOG performance status 0-1, and were eligible for first-line oxaliplatin-based therapy. They were randomly assigned to FLOX (oxaliplatin 85 mg/m2 day 1, bolus 5-fluorouracil 500 mg/m2 and folinic acid 100 mg days 1-2) Q2W (control arm) or alternating cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W (experimental (exp) arm) with break periods at prespecified intervals. Response assessment per i/RECIST by blinded central review was done every 8 weeks with progression-free survival (PFS) as primary endpoint. Sample size of 40 in each arm with 1:1 randomization would detect exp arm doubling of median PFS. Associations between PFS and relevant patient and disease variables were estimated by Cox proportional-hazards regression models. Prespecified correlative analyses included circulating tumor DNA (ctDNA) by droplet digital PCR and circulating immune cell composition by high-dimensional single-cell mass cytometry. Results: Of 80 enrolled subjects (05/2018-10/2021), 76 intention-to-treat (ITT) cases were equally allocated to the study arms and followed to censoring at 10/2022 with identical median PFS of 9.3 months (95% CI, 6.4-12.9 (control arm) and 4.6-15.2 (exp arm)). The adjusted Cox model revealed interaction between age and study arm, as patients ≥60 years had significantly lowered risk of progression when receiving exp therapy (median PFS 13.6 months (95% CI, 8.5-18.8); p = 0.022). No unexpected adverse events were recorded; specifically, no grade ≥4 immune-mediated adverse event occurred. Of note, 17% of exp arm patients had durable complete response, among whom all BRAF-mutant cases ( n = 3) with PFS 21-35 months and rapid clearance of baseline BRAF-mutant ctDNA (control arm BRAF-mutant cases ( n = 10), median PFS 3.6 months). Responding exp arm patients showed distinct subsets of circulating immune cells with more homogenous profiles than ICB-unresponsive subjects. Conclusions: With equal primary endpoint for the ITT cases, alternating short-course oxaliplatin-based therapy and nivolumab significantly improved PFS compared to standard first-line chemotherapy in MSS-CRC patients ≥60 years with abdominal metastases. Clinical trial information: NCT03388190 .
Purpose: Most mCRC patients harbor MSS disease without inherent immunogenicity. The METIMMOX stud... more Purpose: Most mCRC patients harbor MSS disease without inherent immunogenicity. The METIMMOX study (NCT03388190) explored an unconventional concept, that patients with previously untreated, unresectable abdominal metastases from MSS-CRC may achieve therapeutic efficacy from short-course oxaliplatin-based chemotherapy (FLOX) and sequential ICB (nivolumab). Among study patients who were assigned this highly experimental treatment, 15% obtained long-lasting complete response and more than a half met an early occurring radiologic signal of ICB responsiveness predicting significantly extended progression-free survival (PFS) compared to study control arm patients given standard FLOX chemotherapy [PMID: 36229579]. The aim of the present study was to verify if systemic tumor-defeating immunity had been invoked by the short-course FLOX treatment in the responding patients. The fms-related tyrosine kinase-3 ligand (Flt3L) is a circulating factor that reflects the direct cytotoxic effects of chemotherapy and also activates dendritic cells that present the shed tumor antigens to tumor-targeting T-cells. Procedures: Study patients were randomly assigned to the control arm of FLOX (oxaliplatin 85 mg/m2 on day 1 and bolus 5-fluorouracil 500 mg/m2 and folinic acid 100 mg on days 1 and 2) Q2W or the experimental arm of repeat sequential cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W. Radiologic response assessment was done every 8 weeks with PFS as the primary endpoint. Patients were categorized into those with target lesion (TL) reduction of ≥10% or &lt;10% at the first post-baseline assessment (8 weeks) [PMID: 36229579]. Serum Flt3L was measured at baseline and following the initial 2 FLOX cycles (at 4 weeks) using a Luminex assay. Results: For all subjects, median Flt3L was 103.8 pg/ml (range 24.6-306.1) at baseline and 162.4 pg/ml (range 53.3-503.8) at 4 weeks. For the experimental arm patients (n = 34), the higher 4-week Flt3L level, the deeper overall radiologic response (rho = -0.39, p = 0.022, Spearman correlation). The 4-week Flt3L level was higher in patients who obtained ≥10% TL reduction (n = 18; median 233.5 pg/ml, range 94.9-466.7) than in those who did not meet this 8-week predictive signal of extended PFS (n = 16; median 161.9 pg/ml, range 53.3-374.8; p = 0.022, Mann-Whitney U test). Selecting a 160 pg/ml cut-off, patients with 4-week Flt3L values above (n = 21) obtained longer PFS (median of 13.6 months, 95% CI 7.6-19.7) than those with serum values below (n = 13; median PFS of 5.9 months, 95% CI 2.4-9.3; p = 0.046, log-rank test). Conclusions: High circulating Flt3L after initial short-course FLOX chemotherapy, as a proxy of invoked tumor-defeating immunity, was associated with an early radiologic signal of ICB responsiveness and improved PFS in patients with MSS-mCRC. Citation Format: Sebastian Meltzer, Kjersti Flatmark, Anniken J. Fuglestad, Hanne M. Hamre, Christian Kersten, Eva Hofsli, Marianne G. Guren, Halfdan Sorbye, Anne Negård, Anne Hansen Ree. Systemic immune response invoked by short-course oxaliplatin-based chemotherapy (FLOX) for efficacy of sequential immune checkpoint blockade (ICB; nivolumab) in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3279.
BACKGROUND Using mobile health (mHealth) interventions such as smartphone apps to deliver health ... more BACKGROUND Using mobile health (mHealth) interventions such as smartphone apps to deliver health services is an opportunity to engage patients more actively in their own treatment. Usability tests allow for the evaluation of a service by testing it out on the relevant users before implementation in clinical practice. OBJECTIVE The objective of this study was to design, develop, and evaluate the user interface of an app that would aid patients with cancer in reporting a more comprehensive summary of their side effects. METHODS The usability test was conducted by exposing patients with cancer to a prototype of an mHealth app that allowed for reporting of side effects from a chemotherapy regimen. After solving a set of 13 tasks, the test participants completed a system usability scale questionnaire and were interviewed using a semistructured interview guide. The interviews were later transcribed and analyzed. RESULTS The 10 test participants had a mean age of 56.5 (SD 7.11) years. The ...
BACKGROUND: We evaluated first-line treatment of metastatic microsatellite-stable colorectal canc... more BACKGROUND: We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatinbased chemotherapy alternating with immune checkpoint blockade. METHODS: Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. RESULTS: Eighty patients were randomised and 38 in each group received treatment. PFS was comparable-control group: median 9.2 months (95% confidence interval (CI), 6.3-12.7); experimental group: median 9.2 months (95% CI, 4.5-15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04-0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8-23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. CONCLUSIONS: The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03388190 (02/01/2018).
PURPOSE Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor progn... more PURPOSE Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor prognosis. Most GEP-NEC are diagnosed with metastatic disease, with only minor biopsies available for molecular diagnostics. We assessed the applicability of liquid biopsies for molecular profiling of GEP-NEC. MATERIALS AND METHODS We performed massive parallel sequencing of 76 cancer-related genes in circulating tumor DNA from 50 patients with advanced GEP-NEC and compared findings to previous analyses of solid tumor biopsies from the same patients. Plasma samples were collected before therapy, and the median time span between blood and tissue sampling was 25 days. RESULTS We detected 178 somatic mutations in the liquid biopsies, 127 (71%) were also detected in the solid biopsies, whereas 51 (29%) were unique to the liquid biopsies. In the same 76 genes, we previously detected 199 somatic mutations (single nucleotide variants) in solid biopsies, of which 127 (64%) were also now detected in l...
PURPOSE Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor progn... more PURPOSE Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor prognosis. Most GEP-NEC are diagnosed with metastatic disease, with only minor biopsies available for molecular diagnostics. We assessed the applicability of liquid biopsies for molecular profiling of GEP-NEC. MATERIALS AND METHODS We performed massive parallel sequencing of 76 cancer-related genes in circulating tumor DNA from 50 patients with advanced GEP-NEC and compared findings to previous analyses of solid tumor biopsies from the same patients. Plasma samples were collected before therapy, and the median time span between blood and tissue sampling was 25 days. RESULTS We detected 178 somatic mutations in the liquid biopsies, 127 (71%) were also detected in the solid biopsies, whereas 51 (29%) were unique to the liquid biopsies. In the same 76 genes, we previously detected 199 somatic mutations (single nucleotide variants) in solid biopsies, of which 127 (64%) were also now detected in liquid biopsies. In exploratory subgroup assessments, concordance was higher in patients with liver metastases (P = 1.5 × 10-5) and increasing with level of liver involvement (P = 1.2 × 10-4). The concordance was similar between GEP-NEC with different primary sites, except being lower in esophageal cases (P = .001). Concordance was not associated with tumor mutation burden. Tumor tissue mutations also detected in liquid biopsies was lower for MSI (40%) versus MSS tumors (70%; P = 7.8 × 10-4). We identified potentially targetable mutations in plasma of 26 (52%) of patients with GEP-NEC; nine patients (18%) had potentially targetable mutation detected only in liquid biopsies. CONCLUSION Liquid biopsy analyses may be an applicable alternative to solid biopsies in GEP-NEC. Liquid biopsies may add additional mutations compared with tumor biopsies alone and could be useful for biomarker assessment in clinical trials for these patients.
BACKGROUND: Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mut... more BACKGROUND: Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mutation (mutKRAS) have an inferior prognosis after liver or lung surgery, whereas the prognostic role in the context of peritoneal metastasis (PM) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been less investigated. METHODS: In total, 257 patients with non-appendiceal PM-CRC were included from the Norwegian National Unit for CRS-HIPEC. RESULTS: In total, 180 patients received CRS-HIPEC with Mitomycin C, 77 patients received palliative surgery only. In the CRS-HIPEC group, mutBRAF was found in 24.7%, mutKRAS 33.9% and double wild-type 41.4% without differences in survival. MSI was found in 29.3% of mutBRAF cases. Patients with mutBRAF/MSI had superior 5-year survival compared to mutBRAF with MSS (58.3% vs 25.2%, P = 0.022), and better 3-year disease-free survival (DFS) compared to mutKRAS (48.6% vs 17.2%, P = 0.049). Peritoneal Cancer Index and the number of lymph node metastasis were prognostic for OS, and the same two, location and gender prognostic for DFS in multivariate analysis. CONCLUSIONS: PM-CRC with CRS-HIPEC patients has a surprisingly high proportion of mutBRAF (24.7%). Survival was similar comparing mutBRAF, mutKRAS and double wild-type cases, whereas a small subgroup with mutBRAF and MSI had better survival. Patients with mutBRAF tumours and limited PM should be considered for CRS-HIPEC.
High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive ... more High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive cancers. The molecular etiology of these tumors remains unclear, and the prevalence of pathogenic germline variants in patients with HG-GEP NENs is unknown. We assessed sequencing data of 360 cancer genes in normal tissue from 240 patients with HG-GEP NENs; 198 patients with neuroendocrine carcinomas (NECs) and 42 with grade 3 neuroendocrine tumors (NET G3). Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in three patients and a recurrent MUTYH variant in two patients, indicating that these genes may be important underlying risk factors for HG-GEP NENs when mutated. Further, germline variants were found in canonical tumor-suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0–17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP NECs. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG-GEP NENs with germline pathogenic variants is relatively high, but still &lt;10%, meaning that that germline mutations cannot be the major underlying cause of HG-GEP NENs.
Purpose: Immune checkpoint inhibition (ICI) may result in tumor response patterns that differ fro... more Purpose: Immune checkpoint inhibition (ICI) may result in tumor response patterns that differ from efficacy measures of directly cytotoxic chemotherapies. Hence, the selection of patients for experimental ICI schedules, for instance in MSS-mCRC, calls for applicable and reliable signals of activity or early failure that enable treatment adaptation and maintain patient safety. Experimental procedures: In the ongoing METIMMOX phase 2 study, we hypothesize that patients with previously untreated unresectable MSS-mCRC can obtain durable disease control to ICI when given short-course oxaliplatin-based chemotherapy (2 cycles of FLOX Q2W) before 2 cycles of nivolumab (240 mg Q2W) in a repeat sequential schedule to a total of 8 cycles. Patients have been randomly assigned to either this experimental study arm or a control arm of 8 FLOX cycles Q2W (standard-of-care; SoC), in both cases before treatment break until disease progression and reintroduction of a new treatment sequence. Radiologic response assessment is performed every 8 weeks with progression-free survival (PFS) as the primary end point. Results: At analysis 10 November 2021, median PFS was 9.3 months (95% CI, 8.3-10.3) for SoC (n = 34) and 11.4 months (95% CI, 7.4-15.5) for the experimental therapy (n = 39) (p = 0.335; log-rank test). In the latter group, 37 patients had available response evaluation at minimum 8 weeks of study treatment, as 2 patients (compared to 4 in the control group) had discontinued treatment due to intolerable toxicity before the first post-baseline assessment. The control arm patients had deeper responses with mean 23% (SD, 19%) target lesion reduction compared to mean 8%(SD, 33%) reduction for the experimental schedule (p = 0.028; Student’s t-test). We categorized the experimental arm patients into those with ≥10% (n = 20) or &lt;10% (n = 17) target lesion reduction at 8 weeks. Median PFS for the ≥10% group was 15.2 months (95% CI, 11.4-19.0) and for the &lt;10% group 4.5 months (95% CI, 3.2-5.7), which was clearly superior and inferior to the control arm PFS (p = 0.007 for the ≥10% group and p = 0.019 for the &lt;10% group; log-rank test). Categorisation of experimental arm patients set at higher than 10% target lesion change at the first radiologic response assessment did not identify patients with longer PFS. Conclusions: While the SoC first-line chemotherapy resulted in deeper early responses, target lesion reduction of ≥10% at 8 weeks identified MSS-mCRC patients who held ICI responsiveness evoked by short-course oxaliplatin-based chemotherapy, with significantly improved PFS compared to the SoC. An early radiologic signal of clinical activity may guide the selection of patients to the safe continuation of investigational ICI schedules; however, we do not know if adopting it may compromise prognosis for patients with early ICI failure who can proceed with SoC. Citation Format: Sebastian Meltzer, Anne Negård, Hanne Mari Hamre, Christian Kersten, Eva Hofsli, Marianne Grønlie Guren, Halfdan Sørbye, Kjersti Flatmark, Anne Hansen Ree. Early radiologic signal of nivolumab responsiveness after short-course oxaliplatin-based chemotherapy in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1279.
MicroRNAs (miRNAs) are promising prognostic and diagnostic biomarkers due to their high stability... more MicroRNAs (miRNAs) are promising prognostic and diagnostic biomarkers due to their high stability in blood. Here we investigate the expression of miRNAs and other noncoding (nc) RNAs in serum of rectal cancer patients. Serum from 96 rectal cancer patients was profiled using small RNA sequencing and expression of small RNAs was correlated with the clinicopathological characteristics of the patients. Multiple classes of RNAs were detected, including miRNAs and fragments of tRNAs, snoRNAs, long ncRNAs, and other classes of RNAs. Several miRNAs, miRNA variants (isomiRs) and other ncRNAs were differentially expressed between Stage IV and Stage I-III rectal cancer patients, including several members of the miR-320 family. Furthermore, we show that high expression of miR-320d as well as one tRNA fragment is associated with poor survival. We also show that several miRNAs and isomiRs are differentially expressed between patients receiving preoperative chemoradiotherapy and patients who did not receive any treatment before serum collection. In summary, our study shows that the expression of miRNAs and other small ncRNAs in serum may be used to predict distant metastasis and survival in rectal cancer.
3552 Background: The CRC incidence increases sharply from the age of 60. Most patients harbor pri... more 3552 Background: The CRC incidence increases sharply from the age of 60. Most patients harbor primarily non-immunogenic MSS disease and abdominal metastases are in particular considered unresponsive to immune checkpoint blockade (ICB). The METIMMOX trial explored if MSS-CRC can be transformed into an immunogenic malignancy by short-course oxaliplatin-based therapy and if followed by ICB (without concomitant chemotherapy that might compromise an invoked tumor-defeating immunity) may result in durable clinical response for patients with abdominal metastases. Methods: Patients had MSS-CRC with infradiaphragmatic metastases deemed unresectable, ECOG performance status 0-1, and were eligible for first-line oxaliplatin-based therapy. They were randomly assigned to FLOX (oxaliplatin 85 mg/m2 day 1, bolus 5-fluorouracil 500 mg/m2 and folinic acid 100 mg days 1-2) Q2W (control arm) or alternating cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W (experimental (exp) arm) with break periods at prespecified intervals. Response assessment per i/RECIST by blinded central review was done every 8 weeks with progression-free survival (PFS) as primary endpoint. Sample size of 40 in each arm with 1:1 randomization would detect exp arm doubling of median PFS. Associations between PFS and relevant patient and disease variables were estimated by Cox proportional-hazards regression models. Prespecified correlative analyses included circulating tumor DNA (ctDNA) by droplet digital PCR and circulating immune cell composition by high-dimensional single-cell mass cytometry. Results: Of 80 enrolled subjects (05/2018-10/2021), 76 intention-to-treat (ITT) cases were equally allocated to the study arms and followed to censoring at 10/2022 with identical median PFS of 9.3 months (95% CI, 6.4-12.9 (control arm) and 4.6-15.2 (exp arm)). The adjusted Cox model revealed interaction between age and study arm, as patients ≥60 years had significantly lowered risk of progression when receiving exp therapy (median PFS 13.6 months (95% CI, 8.5-18.8); p = 0.022). No unexpected adverse events were recorded; specifically, no grade ≥4 immune-mediated adverse event occurred. Of note, 17% of exp arm patients had durable complete response, among whom all BRAF-mutant cases ( n = 3) with PFS 21-35 months and rapid clearance of baseline BRAF-mutant ctDNA (control arm BRAF-mutant cases ( n = 10), median PFS 3.6 months). Responding exp arm patients showed distinct subsets of circulating immune cells with more homogenous profiles than ICB-unresponsive subjects. Conclusions: With equal primary endpoint for the ITT cases, alternating short-course oxaliplatin-based therapy and nivolumab significantly improved PFS compared to standard first-line chemotherapy in MSS-CRC patients ≥60 years with abdominal metastases. Clinical trial information: NCT03388190 .
Purpose: Most mCRC patients harbor MSS disease without inherent immunogenicity. The METIMMOX stud... more Purpose: Most mCRC patients harbor MSS disease without inherent immunogenicity. The METIMMOX study (NCT03388190) explored an unconventional concept, that patients with previously untreated, unresectable abdominal metastases from MSS-CRC may achieve therapeutic efficacy from short-course oxaliplatin-based chemotherapy (FLOX) and sequential ICB (nivolumab). Among study patients who were assigned this highly experimental treatment, 15% obtained long-lasting complete response and more than a half met an early occurring radiologic signal of ICB responsiveness predicting significantly extended progression-free survival (PFS) compared to study control arm patients given standard FLOX chemotherapy [PMID: 36229579]. The aim of the present study was to verify if systemic tumor-defeating immunity had been invoked by the short-course FLOX treatment in the responding patients. The fms-related tyrosine kinase-3 ligand (Flt3L) is a circulating factor that reflects the direct cytotoxic effects of chemotherapy and also activates dendritic cells that present the shed tumor antigens to tumor-targeting T-cells. Procedures: Study patients were randomly assigned to the control arm of FLOX (oxaliplatin 85 mg/m2 on day 1 and bolus 5-fluorouracil 500 mg/m2 and folinic acid 100 mg on days 1 and 2) Q2W or the experimental arm of repeat sequential cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W. Radiologic response assessment was done every 8 weeks with PFS as the primary endpoint. Patients were categorized into those with target lesion (TL) reduction of ≥10% or &lt;10% at the first post-baseline assessment (8 weeks) [PMID: 36229579]. Serum Flt3L was measured at baseline and following the initial 2 FLOX cycles (at 4 weeks) using a Luminex assay. Results: For all subjects, median Flt3L was 103.8 pg/ml (range 24.6-306.1) at baseline and 162.4 pg/ml (range 53.3-503.8) at 4 weeks. For the experimental arm patients (n = 34), the higher 4-week Flt3L level, the deeper overall radiologic response (rho = -0.39, p = 0.022, Spearman correlation). The 4-week Flt3L level was higher in patients who obtained ≥10% TL reduction (n = 18; median 233.5 pg/ml, range 94.9-466.7) than in those who did not meet this 8-week predictive signal of extended PFS (n = 16; median 161.9 pg/ml, range 53.3-374.8; p = 0.022, Mann-Whitney U test). Selecting a 160 pg/ml cut-off, patients with 4-week Flt3L values above (n = 21) obtained longer PFS (median of 13.6 months, 95% CI 7.6-19.7) than those with serum values below (n = 13; median PFS of 5.9 months, 95% CI 2.4-9.3; p = 0.046, log-rank test). Conclusions: High circulating Flt3L after initial short-course FLOX chemotherapy, as a proxy of invoked tumor-defeating immunity, was associated with an early radiologic signal of ICB responsiveness and improved PFS in patients with MSS-mCRC. Citation Format: Sebastian Meltzer, Kjersti Flatmark, Anniken J. Fuglestad, Hanne M. Hamre, Christian Kersten, Eva Hofsli, Marianne G. Guren, Halfdan Sorbye, Anne Negård, Anne Hansen Ree. Systemic immune response invoked by short-course oxaliplatin-based chemotherapy (FLOX) for efficacy of sequential immune checkpoint blockade (ICB; nivolumab) in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3279.
Uploads
Papers by Eva Hofsli