Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further ...our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of nonmetastatic colorectal cancer (CRC). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using a massively parallel sequencing technique called SafeSeqS. We analyzed 485 CRC patients (230 Stage II colon, 96 Stage III colon, and 159 locally advanced rectum). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4‐6, 6‐8 and 8‐10 weeks; P = .740). ctDNA detection was associated with poorer 5‐year recurrence‐free (38.6% vs 85.5%; P < .001) and overall survival (64.6% vs 89.4%; P < .001). The predictive accuracy of postsurgery ctDNA for recurrence was higher than that of individual clinicopathologic risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele frequency (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1%, 0.5% and 1%). Postsurgery ctDNA was detected in 3 of 20 (15%) patients with locoregional and 27 of 60 (45%) with distant recurrence (P = .018). This analysis demonstrates a consistent long‐term impact of ctDNA as a prognostic marker across nonmetastatic CRC, where ctDNA outperforms other clinicopathologic risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant vs locoregional recurrence.
What's new?
Pathology‐based cancer staging, by which a patient is classified as high‐risk or low‐risk, cannot perfectly predict which patients will experience a recurrence. Circulating tumor DNA (ctDNA) analysis can more accurately predict recurrence than clinico‐pathologic features. Here, the authors report a combined analysis of three independent cohort studies of patients with non‐metastatic colorectal cancer (CRC). Patients with detectable ctDNA after surgery had a significantly lower 5‐year survival rate. The ctDNA was sequenced to detect mutations, and recurrence risk increased exponentially with increasing mutant allele fraction of ctDNA.
We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected ...high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio HR, 0.57;
< .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up.
A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors.
Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7%
44.1% for pembrolizumab
placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and
mutation status (HR, 0.51 99% CI, 0.36 to 0.73
0.66 99% CI, 0.46 to 0.95 for V600
wild type).
In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.
The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month ...median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio HR 0·57 98·4% CI 0·43–0·74, p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results.
This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.
Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% 95% CI 60·9–69·5 in the pembrolizumab group vs 49·4% 44·8–53·8 in the placebo group; HR 0·60 95% CI 0·49–0·73; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8–71·2) in the pembrolizumab group and 51·6% (46·6–56·4) in the placebo group (HR 0·61 95% CI 0·49–0·76; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3–64·1) than the placebo group 41·4% (37·0–45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 95% CI 0·49–0·70) and in those with PD-L1-positive tumours 61·4% (56·3–66·1) in the pembrolizumab group and 44·1% (39·2–48·8) in the placebo group (HR 0·59 95% CI 0·49–0·73).
Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.
Merck Sharp & Dohme.
The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival ...with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 98·4% CI 0·43–0·74; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint.
This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.
Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8–16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 SD 18·20 in the pembrolizumab group and 76·54 17·81 in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was −2·2 points (95% CI −4·3 to −0·2). The difference in average score during treatment was −1·1 points (95% CI −3·2 to 0·9) and the difference in average score after treatment was −2·2 points (−4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.
Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.
Merck Sharp & Dohme.
β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of ...β-adrenoreceptor blockade by β-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial.
Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47–0.68). β-blocker use was defined as oral administration of any β-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of β-blockers and RFS.
Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70–1.31). The HRs of RFS associated with β-blocker use were 0.67 (95% CI 0.38–1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80–1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18–0.65) among β-blocker users and 0.59 (95% CI 0.48–0.71) among those not using β-blockers.
This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation.
This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.
•β-blockers have no independent prognostic effect on recurrence-free survival in resected melanoma.•However, β-blockers may prolong recurrence-free survival when combined with adjuvant pembrolizumab.•Our results warrant further investigation of β-blockers combined with immunotherapy.
BackgroundAcral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab ...and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.MethodsPatients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).ResultsIn total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.ConclusionWhile the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.
Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the ...colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (>25% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all P<0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.
Metformin is a commonly prescribed and well-tolerated medication. In laboratory studies, metformin suppresses BRAF wild-type melanoma cells but accelerates the growth of BRAF-mutated cells. This ...study investigated the prognostic and predictive value of metformin, including with respect to BRAF mutation status, in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 randomised controlled trial.
Patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma received 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for twelve months. Pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at approximately 42 months median follow-up (Eggermont et al., TLO, 2021). Multivariable Cox regression was used to estimate associations of metformin with RFS and DMFS. Interaction terms were used to model effect modification by treatment and BRAF mutation.
Fifty-four patients (0.5%) used metformin at baseline. Metformin was not significantly associated with RFS (hazard ratio HR 0.87, 95% confidence interval CI 0.52–1.45) and DMFS (HR 0.82, 95% CI 0.47–1.44). The interaction between metformin and the treatment arm was not significant for either RFS (p = 0.92) or DMFS (p = 0.93). Among patients with mutated BRAF, the association of metformin with RFS (HR 0.70, 95% CI 0.37–1.33) was greater in magnitude though not significantly different to those without mutated BRAF (HR 0.98, 95% CI 0.56–1.69).
There was no significant impact of metformin use on pembrolizumab efficacy in resected high-risk stage III melanoma. However, larger studies or pooled analyses are needed, particularly to explore a possible effect of metformin in BRAF-mutated melanoma.
•In the EORTC 1325/KEYNOTE-054 phase III trial, concomitant use of Metformin.•Was not significantly associated with recurrence-free survival (RFS).•Did not alter the treatment difference regarding RFS.•Did not shorten RFS in BRAF-mutated melanoma, as suggested by preclinical data.
Pain is common in patients with cancer. The World Health Organisation recommends paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and combined with other agents for ...moderate/severe pain. This study estimated associations of NSAIDs with recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and the incidence of immune-related adverse events (irAEs) in high-risk patients with resected melanoma in the EORTC 1325/KEYNOTE-054 phase III clinical trial.
Patients with AJCC7 stage IIIA, IIIB or IIIC resected melanoma were randomized to receive 200 mg of adjuvant pembrolizumab (N = 514) or placebo (N = 505) 3-weekly for one year or until recurrence. As previously reported, pembrolizumab prolonged RFS and DMFS. NSAID use was defined as administration between 7 days pre-randomization and starting treatment. Multivariable Cox and Fine and Gray models were used to estimate hazard ratios (HRs) for associations of NSAIDs with RFS, DMFS and irAEs.
Of 1019 patients randomized, 59 and 44 patients in the pembrolizumab and placebo arms, respectively, used NSAIDs. NSAIDs were not associated with RFS (HR 0.91, 95% CI 0.58–1.43) or DMFS in the pembrolizumab (HR 1.03, 95% CI 0.65–1.66) or placebo arms (for RFS, HR 0.76, 95% CI 0.48–1.20; for DMFS, HR 0.80, 95% CI 0.49–1.31). NSAIDs were associated with the incidence of irAEs in the placebo arm (HR 3.06, 95% CI 1.45–6.45) but not in the pembrolizumab arm (HR 0.94, 95% CI 0.58–1.53).
NSAIDs were not associated with efficacy outcomes nor the risk of irAEs in patients with resected high-risk stage III melanoma receiving adjuvant pembrolizumab.
•NSAIDs were not associated with recurrence-free survival.•NSAIDs were not associated with distant metastasis-free survival.•NSAIDs were not associated with the incidence of immune-related adverse events.
To examine associations between diet and risk of developing gastro-oesophageal reflux disease (GERD).
Prospective cohort with a median follow-up of 15·8 years. Baseline diet was measured using a FFQ. ...GERD was defined as self-reported current or history of daily heartburn or acid regurgitation beginning at least 2 years after baseline. Sex-specific logistic regressions were performed to estimate OR for GERD associated with diet quality scores and intakes of nutrients, food groups and individual foods and beverages. The effect of substituting saturated fat for monounsaturated or polyunsaturated fat on GERD risk was examined.
Melbourne, Australia.
A cohort of 20 926 participants (62 % women) aged 40-59 years at recruitment between 1990 and 1994.
For men, total fat intake was associated with increased risk of GERD (OR 1·05 per 5 g/d; 95 % CI 1·01, 1·09; P = 0·016), whereas total carbohydrate (OR 0·89 per 30 g/d; 95 % CI 0·82, 0·98; P = 0·010) and starch intakes (OR 0·84 per 30 g/d; 95 % CI 0·75, 0·94; P = 0·005) were associated with reduced risk. Nutrients were not associated with risk for women. For both sexes, substituting saturated fat for polyunsaturated or monounsaturated fat did not change risk. For both sexes, fish, chicken, cruciferous vegetables and carbonated beverages were associated with increased risk, whereas total fruit and citrus were associated with reduced risk. No association was observed with diet quality scores.
Diet is a possible risk factor for GERD, but food considered as triggers of GERD symptoms might not necessarily contribute to disease development. Potential differential associations for men and women warrant further investigation.
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