Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis

BackgroundMicrosatellite instability (MSI) status in predicting the efficacy of adjuvant chemotherapy in colorectal cancer remains controversial.Materials and methodsStudies were identified through PubMed, Embase and ASCO proceedings with a combination of keywords (colorectal cancer, chemotherapy and MSI).ResultsA MA was performed for treated and non-treated MSI population on seven studies. Statistical calculations were performed on 7 studies representing 3690 patients; mean age: 65.5 years; 810 stage II and 2444 stage III (75%). MSI-high (MSI-H) was found in 454 patients (14% of the global population), and microsatellite stable (MSS) in 2871. A total of 1444 patients received 5-fluorouracil (5FU)-based chemotherapy, whereas 1518 patients did not.For MSI-H patients, there was no statistically significant difference for RFS whether or not they received chemotherapy (5 studies); HR RFS: 0.96 (95% confidence interval (CI): 0.62–1.49); HR OS (6 studies): 0.70 (95% CI: 0.44–1.09; p = 0.12). Elsewhere, we found a significant interaction between MSI status (MSI-H or MSS) and therapeutic status suggesting a lesser benefit for MSI-H than for MSS patients (HR interaction RFS: 0.77 (95% CI: 0.67–0.87)).ConclusionWe found similar RFS for treated and untreated MSI-H patients, showing that MSI-H status, in addition to being a good prognostic factor is also a predictive factor of non response.     

Prognostic Value of the Microsatellite Instability Status in Patients With Stage II/III Rectal Cancer Following Upfront Surgery

Background

We investigated whether the microsatellite instability (MSI) status affects the survival outcomes in patients with stage II/III rectal cancer who have undergone an upfront curative resection.

The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients

BackgroundMolecular markers in colon cancer are needed for a more accurate classification and personalized treatment. We determined the effects on clinical outcome of the BRAF mutation, microsatellite instability (MSI) and KRAS mutations in stage II and stage III colon carcinoma.Patients and methodsStage II colon carcinoma patients (n = 106) treated with surgery only and 258 stage III patients all adjuvantly treated with 5-fluorouracil chemotherapy were included. KRAS mutations in codons 12 and 13, V600E BRAF mutation and MSI status were determined.ResultsOlder patients (P < 0.001), right-sided (P = 0.018), better differentiated (P = 0.003) and MSI tumors (P < 0.001) were significantly more frequent in stage II than stage III. In both groups, there was a positive association between mutated BRAF and MSI (P = 0.001) and BRAF mutation and right-sided tumors (P = 0.001). Mutations in BRAF and KRAS were mutually exclusive. In a multivariate survival analysis with pooled stage II and stage III data, BRAF mutation was an independent prognostic factor for overall survival (OS) and cancer-specific survival [hazards ratio (HR) = 0.45, 95% confidence interval (CI) 0.25–0.8 for OS and HR = 0.47, 95% CI 0.22–0.99]. KRAS mutation conferred a poorer disease-free survival (HR = 0.6, 95% CI 0.38–0.97).ConclusionsThe V600E BRAF mutation confers a worse prognosis to stage II and stage III colon cancer patients independently of disease stage and therapy.     

Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H)

BackgroundThe microsatellite instability-high (MSI-H) phenotype, present in 15% of early colorectal cancer (CRC), confers good prognosis. MSI-H metastatic CRC is rare and its impact on outcomes is unknown. We describe survival outcomes and the impact of chemotherapy, metastatectomy, and BRAF V600E mutation status in the largest reported cohort of MSI-H metastatic colorectal cancer (CRC).Patients and methodsA retrospective review of 55 MSI-H metastatic CRC patients from two institutions, Royal Melbourne Hospital (Australia) and The University of Texas MD Anderson Cancer Center (United States), was conducted. Statistical analyses utilized Kaplan–Meier method, Log-rank test, and Cox proportional hazards models.ResultsMedian age was 67 years (20–90), 58% had poor differentiation, and 45% had stage IV disease at presentation. Median overall survival (OS) from metastatic disease was 15.4 months. Thirteen patients underwent R0/R1 metastatectomies, with median OS from metastatectomy 33.8 months. Thirty-one patients received first-line systemic chemotherapy for metastatic disease with median OS from the start of chemotherapy 11.5 months. No statistically significant difference in progression-free survival or OS was seen between fluoropyrimidine, oxaliplatin, or irinotecan based chemotherapy. BRAF V600E mutation was present in 14 of 47 patients (30%). BRAF V600E patients demonstrated significantly worse median OS; 10.1 versus 17.3 months, P = 0.03. In multivariate analyses, BRAF V600E mutants had worse OS (HR 4.04; P = 0.005), while patients undergoing metastatectomy (HR 0.11; P = <0.001) and patients who initially presented as stage IV disease had improved OS (HR 0.27; P = 0.003).ConclusionsPatients with MSI-H metastatic CRC do not appear to have improved outcomes. BRAF V600E mutation is a poor prognostic factor in MSI-H metastatic CRC.     

Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence following adjuvant treatment: results of an ACCENT pooled analysis of seven studies

BackgroundMicrosatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAF^V600E complicates the association.Patients and methodsPatients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAF^V600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence.ResultsAmong 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19–85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69–0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58–1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAF^V600E (aHR, 0.84; P = 0.10) or those harboring BRAF^V600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAF^V600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73–2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67–4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence.ConclusionsIn stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAF^V600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients.Trial identification numbersNCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.     

Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large,consecutive Norwegian series

BackgroundMicrosatellite instability (MSI) was suggested as a marker for good prognosis in colorectal cancer in 1993 and a systematic review from 2005 and a meta-analysis from 2010 support the initial observation. We here assess the prognostic impact and prevalence of MSI in different stages in a consecutive, population-based series from a single hospital in Oslo, Norway.Patients and methodsOf 1274 patients, 952 underwent major resection of which 805 were included in analyses of MSI prevalence and 613 with complete resection in analyses of outcome. Formalin-fixed tumor tissue was used for PCR-based MSI analyses.ResultsThe overall prevalence of MSI was 14%, highest in females (19%) and in proximal colon cancer (29%). Five-year relapse-free survival (5-year RFS) was 67% and 55% (P = 0.030) in patients with MSI and MSS tumors, respectively, with the hazard ratio (HR) equal to 1.60 (P = 0.045) in multivariate analysis. The improved outcome was confined to stage II patients who had 5-year RFS of 74% and 56% respectively (P = 0.010), HR = 2.02 (P = 0.040).Examination of 12 or more lymph nodes was significantly associated with proximal tumor location (P < 0.001).ConclusionsMSI has an independent positive prognostic impact on stage II colorectal cancer patients after complete resection.     

Prognostic Value of Body Mass Index in Stage II/III Colon Cancer: Posthoc Analysis From the TOSCA Trial

BackgroundHigh body mass index (BMI) plays a key role in the development of colon cancer (CC). Our post-hoc analysis from the TOSCA trial analyzed the association between BMI and survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS) in stage II/III CC patients.Patients and methodsPatients enrolled in the TOSCA trial between 2007-2013 with BMI data entered the study. The prognostic impact of BMI on survival outcomes was investigated through uni- and multivariable Cox regression analyses.ResultsOverall, 1455 patients with stage II/III CC patients were included. The median follow-up was of 61.5 months; 16.1% of patients relapsed, 11.2% died and 19.5% patients relapsed or died. No impact of BMI on RFS was detected at univariate or multivariable analyses. By univariate analysis for OS, a significantly impact of a BMI > 30 kg/m² was reported (HR [>30 vs <25] 1.57, 95% CI 1.00-2.47, p = 0.049; HR [>30 vs <30] 1.55, 95% CI 1.01-2.37, p = 0.045). Multivariable analyses did not confirm this data. In the subgroup of stage III patients, a negative survival impact of BMI was found in univariate and multivariable models both for RFS and for OS.ConclusionsIn our study, obesity with BMI > 30 kg/m² was an independent prognostic factor for RFS and OS in CC patients treated with adjuvant chemotherapy, regardless of its duration (3 or 6 months). However, the prognostic impact of adiposity and body composition measurement should be considered to better classify patients with high visceral fat and refine their risk assessment.     

Nomograms for Predicting Overall and Recurrence-free Survival From Pathologic Stage IA and IB Lung Cancer After Lobectomy

BackgroundStage I non–small-cell lung cancer (NSCLC) is potentially curable with surgical resection. Significant proportions of patients may still experience recurrence and death despite undergoing curative surgery. This study describes predictive nomograms for recurrence-free (RFS) and overall survival (OS) after lobectomy.Patients and MethodsA total of 301 patients with the American Joint Committee on Cancer pathologic stage IA and IB NSCLC who underwent open, thoracoscopic, or robotic lobectomy from January 2011 to April 2017 were analyzed. Multivariate Cox proportional hazards regression models were used to create nomograms for OS and RFS. Kaplan-Meier survival curves were calculated for OS and RFS comparing high-risk and low-risk cohorts based on nomogram scores.ResultsHistology (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.10-0.56; P = .002), lymphovascular invasion (HR, 0.46; 95% CI, 0.29-0.74; P = .001), smoking status (HR, 3.46; 95% CI, 1.25-9.55: P = .02), and total lymph nodes removed (HR, 1.05; 95% CI, 1.01-1.10; P = .021) were significant predictors for OS in a multivariate model. Lymphovascular invasion (HR, 0.55; 95% CI, 0.36-0.83; P = .0040), smoking status (HR, 2.56; 95% CI, 1.16-5.62; P = .02), total lymph nodes removed (HR, 1.04; 95% CI, 1.00-1.08; P = .029), and tumor size (HR, 1.30; 95% CI, 1.30-1.68; P = .047) were significant predictors of RFS in a multivariate model.ConclusionNomograms can predict OS and RFS for pathologic stage IA and IB NSCLC after lobectomy regardless of operative approach. The risk for death and recurrence after stratification by the nomogram scores may provide guidance regarding adjuvant therapy and surveillance.     

Clinical significance of microsatellite instability for stage II or III colorectal cancer following adjuvant therapy with doxifluridine

Microsatellite instability (MSI) is a molecular marker that can provide valuable prognostic information for colorectal cancer (CRC). However, the predictive role of the MSI status remains less clear than its role in prognostication due to mixed results from previous studies. Therefore, this study investigated the usefulness of the MSI status as a predictive factor for stage II or III CRC patients who received adjuvant doxifluridine therapy. Among 3030 patients with CRC who underwent surgical resection between 1997 and 2006, 564 patients were diagnosed with stage II or III, and adjuvant doxifluridine therapy was administered to 394 patients (70.0%). The MSI status was assessed using the markers BAT25 and BAT26, and samples with instability at both markers were scored as exhibiting high-frequency MSI (MSI-H). Among the 564 patients, 290 patients (51.4%) had stage II, and MSI-H was found in 41 patients (7.3%). With a median follow-up duration of 35.1 months (range, 0.5–135.2), the 5-year overall survival (OS) rate and relapse-free survival (RFS) rate were 87.5 and 76.2%, respectively. MSI-H showed a favorable survival trend for OS (P = 0.098) and significant survival benefit for RFS (P = 0.037) in all patients. In a univariate analysis, the doxifluridine-treated patients with MSI-H showed improved RFS compared to those with low or stable MSI (MSI-L/S) (P = 0.036), while the MSI status was not significantly associated with OS (P = 0.107). In a multivariate analysis, MSI-H was not significantly associated with RFS (Hazard ratio = 2.467, P = 0.125). In conclusion, this study confirmed the positive prognostic role of MSI-H. However, MSI-H patients with stage II or III CRC did not seem to benefit from doxifluridine adjuvant therapy.

     

The impact of molecular profile on the lymphatic spread pattern in stage III colon cancer

The anatomical spread of lymph node (LN) metastasis is of practical importance in the surgical management of colon cancer (CC). We examined the effect of KRAS, BRAF, and microsatellite instability (MSI) on LN count and anatomical spread pattern in stage III CC. We determined KRAS, BRAF, and MSI status from stage III CC patients. Biomarker status was correlated with LN count and anatomical spread pattern, which was classified as sequential or skipped. Relapse-free survival (RFS) was estimated using Kaplan-Meier method, and correlations were assessed using log-rank and Cox regression analyses. We analyzed 369 stage III CC patients. The proportion of KRAS mutant (mt), BRAF mt, and MSI-high (H) were 44.2% (163/344), 6.8% (25/344), and 6.8% (25/344), respectively. The mean number of metastatic LN was higher in microsatellite-stable (MSS) compared with MSI patients (3.5 vs. 2.7, P = .0406), although no differences were observed in accordance with KRAS or BRAF status. Interestingly, patients with BRAF mt and MSI-H were less likely to harbor skipped metastatic LN (9.3% vs 20% and 4% vs 10.5% compared with BRAF wild-type (wt) and MSS, respectively), but KRAS status did not predict anatomical spread pattern. Patients with KRAS wt and MSI-H showed superior RFS compared with KRAS mt and MSS patients, respectively, whereas BRAF status did not affect RFS. Differences exist in the anatomical pattern of invaded LN in accordance with the molecular status of stage III CC. Patients with MSI-H CC have less invaded and skipped LN, suggesting that a tailored surgical approach is possible.     

Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers

Microsatellite instability (MSI) has been associated with favourable survival in early stage colorectal cancer (CRC) compared to microsatellite stable (MSS) CRC. The BRAF V600E mutation has been associated with worse survival in MSS CRC. This mutation occurs in 40% of MSI CRC and it is unclear whether it confers worse survival in this setting. The prognostic value of KRAS mutations in both MSS and MSI CRC remains unclear. We examined the effect of BRAF and KRAS mutations on survival in stage II and III MSI colon cancer patients. BRAF exon 15 and KRAS exon 2–3 mutation status was assessed in 143 stage II (n = 85) and III (n = 58) MSI colon cancers by high resolution melting analysis and sequencing. The relation between mutation status and cancer‐specific (CSS) and overall survival (OS) was analyzed using Kaplan–Meier and Cox regression analysis. BRAF V600E mutations were observed in 51% (n = 73) and KRAS mutations in 16% of cases (n = 23). Patients with double wild‐type cancers (dWT; i.e., BRAF and KRAS wild‐type) had a highly favourable survival with 5‐year CSS of 93% (95% CI 84–100%), while patients with cancers harbouring mutations in either BRAF or KRAS, had 5‐year CSS of 76% (95% CI 67–85%). In the subgroup of stage II patients with dWT cancers no cancer‐specific deaths were observed. On multivariate analysis, mutation in either BRAF or KRAS vs. dWT remained significantly prognostic. Mutations in BRAF as well as KRAS should be analyzed when considering these genes as prognostic markers in MSI colon cancers.     

Real-world Data for High-risk Stage II Colorectal Cancer – The Role of Tumor Side in the Adjuvant Setting

BackgroundThe impact of sidedness in the high-risk stage II colorectal cancer (CRC) setting is uncertain. Although controversial, available data suggest a possible modest benefit of adjuvant chemotherapy (CT) in the adjuvant scenario. The aim of this study is to analyze the overall survival (OS) and recurrence-free survival (RFS) according to the tumor side.Patients and MethodsIn this single-center retrospective cohort, we analyzed patients treated between January 2011 and December 2018. We evaluated OS and RFS of high-risk patients according to the tumor side and considering adjuvant CT exposure and clinical and molecular features.ResultsA total of 1047 patients with stage II CRC were evaluated. Of these, 540 had high-risk criteria and microsatellite stability (MSS) or unknown status. One hundred fifty-seven (29%) patients had right-sided tumors, and 352 (65.2%) had left-sided tumors. Most patients received adjuvant CT, and the majority of them had T3 stage tumors, ≥ 12 lymph node resection, left tumor, MSS, and moderate differentiation. OS did not differ according to tumor side (5-year OS rates: 81.9% for right-sided tumors vs. 83% for left-sided tumors; hazard ratio, 0.91; 95% confidence interval, 0.55-1.53; P = .744). Adjuvant CT was associated with a superior RFS and OS, with 5-year OS rates of 87.7% versus 76.1% in the no-adjuvant group (hazard ratio, 0.46; 95% CI, 0.28-0.73; P = .001).ConclusionThe tumor side did not influence the outcomes in this study. Adjuvant CT was associated with improved RFS and OS in patients with high-risk stage II CRC, with a total gain of 11.6% in 5-year OS.     

Clinical significance of microsatellite instability for stage II or III colorectal cancer following adjuvant therapy with doxifluridine

Microsatellite instability (MSI) is a molecular marker that can provide valuable prognostic information for colorectal cancer (CRC). However, the predictive role of the MSI status remains less clear than its role in prognostication due to mixed results from previous studies. Therefore, this study investigated the usefulness of the MSI status as a predictive factor for stage II or III CRC patients who received adjuvant doxifluridine therapy. Among 3030 patients with CRC who underwent surgical resection between 1997 and 2006, 564 patients were diagnosed with stage II or III, and adjuvant doxifluridine therapy was administered to 394 patients (70.0%). The MSI status was assessed using the markers BAT25 and BAT26, and samples with instability at both markers were scored as exhibiting high-frequency MSI (MSI-H). Among the 564 patients, 290 patients (51.4%) had stage II, and MSI-H was found in 41 patients (7.3%). With a median follow-up duration of 35.1 months (range, 0.5-135.2), the 5-year overall survival (OS) rate and relapse-free survival (RFS) rate were 87.5 and 76.2%, respectively. MSI-H showed a favorable survival trend for OS (P = 0.098) and significant survival benefit for RFS (P = 0.037) in all patients. In a univariate analysis, the doxifluridine-treated patients with MSI-H showed improved RFS compared to those with low or stable MSI (MSI-L/S) (P = 0.036), while the MSI status was not significantly associated with OS (P = 0.107). In a multivariate analysis, MSI-H was not significantly associated with RFS (Hazard ratio = 2.467, P = 0.125). In conclusion, this study confirmed the positive prognostic role of MSI-H. However, MSI-H patients with stage II or III CRC did not seem to benefit from doxifluridine adjuvant therapy.     

CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer

BackgroundThe prognostic impact of KRAS and BRAF^V600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression–based consensus molecular subtypes (CMSs) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups.Patients and methodsTotally 1197 primary tumors from a Norwegian series of CRC stage I–IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAF^V600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups.ResultsBRAF^V600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAF^V600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P < 0.001; KRAS mutation versus KRAS/BRAF wild-type: HR 1.30, P = 0.013). BRAF^V600E-mutated MSS tumors were strongly enriched and associated with metastatic disease in CMS1, leading to negative prognostic impact in this subtype (OS: BRAF^V600E mutation versus wild-type: HR 7.73, P = 0.001). In contrast, the poor prognosis of KRAS mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P = 0.011). The subtype-specific prognostic associations were substantiated by differential effects of BRAF^V600E and KRAS mutations on gene expression signatures according to the MSI status and CMS group.ConclusionsBRAF^V600E mutations are enriched and associated with metastatic disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS tumors.     

Pathologic complete response to neoadjuvant chemotherapy with trastuzumab predicts for improved survival in women with HER2-overexpressing breast cancer

BackgroundWe sought to determine the prognostic value of pathologic response to neoadjuvant chemotherapy with concurrent trastuzumab.Patients and methodsTwo hundred and twenty-nine women with HER2/neu (HER2)-overexpressing breast cancer were treated with neoadjuvant chemotherapy plus trastuzumab between 2001 and 2008. Patients were grouped based on pathologic complete response (pCR, n = 114) or less than pCR (<pCR, n = 115); as well as by pathologic stage. Locoregional recurrence-free (LRFS), distant metastasis-free (DMFS), recurrence-free (RFS), and overall survival (OS) rates were compared.ResultsThe median follow-up was 63 (range 53–77) months. There was no difference in clinical stage between patients with pCR or <pCR. Compared with patients achieving <pCR, those with the pCR had higher 5-year rates of LRFS (100% versus 95%, P = 0.011), DMFS (96% versus 80%, P < 0.001), RFS (96% versus 79%, P < 0.001), and OS (95% versus 84%, P = 0.006). Improvements in RFS and OS were seen with decreasing post-treatment stage. Failure to achieve a pCR was the strongest independent predictor of recurrence (hazard ratio [HR] = 4.09, 95% confidence interval [CI]: 1.67–10.04, P = 0.002) and death (HR = 4.15, 95% CI: 1.39–12.38, P = 0.011).ConclusionspCR and lower pathologic stage after neoadjuvant chemotherapy with trastuzumab are the strongest predictors of recurrence and survival and are surrogates of the long-term outcome in patients with HER2-overexpressing disease.     

Circulating tumor DNA predicts survival in patients with resected high-risk stage II/III melanoma

BackgroundPatients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those who are cured by surgery. We investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in patients with resected melanoma.Patients and methodsWe carried out droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial.ResultsMutant BRAF or NRAS ctDNA was detected (≥1 copy of mutant ctDNA) in 15/132 (11%) BRAF mutant patient samples and 4/29 (14%) NRAS mutant patient samples. Patients with detectable ctDNA had a decreased disease-free interval [DFI; hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.79–5.47; P < 0.0001] and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80–5.79; P < 0.0001) versus those with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for performance status and disease stage (DFI: HR 3.26, 95% CI 1.83–5.83, P < 0.0001; DMFI: HR 3.45, 95% CI 1.88–6.34, P < 0.0001). Five-year overall survival rate for patients with detectable ctDNA was 33% (95% CI 14%–55%) versus 65% (95% CI 56%–72%) for those with undetectable ctDNA. Overall survival was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.40–4.96); P = 0.003) and remained significant after adjustment for performance status (HR 2.50, 95% CI 1.32–4.74, P = 0.005).ConclusionctDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy.Clinical trial numberISRCTN 81261306     

Molecular heterogeneity and prognostic implications of synchronous advanced colorectal neoplasia

Background:

It is uncertain whether synchronous colorectal cancers (S-CRCs) preferentially develop through widespread DNA methylation and whether they have a prognosis worse than solitary CRC. As tumours with microsatellite instability (MSI) may confound the effect of S-CRC methylation on outcome, we addressed this issue in a series of CRC characterised by BRAF and MS status.

Methods:

Demographics, clinicopathological records and disease-specific survival (DSS) were assessed in 881 consecutively resected CRC undergoing complete colonoscopy. All tumours were typed for BRAF^c.1799T>A mutation and MS status, followed by search of germ-line mutation in patients with MSI CRC.

Results:

Synchronous colorectal cancers (50/881, 5.7%) were associated with stage IV microsatellite-stable (MSS) CRC (19/205, 9.3%, P=0.001) and with HNPCC (9/32, 28%, P<0.001). BRAF mutation (60/881, 6.8%) was associated with sporadic MSI CRC (37/62, 60%, P<0.001) but not with S-CRC (3/50, 6.0%, P=0.96). Synchronous colorectal cancer (HR 1.82; 95% CI 1.15–2.87; P=0.01), synchronous advanced adenoma (HR 1.81; 95% CI 1.27–2.58; P=0.001), and BRAF^c.1799T>A mutation (HR 2.16; 95% CI 1.25–3.73; P=0.01) were stage-independent predictors of death from MSS CRC. Disease-specific survival of MSI CRC patients was not affected by S-CRC (HR 0.74; 95% CI 0.09–5.75; P=0.77).

Conclusion:

Microsatellite-stable CRCs have a worse prognosis if S-CRC or synchronous advanced adenoma are diagnosed. The occurrence and the enhanced aggressiveness of synchronous MSS advanced neoplasia are not associated with BRAF mutation.     

BRAF Mutations Are Associated with Poor Survival Outcomes in Advanced-stage Mismatch Repair-deficient/Microsatellite High Colorectal Cancer

BackgroundMismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) is a unique disease entity with growing interest given the rise of young-onset CRC. Given its heterogeneous behavior and potential for highly effective treatment outcomes, we sought to identify the clinical and molecular features that offer prognostic value for MMR-D CRC.Materials/MethodsThis was a retrospective cohort study of patients with metastatic CRC with MMR-D or microsatellite instability in a real-world database. Overall survival (OS) was determined by the date of metastatic disease to date of death with stratification made based on factors including BRAF and RAS mutation status, age, and MMR protein loss type.ResultsThere were 1101 patients in the study. Patients with BRAF mutations had worse OS compared with patients with wild-type BRAF with a median survival of 18.9 months versus 33.2 months (hazard ratio [HR] 1.52, 95% confidence interval [CI]: 1.25-1.86, P < .001). Patients with age >50 were found to have decreased OS versus age ≤50 with a median survival of 21.4 months versus 38.7 months (HR 1.66, 95% CI: 1.33-2.07, P < .001). BRAF mutations and age >50 remained significant predictors of OS in multivariate analysis.Conclusion BRAF mutations and age >50 are associated with worse survival outcomes for patients with MMR-D mCRC. RAS mutations and specific MMR alterations are not associated with survival outcomes.     

The differential impact of microsatellite instability as a marker of prognosis and tumour response between colon cancer and rectal cancer

BackgroundMicrosatellite instability (MSI) is a distinct molecular phenotype of colorectal cancer related to prognosis and tumour response to 5-fluorouracil (5-FU)-based chemotherapy. We investigated the differential impact of MSI between colon and rectal cancers as a marker of prognosis and chemotherapeutic response.MethodsPCR-based MSI assay was performed on 1125 patients. Six hundred and sixty patients (58.7%) had colon cancer and 465 patients (41.3%) had rectal cancer.ResultsAmong 1125 patients, 106 (9.4%) had high-frequency MSI (MSI-H) tumours. MSI-H colon cancers (13%) had distinct phenotypes including young age at diagnosis, family history of colorectal cancer, early Tumor, Node, Metastasis (TNM) stage, proximal location, poor differentiation, and high level of baseline carcinoembryonic antigen (CEA), while MSI-H rectal cancers (4.3%) showed similar clinicopathological characteristics to MSS/MSI-L tumours except for family history of colorectal cancer. MSI-H tumours were strongly correlated with longer disease free survival (DFS) (P = 0.005) and overall survival (OS) (P = 0.009) than MSS/MSI-L tumours in colon cancer, while these positive correlations were not observed in rectal cancers. The patients with MSS/MSI-L tumours receiving 5-FU-based chemotherapy showed good prognosis (P = 0.013), but this positive association was not observed in MSI-H (P = 0.104).ConclusionThese results support the use of MSI status as a marker of prognosis and response to 5-FU-based chemotherapy in patients with colon cancers. Further study is mandatory to evaluate the precise role of MSI in patients with rectal cancers and the effect of 5-FU-based chemotherapy in MSI-H tumours.