Outcomes following synchronous liver resection,cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases: A bi-institutional study

PurposeSynchronous liver resection, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal liver (CRLM) and peritoneal metastases (CRPM) has traditionally been contraindicated. However, latest practice promotes specialist, multidisciplinary-led consideration for select patients. This study aimed to evaluate the perioperative and oncological outcomes of synchronous resection in the management of CRLM and CRPM from two tertiary referral centres.MethodThis bi-institutional, retrospective, cohort study included patients undergoing simultaneous liver resection, CRS and HIPEC for metastatic colorectal cancer from 2013 to 2020. Patients treated with ablative liver techniques, staged operative approaches and extra abdominal disease were excluded. Overall survival (OS) and disease-free survival (DFS) rates were assessed. Univariate and multivariate analyses identified variables associated with survival and major morbidity (Clavien-Dindo grade III/IV).ResultsTwenty-three patients were included. The median peritoneal carcinomatosis index (PCI) was 9 (range 0–22). There were two major liver resections and 21 minor resections. CC-0 resections were achieved in all patients. Major morbidity occurred in 7 patients. There were no deaths at 90 days. PCI was independently associated with morbidity (p = 0.04). PCI >10 (p = 0.069), major morbidity (p = 0.083) and presence of KRAS mutation (p = 0.052) approached significance for poor OS. Median follow up was 21 months (4–54 months). Median OS was 37 months, 3-year survival 54%, and median DFS 18 months.ConclusionSynchronous liver resection, cytoreductive surgery and HIPEC is feasible in selected patients with low-volume CRPM and CRLM. Increasing PCI is associated with postoperative major morbidity, and should be considered during operative planning.     

Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency

BackgroundPatients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs.Patients and methodsMSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2 loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation.ResultsAmong 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (37%) had sporadic tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR, BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were associated with more frequent liver involvement, metastatic resection and better disease-free survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar between the two groups (4.2 and 4.2 months; P = 0.44).ConclusionsLS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs in these two populations.     

Pattern of recurrence after interval cytoreductive surgery and HIPEC following neoadjuvant chemotherapy in primary advanced stage IIIC/IVA epithelial ovarian cancer

ObjectiveThe aim of this study was to evaluate the patterns of recurrence and factors affecting the same after interval cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in primary stage IIIC and IV A epithelial ovarian cancer.MethodsIn this retrospective multicentric study, all patients with FIGO stages III-C and IV-A epithelial ovarian carcinoma were treated with CRS and HIPEC after receiving neoadjuvant chemotherapy. Relevant clinical and demographic data were captured. Multivariable logistic regression was performed to evaluate the factors affecting recurrence after CRS and HIPEC.ResultsFrom January 2017 to Jan 2020, 97, consecutive patients of Stage IIIC/IVA epithelial ovarian cancer underwent interval cytoreductive surgery and HIPEC after receiving neoadjuvant chemotherapy. The median duration of follow up duration was 20 months [1–36months]. 21/97 (21.6%) patients presented with disease recurrence. Visceral recurrences involving the lungs, liver and brain were seen in 8/21 (38%) of cases and comprised the commonest sites. On multivariable analysis, nodal involvement (p = 0.05), selective peritonectomy (p = 0.001) and leaving behind residual disease <0.25 mm (CC1) (p = 0.01) was associated with increased risk of disease recurrence. Extent of peritonectomy (OS,p = 0.56, PFS p = 0.047, Log Rank test) and nodal positivity (OS, p = 0.13,PFS,p = 0.057, Log Rank test) were found to impact progression free survival but had no impact on overall survival.ConclusionThere is a higher incidence of systemic recurrences in patients with Stage IIIC/IVA epithelial ovarian carcinoma after CRS and HIPEC. Extent of peritonectomy and nodal clearance impacts patterns of recurrence and progression free survival.     

Indications and outcomes for repeat cytoreductive surgery and heated intra-peritoneal chemotherapy in peritoneal surface malignancy

IntroductionCytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is offered in specialist centres as a treatment for peritoneal surface tumours. Despite its demonstrated efficacy, intra-abdominal recurrence occurs in 31–57% of patients. The aim of this study is to review the early and long-term outcomes in patients who undergo repeat CRS/HIPEC.Materials and methodsA retrospective review of a prospectively maintained database of patients who had undergone repeat CRS/HIPEC for appendiceal neoplasms and colorectal peritoneal metastases (CRPM) from 2003 to 2019 was performed at a single specialist centre. Data pertaining to both short term outcomes and survival were evaluated.ResultsOf 1259 patients who had undergone CRS/HIPEC, 84(6.7%) underwent repeat surgery: 45(53.6%) had pseudomyxoma peritonei (PMP) secondary to low grade appendiceal mucinous neoplasms (LAMN), 21(25.0%) had appendix carcinoma and 18(21.4%) had CRPM. Demographics, intra-operative findings and short-term outcomes were comparable across tumour types and between procedures. Median (95% CI) interval between procedures was 22.7(18.9–26.6) months and was comparable between tumour types. Median (95%CI) overall survival was not reached for the cohort overall or for those with PMP, but was 61.0(32.6–89.4) months for those with appendix cancer and 76.9(47.4–106.4) months for CRPM (p=<0.001). Survival was favourable in the PMP group (HR [95%CI] 0.044 [0.008–0.262]; p = 0.000) and unfavourable in the CC2-3 at index CRS procedure group (HR [95%CI] 25.612 [2.703–242.703]; p = 0.005).ConclusionOur findings demonstrate that repeat cytoredutive surgery with HIPEC can result in favourable survival, especially for patients with PMP when complete cytoreduction is achieved at index operation. We recommend that detailed patient assessment is performed through an expert multidisciplinary team meeting (MDT).     

Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study

BackgroundRAS and BRAF mutations have been identified as negative prognostic factors in metastatic colorectal cancer. Efficacy of 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) plus bevacizumab in patients with RAS-mutant tumours needs to be further evaluated. Whether to treat patients with BRAF-mutant tumours with either bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies remains unclear.MethodsPatients treated within the FIRE-3 trial were retrospectively tested for BRAF and RAS mutations using formalin fixated paraffin embedded (FFPE) tumour material applying pyrosequencing for KRAS and NRAS exon 2, 3 and 4 mutations as far as for BRAF mutations. Survival analysis was done using Kaplan–Meier estimation and differences were expressed using the log-rank test. Overall response rate (ORR) was compared using Fisher's exact test. Data from a central independent radiological response evaluation were used to calculate early tumour shrinkage (ETS) and depth of response (DpR).ResultsOverall, 188 patients with RAS-mutant tumours and 48 with BRAF-mutant tumours were identified. In BRAF-mutant patients, ORR was numerically higher in the cetuximab versus the bevacizumab arm (52% versus 40%), while comparable results were achieved for progression-free survival (PFS; hazard ratio [HR] = 0.84, p = 0.56) and overall survival (OS; HR 0.79, p = 0.45). RAS mutation was associated with a trend towards lower ORR (37% versus 50.5%, p = 0.11) and shorter PFS (7.4 versus 9.7 months; HR 1.25; p = 0.14) in patients receiving FOLFIRI plus cetuximab versus bevacizumab, but OS was comparable (19.1 versus 20.1 months; HR 1.05; p = 0.73), respectively. ETS identified subgroups sensitive to cetuximab-based treatment in both BRAF- (9/17) and RAS-mutant (18/48) patients and was associated with significantly longer OS. DpR was comparable between both treatment arms in RAS- and BRAF-mutant patients, respectively.ConclusionsIn BRAF- and RAS-mutant patients, cetuximab- and bevacizumab-based treatment had comparable survival times. ETS represents an early parameter associated with the benefit from anti-EGFR, while this was not the case with vascular endothelial growth factor A blockade.     

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.     

RAC1b overexpression correlates with poor prognosis in KRAS/BRAF WT metastatic colorectal cancer patients treated with first-line FOLFOX/XELOX chemotherapy

IntroductionChemotherapy is the principal treatment in metastatic colorectal cancer (mCRC) patients. RAC1b, a RAC1 spliced variant, is over-expressed in colorectal cancer (CRC), and impairs apoptosis by activation of nuclear-factor-KB. Since RAC1b has been associated with the BRAF^V600E mutation, associated with poor prognosis in CRC, we evaluated the role of RAC1b expression as a predictor of chemotherapy efficacy in mCRC.MethodsWe analysed KRAS and BRAF mutation, microsatellite instability and RAC1b expression in 157 mCRC patients treated with FOLFOX/XELOX in first-line therapy.ResultsKRAS mutations were detected in 46 patients (34%), 10 patients were BRAF mutant (7%) and 79 were WT for both, KRAS and BRAF (59%). RAC1b overexpression was found in 30 patients (19%). In the multivariate analysis, BRAF mutational status was a poor prognostic factor for overall survival (OS); hazard ratio (HR), 2.78 (95% confidence interval (CI), 1.35–5.72; p = 0.0057). RAC1b overexpression was a poor survival factor for OS (HR, 2.35; 95% CI, 1.2–4.59; p = 0.01) and progression-free survival (PFS) (HR, 2.4; 95% CI, 1.2–4.78; p = 0.01) in KRAS/BRAF WT mCRC patients.ConclusionsRAC1b overexpression constitutes a marker of poor prognosis in KRAS/BRAF WT mCRC patients treated with first-line FOLFOX/XELOX therapy.     

Potential for cure and predictors of long-term survival after radiofrequency ablation for colorectal liver metastases: A 20-years single-center experience

BackgroundAdditional radiofrequency ablation (RFA) of liver-limited colorectal liver metastases (CRLM) improves overall (OS) and recurrence-free survival (RFS) over systemic therapy alone. We aimed to assess the potential and predictive factors of long-term survival and cure to optimize patient selection for RFA application.MethodsRetrospective review of a prospectively maintained single-center database of consecutive patients undergoing RFA for liver-limited CRLM after systemic therapy between 2002 and 2020. Clinicopathologic characteristics and KRAS/BRAF-genotype data (tested routinely since 2010) were correlated to RFS and OS. Cure was defined as ≥10-years RFS (long-term survival as ≥5-years OS) following RFA.ResultsFor the entire cohort of 158 patients (median follow-up 13.6 years), co-occurrence of three factors, RECIST-defined response, number of ≤3 CRLM, and ≤3 cm maximum size determined a survival plateau that distinguished cured from non-cured patients (10-years RFS: 15.5% vs 0%, p < 0.0001). Among 59 patients (37.3%) being tested, 4(6.8%) were BRAF-mt, 15(25.4%) KRAS-mt, and 40(67.8%) KRAS/BRAF-wt. OS (median follow-up 8.3 years) was estimated to be higher with KRAS/BRAF-wt compared to a mutant KRAS or BRAF status (5-years OS: 22.8% vs 3.4%, p = 0.0018).ConclusionThis study indicates about 15% chance of cure following RFA of low-volume liver-limited CRLM after downsizing by systemic therapy and a negative effect of KRAS or BRAF mutation on long-term survival after CRLM ablation. These findings may improve clinical decision-making in patients potentially candidate to RFA of CRLM and encourage further investigations on molecular factors determining an oligometastatic state of CRLM curable with focal ablative therapy.     

Long-term Survival Update and Extended RAS Mutational Analysis of the CAIRO2 Trial: Addition of Cetuximab to CAPOX/Bevacizumab in Metastatic Colorectal Cancer

BackgroundHere we present updated survival of the CAIRO2 trial and assessed whether the addition of anti-EGFR to anti-VEGF therapy could still be an effective treatment option for patients with extended RAS/BRAF wildtype and left-sided metastatic colorectal cancer (mCRC).Materials and MethodsRetrospective updated survival and extended RAS and BRAF V600E mutational analysis were performed in the CAIRO2 trial, a multicenter, randomized phase III trial on the effect of adding cetuximab to a combination of capecitabine, oxaliplatin (CAPOX), and bevacizumab in mCRC.ResultsUpdated survival analysis confirmed that the addition of cetuximab did not provide a benefit on either progression free (PFS) or overall survival (OS) in the intention-to-treat population. With the extended mutational analyses 31 KRAS, 31 NRAS and 12 BRAF V600E additional mutations were found. No benefit of the addition of cetuximab was observed within the extended wildtype group, even when selecting only left-sided tumors (PFS HR 0.96, p = 0.7775). However, compared to the original trial an increase of 6.5 months was seen for patients with both extended wildtype and left-sided tumors (median OS 28.6 months).ConclusionAdding cetuximab to CAPOX and bevacizumab does not provide clinical benefit in patients with mCRC, even in the extended wildtype group with left-sided tumors. However, in the extended wildtype group we did observe clinically relevant higher survival compared to the initial trial report, indicating that it is important to analyze a broader panel of RAS and BRAF variants using more recent sequencing techniques when assessing survival benefit after anti-EGFR therapy.     

Patterns and Timing of Recurrence following CRS and HIPEC in Colorectal Cancer Peritoneal Metastasis

IntroductionCytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC) is an established treatment of Colorectal Peritoneal Metastases (CRPM). This study aims to determine the timing and patterns of recurrent disease on imaging following complete CRS/HIPEC.MethodsRetrospective analysis of a national peritoneal tumour service database identified CRPM patients with complete CRS/HIPEC(CC0) from 2005 to-2018. Patients with<2 years follow-up or and those where post-operative histology from the CRS/HIPEC procedure did not confirm CRPM from their original colorectal cancer were excluded. Time to recurrence was measured from surgery to first radiologically illustrated recurrence. CT was the primary modality used, supplemented by PET-CT or MRI if required. Outcomes of interest were survival data (including overall survival (OS), disease-free survival (DFS) and peritoneal-recurrence free survival (PRFS)), timing and patterns of recurrent disease.Results146 of the 176 patients identified were eligible for inclusion. Median OS for all study patients was 45.2 months (95% CI 38–53 months), median DFS was 11.7 months (95% CI 9–14 months), and median PRFS was 25.2 months (95% CI 14.7–30 months). Recurrent disease was seen in 112 cases (77%), radiologically classified as intraperitoneal in 50 patients (44%), single site systemic in 21 patients (19%) and multi-site in 41 patients (37%). CT detection rate for disease recurrence was 88%. Subgroup analyses showed that PCI ≥12, positive nodal primary disease and synchronous peritoneal disease were associated with worse outcomes.ConclusionPatients selected for CRS/HIPEC for CRPM have an OS > 45 months, with the majority recurring systemically within a year. Peritoneal recurrence is a later event after several years. Surveillance programs in this group should be most intensive in the first 2 years after surgery, using CT with oral and intravenous contrast.     

Impact of KRAS,BRAF and microsatellite instability status after cytoreductive surgery and HIPEC in a national cohort of colorectal peritoneal metastasis patients

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.Subject terms: Colon cancer, Microsatellite instability     

Final results of the CAVE trial in RAS wild type metastatic colorectal cancer patients treated with cetuximab plus avelumab as rechallenge therapy: Neutrophil to lymphocyte ratio predicts survival

BackgroundHigh neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic factor in metastatic colorectal cancer (mCRC). Here we provide final results of CAVE mCRC trial, of cetuximab plus avelumab rechallenge in chemo-refractory mCRC patients and investigated the predictive role of NLR.MethodsAll the 77 patients enrolled were included in the analysis. A cut-off of 3 was used to correlate baseline NLR with with overall survival (OS) and with progression free survival (PFS), in intention to treat (ITT) and in circulating tumor DNA (ctDNA) RAS/BRAF Wild Type (WT) patients.ResultsIn ITT population, NLR <3 (49%) group had median overall survival (mOS) of 17.8 months, vs. 8.9 months in NLR ≥ 3 group (51%) [HR 0.50, (CI 95% 0.3-0.8), P = .006]. Median progression free survival (mPFS) was 3.9 months in NLR <3 group and 3.5 months in NLR≥3 [HR 0.79, (CI 95% 0.5-1.24), P = .3]. In ctDNA RAS/BRAF WT population, mOS was 22 months in NLR <3 group (48%), vs. 8.9 months in NLR ≥3 group (52%), [HR 0.38, (CI 95% 0.19-0.75), P = .005]. A trend towards increased mPFS was observed in patients with NLR <3 versus NLR ≥3: 5.3 vs. 3.6 months [HR: 0.79, (CI 95% 0.44-1.4), P = .43]. In contrast, NLR did not correlate either with PFS or OS in ctDNA RAS/BRAF mutated patients.ConclusionIn the exploratory analysis of the CAVE mCRC trial, baseline NLR <3 significantly correlated with improved survival and may represent a potential predictive biomarker of cetuximab plus avelumab rechallenge activity in ctDNA RAS/BRAF WT patients, that must be confirmed in randomized studies.     

High prevalence of deficient mismatch repair phenotype and the V600E BRAF mutation in elderly patients with colorectal cancer

AimsColorectal cancer (CRC) occurs mostly in the elderly. However, the biology of CRC in elderly has been poorly studied. This study examined the prevalence of deficient mismatch repair phenotype (dMMR) and BRAF mutations according to age.Patients and MethodsMMR phenotype was prospectively determined by molecular analysis in patients of all ages undergoing surgery for CRC. BRAF V600E mutation status was analysed in a subset of dMMR tumours.ResultsA total of 754 patients who underwent surgery between 2005 and 2008 were included in the study. Amongst them, 272 (36%) were ≥ 75 years old. The proportion of women < 75 was 38% and that ≥ 75 was 53% (p < 0.0001). The prevalence of dMMR was 19.4% in patients ≥ 75 and 10.7% in patients < 75 (p = 0.0017). For patients ≥ 75, the prevalence of dMMR was significantly higher in women than in men (27% vs 10.2%, respectively; p = 0.003) but was similar in women and men < 75 (12.5% vs 9.7%, respectively; p = 0.4). We examined BRAF mutation status in 80 patients with dMMR tumours. The V600E BRAF mutation was significantly more frequent in patients ≥ 75 than in patients < 75 (72.2% vs 11.4%, respectively; p < 0.001). In patients ≥ 75, there was no difference in the prevalence of the BRAF V600E mutation according to sex (78% in women and 70% in men, p = 0.9).ConclusionsThe prevalence of dMMR in CRC is high in patients over 75. In elderly patients, dMMR tumours are significantly more frequent in women than in men. The BRAF mutation is frequent in elderly patients with CRC.     

Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies,clinical behaviour,and phenotypic associations of resistance mechanisms

BackgroundAcquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance.MethodsWe compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing.ResultsAmong 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF^V600E/K amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms.ConclusionsThis is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.     

Clinico-pathological outcomes after total parietal peritonectomy,cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in advanced serous papillary peritoneal carcinoma submitted to neoadjuvant systemic chemotherapy- largest single institute experience

IntroductionSerous papillary peritoneal carcinoma (SPPC) is a rare clinical entity. Based on the understanding of the pattern of spread, its multifocality, polyclonality and the high frequency of diffuse, widespread peritoneal metastasis, a robust rationale for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for SPPC exists. Herein we report the clinical outcomes of SPPC patients treated with neoadjuvant systemic chemotherapy (NACT) followed by CRS including total parietal peritonectomy and HIPEC.MethodsClinico-pathological data of 22 patients of serous papillary peritoneal carcinoma (SPPC) was retrospectively analyzed from a prospectively maintained database from June 2000 to July 2017. Patients were treated with CRS, total parietal peritonectomy and HIPEC with cisplatin (42 mg/L of perfusate) and doxorubicin (15 mg/L of perfusate) after NACT. Survival curves were calculated from the date of surgery.Results22 patients underwent CRS, total parietal peritonectomy and HIPEC. The median age was 62 years (Range 47–72). On histological evaluation, 18/30 (60%) parietal peritonectomy specimens showed microscopic disease, when no disease was evident macroscopically at surgical exploration. Grade III-IV surgical complications were recorded in 4/22 (18%) patients. There was no postoperative mortality. At a median follow up of 12 months, the five-year overall survival (OS) was 64.9%. The median OS was not reached. Median progression-free survival was 32.9 months and progression-free survival at 5 years was 33.2%.ConclusionCRS with total peritonectomy + HIPEC after NACT, presents as a promising treatment modality for SPPC, and could be associated with good survival results in patients with SPPC.     

Short and long-term outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for colorectal and appendiceal cancer peritoneal metastasis: Propensity score-matched comparison between laparoscopy vs. open approaches

BackgroundIn light of today's role of minimally access surgery in colorectal oncologic treatment, we analyzed the impact of laparoscopic cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in selected patients with peritoneal metastases (PM) originating from colorectal and appendiceal cancer (CRAC).MethodsPostoperative and oncologic outcomes were compared between patients with CRAC-PM treated by CRS/HIPEC undergoing laparoscopic (L-CRS/HIPEC) or open (O-CRS/HIPEC) procedures according to data collected from our tertiary referral hospital prospective database from April 2016 to April 2021. We excluded patients who did not undergo operation with curative intent. L-CRS was performed in patients who had no multifocal mesenteric lesions, no large abdominal mass, nor massive adhesions. Patients were matched by propensity scores 1:1 for peritoneal cancer index, completeness of cytoreduction score, concomitant resectable distal metastasis, primary tumor location, RAS mutation status and American Society of Anesthesiologists (ASA) classification.ResultsOf 106 eligible patients, 68 were matched (34 L-CRS/HIPEC; 34 O-CRS/HIPEC) by propensity scores. Compared with the open approach, L-CRS/HIPEC was associated with less overall surgical morbidities (14.7% vs. 38.2%; p = 0.028), shorter median hospital stay (10 [5-15] vs. 12 [8–33] days; p < 0.001) and reduced median waiting time before adjuvant chemotherapy (4.7 [3.0–13.2] vs. 5.7 [4.1–24.1] weeks; p = 0.047). No statistically significant difference was found in operative time or major morbidity rates between the two groups. After a median follow-up of 33.2 months, the rate of early peritoneal loco-regional recurrence, location of initial recurrence or 3-year survival outcomes were not statistically significantly related to the type of access (L-CRS/HIPEC vs. O-CRS/HIPEC).ConclusionsLaparoscopy for CRS/HIPEC is technically feasible and oncologically safe to treat selected patients with CRAC-PM. Further randomized control trials are required to confirm the benefits of minimal access surgery for the management of PM.     

Upfront primary tumour resection and survival in synchronous metastatic colorectal cancer according to primary tumour location and RAS status: Pooled analysis of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)

IntroductionRetrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy.Patients and methodsSurvival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling.ResultsOf 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15–1.48; p < 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13–1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00–1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05–1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21–1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13–1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08–1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS.ConclusionConsidering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.     

Small bowel adenocarcinoma phenotyping,a clinicobiological prognostic study

Background:

Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking.

Methods:

Expression of HER2, β-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated.

Results:

We obtained samples from 63 SBA patients (tumour stages: I–II: 30% III: 35% IV: 32% locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9–72.2). For all patients, in univariate analysis, stages I–II (P<0.001), WHO PS 0–1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0–1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0–1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS.

Conclusion:

This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.     

WJOG13219G: The Efficacy and Safety of FOLFOXIRI or Doublet plus Anti-VEGF Therapy in Previously Untreated BRAFV600E Mutant Metastatic Colorectal Cancer: A Multi-Institutional Registry-Based Study (BRACELET Study)

BackgroundThe real-world survival benefit of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus anti-VEGF therapy (Triplet) over doublet chemotherapy (Doublet) remains controversial in patients with BRAF^V600E mutant metastatic colorectal cancer (mCRC).Patients and MethodsWJOG13219G was a multicenter, retrospective, registry-based study of patients with BRAF^V600E mutant mCRC who received first-line triplet or doublet chemotherapy from January 2014 to December 2019 in Japan. Inverse probability of treatment weighting (IPTW) was used to adjust for patient background.ResultsThe analysis included 79 and 91 patients in the Triplet and Doublet groups, respectively. The Triplet group was significantly younger and had better performance status. No statistical difference was noted in progression-free survival (PFS; HR, 0.82; 95% CI, 0.60–1.13; P = .22) and overall survival (OS; HR, 0.88; 95% CI, 0.62–1.25; P = .48) between both groups. IPTW analysis also showed no difference between the 2 groups in PFS (HR, 0.86; 95% CI, 0.69–1.08; P = .20) and OS (HR, 0.93; 95% CI, 0.73–1.20; P = .59). The Triplet and Doublet groups had an objective response rate of 53% and 41%, respectively (P = .10). At least one grade 3 or 4 adverse event was seen in 51 (65%) and 43 (47%) patients in the Triplet and Doublet groups, respectively, with the incidence of neutropenia being significantly higher in the former.ConclusionTriplet therapy had no survival benefit versus doublet therapy in the overall and IPTW cohorts or specific subgroups for real-world patients with BRAF^V600E mutant mCRC.     

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.