scholarly journals Mutational status of plasma exosomal KRAS predicts outcome in patients with metastatic colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donatella Lucchetti ◽  
Ina Valeria Zurlo ◽  
Filomena Colella ◽  
Claudio Ricciardi-Tenore ◽  
Mariantonietta Di Salvatore ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Clinical Information ◽  
Wild Type ◽  
Blood Samples ◽  
Mutational Status ◽  
Fractional Abundance ◽  
Radiological Response ◽  
Metastatic Sites

AbstractLiquid biopsy has become a useful alternative in metastatic colorectal cancer (mCRC) patients when tissue biopsy of metastatic sites is not feasible. In this study we aimed to investigate the clinical utility of circulating exosomes DNA in the management of mCRC patients. Exosomes level and KRAS mutational status in exosomal DNA was assesed in 70 mCRC patients and 29 CRC primary tumor and were analysed at different disease steps evaluating serial blood samples (240 blood samples). There was a significant correlation between the extension of disease and exosomes level and the resection of primary localized tumor was correlated with a decrease of KRAS G12V/ D copies and fractional abundance in metastatic disease. CEA expression and liver metastasis correlated with a higher number of KRAS G12V/D copies/ml and a higher fractional abundance; in the subgroup of mCRC patients eligible for surgery, the size of tumor and the radiological response were related to exosomes level but only the size was related to the number of KRAS WT copies; both KRAS wild-type and mutated levels were identified as a prognostic factor related to OS. Finally, we found that 91% of mutated mCRC patients became wild type after the first line chemotherapy but this status reverted in mutated one at progression in 80% of cases. In a prospective cohort of mCRC patients, we show how longitudinal monitoring using exosome-based liquid biopsy provides clinical information relevant to therapeutic stratification.

scholarly journals Concordance of Acquired Mutations between Metastatic Lesions and Liquid Biopsy in Metastatic Colorectal Cancer Treated with Anti-EGFR Therapy

2021 ◽  
Author(s):  
Fumitaka Taniguchi ◽  
Akihiro Nyuya ◽  
Toshiaki Toshima ◽  
Kazuya Yasui ◽  
Yoshiko Mori ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Acquired Resistance ◽  
Metastatic Tumor ◽  
Primary Tumors ◽  
Blood Samples ◽  
Activating Mutations ◽  
Metastatic Lesions ◽  
Mutational Status

Abstract Background: Acquired mutations are detected in plasma. However, still few reports examine the concordance between liquid biopsy and metastatic lesions with acquired resistance. Herein we evaluated whether a polymerase chain reaction-reverse sequence-specific oligonucleotide (PCR-rSSO) method can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance.Methods: Firstly, we examined the presence of acquired mutations in 7 chemoresistant metastatic lesions and blood samples obtained from a metastatic colorectal cancer (mCRC) patient without RAS activating mutations treated with anti-EGFR treatment. The patient (patient 1) displayed initial early tumor shrinkage and finally progressed to disease (PD). Blood samples were collected before the development of PD and after acquiring resistance. Next, we evaluated RAS and BRAF mutational status among blood samples, primary tumors, and metastatic lesions obtained from three additional mCRC patients without RAS activating mutations. Acquired mutations were examined using Sanger sequencing and the PCR-rSSO approach.Results: Of patient 1, metastatic tumor specimens harbored diverse acquired mutations in the KRAS gene in all of the 7 (100%) metastases, and the three acquired mutations were detected in blood specimens collected after acquiring resistance. Next, we analyzed primary tumors, metastatic lesions after chemotherapy, and blood samples from three additional mCRC patients but noted that none of the patients exhibited mutations in liquid biopsy except for one case with BRAF V600E mutation, which was confirmed in both primary tumor and peritoneal dissemination. Of the four cases, acquired mutations of RAS, as well as BRAF V600E mutation, was detected in the blood obtained only after confirmation of acquiring resistance by radiological examinations.Conclusions: Our results suggest liquid biopsy based on the PCR-rSSO is a successful procedure for capturing acquired mutations with precise information of mutational spectrum that may lend us to reach selective target agents for RAS mutations.

scholarly journals Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

2021 ◽  
Vol 22 (14) ◽  
pp. 7717
Author(s):  
Guido Giordano ◽  
Pietro Parcesepe ◽  
Giuseppina Bruno ◽  
Annamaria Piscazzi ◽  
Vincenzo Lizzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Line Treatment ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Braf Mutations ◽  
Mutational Status ◽  
First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

Liquid biopsy-driven anti-EGFR rechallenge in patients with metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3577-3577
Author(s):  
Stefano Mariani ◽  
Marco Puzzoni ◽  
Nicole Liscia ◽  
Valentino Impera ◽  
Andrea Pretta ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Practice ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Selection Criteria ◽  
Wild Type ◽  
Braf Mutations ◽  
Previous Response ◽  
Clinical Variables ◽  
Ct Dna

3577 Background: The rechallenge with EGFR inhibitors represents an emerging strategy for anti-EGFR pre-treated patients with RAS wild type colorectal cancer (CRC). Unfortunately definitive selection criteria for anti-EGFR rechallenge in this setting are lacking. Very recently RAS wild type status on circulating tumor DNA (ct-DNA) at the time of rechallenge along with already known clinical criteria emerged as a potential watershed for this strategy. In the present study we explored liquid biopsy-driven anti-EGFR rechallenge strategy in the clinical practice for patients with metastatic colorectal cancer. Methods: Ct-DNA from RAS and BRAF wild type metastatic CRC patients previously treated with an anti-EGFR containing therapy was analyzed for RAS/BRAF mutations with the aim to evaluate the rechallenge strategy with anti-EGFR. The ct-DNA was analyzed for RAS-BRAF mutations using pyro-sequencing (PyroMark Q24 MDx Workstation) and nucleotide sequencing (Genetic Analyzer ABI3130) assays. Real-time PCR (Idylla) and droplet digital PCR (QX200 System) were performed to confirm the RAS-BRAF mutation status. Several clinical variables including previous response to anti EGFR containing therapy, tumor sidedness and anti-EGFR free interval were evaluated in relation to outcome. Tumor response evaluation was performed according to RECIST 1.1. Differences between categorical variables were evaluated using the Fisher’s exact test. Survival probability over time was estimated by the Kaplan–Meier method. Significant differences in the probability of survival between the strata were evaluated by log-rank test. Results: Twenty patients were included in the study. All patients were tested for RAS-BRAF mutations in ct-DNA. Fourteen patients (70%) showed a RAS-BRAF WT molecular profile, six patients (30%) showed a KRAS mutation. All the patients with ct-DNA RAS-BRAF WT profile underwent rechallenge with anti-EGFR. In details 11 patients (78.6%) underwent irinotecan+ cetuximab treatment, whereas 3 patients (21.4%) underwent panitumumab monotherapy. As for the outcome results to the rechallenge strategy, the median OS was 7 months (95% CI 5.0 to 13.0), the median PFS was 3 months (95% CI 2.0 to 6.0), the ORR was 27.3% with a DCR of 54.5%. Among the clinical variables evaluated as putative predictive/prognostic factors, previous response to anti-EGFR treatment was related to a not statistically significant improved OS (12 months vs 5 months HR:0.19 p: 0.06) and to a statistically significant improved ORR (75% vs 0% p:0.03). Conclusions: The rechallenge strategy with anti-EGFR confirmed to be feasible in clinical practice. The clinical outcome resulted consistent with the literature data. In addition to the molecular selection through the analysis of ct-DNA for RAS, previous response to anti EGFR treatment is confirmed as a prospective selection criteria for this therapeutic option.

cfDNA for accurate determination of RAS and BRAF mutations using OncoBEAM liquid biopsy in metastatic colorectal cancer patients: Results of the real-world multicentric ColoBEAM study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3542-3542 ◽  
Author(s):  
Alexandre Harle ◽  
Celine Gavoille ◽  
Olivier Bouche ◽  
Meher Ben Abdelghani ◽  
Jérôme Edouard Plaza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Metastatic Colorectal Cancer ◽  
Liquid Biopsy ◽  
Accurate Determination ◽  
Braf V600e ◽  
Molecular Testing ◽  
Braf Mutations ◽  
Blood Samples

3542 Background: Determination of KRAS, NRAS ( RAS) and BRAF mutations is a standard of care for the management of patients with metastatic colorectal cancer (mCRC). RAS mutations are well characterized resistance biomarkers to anti-EGFR antibodies and BRAF V600 mutations indicate poor prognosis. Tissue biopsy has traditionally been used to determine RAS and BRAF status, but liquid biopsy analysis of circulating tumor DNA (ctDNA) has demonstrated utility as a less invasive tool to expedite molecular testing results to the clinic. The ColoBEAM study reports the performance of plasma mutation testing in a real-life prospective series of 278 patients across 8 centers. Methods: Plasma derived ctDNA was prepared from 20mL blood samples prospectively collected from mCRC patients who had not received chemotherapy in the prior 15 days. ctDNA was centrally assessed using OncoBEAM and results compared to those obtained by routine analysis of tissue. Both tissue and blood samples with discrepant RAS results were blindly reassessed with OncoBEAM. Results: Of 278 patients enrolled, 202 blood samples were available for OncoBEAM testing. RAS and BRAF V600E mutations were detected in tissue in 132/202 (65.4%) and 4/198 (2.0%) patients, respectively. Analysis of the first ctDNA sample as compared to tissue DNA resulted in a kappa coefficient (κ) of 0.52 [0.41 – 0.63] and accuracy of 75.2% (65.1% sensitivity; 94.3% specificity). OncoBEAM testing of a second sample resulted (κ) of 0.66 [0.56 - 0.76] and accuracy of 83.2% (77.3% sensitivity; 94.3% specificity). Of the 4 samples with a BRAF V600E mutation in tumor tissue 2 were detected in blood. In the subgroup of patients with liver metastasis (n=136), accuracy was 88.2% (87.4% sensitivity; 90.2% specificity) for RAS and BRAF status with (κ) of 0.73 [0.61 – 0.86]. In a subgroup of chemotherapy naïve patients with liver metastasis (n=49), accuracy was 91.8% (93.3% sensitivity; 89.5% specificity) for RAS and BRAF status with (κ) of 0.83 [0.67 – 0.99]. Conclusions: The results of the ColoBEAM study confirm plasma ctDNA as a credible surrogate marker to tissue DNA for RAS and BRAF status assessment and may be incorporated as a first-line theragnostic assessment. New testing on a second sample for wild-type status demonstrated 91.8% concordance between blood and tissue. Clinical trial information: NCT02751177.

Combination of cetuximab and chemotherapy in the first-line treatment of metastatic colorectal cancer: Slovakian experience.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 622-622 ◽  
Author(s):  
T. Salek ◽  
E. Sebo ◽  
D. Mazalova ◽  
J. Chovanec ◽  
M. Stresko ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Wild Type ◽  
First Line ◽  
Free Survival ◽  
Igg1 Monoclonal Antibody ◽  
Disease Stabilization ◽  
Metastatic Sites

622 Background: Cetuximab is an EGFR-targeting IgG1 monoclonal antibody that is active against EGFR-expressing Kras wild type metastatic colorectal cancer (mCRC) in monotherapy or in combination with chemotherapy. Here, we report efficacy and safety of combination of cetuximab and chemotherapy in patients (pts) with mCRC treated in major cancer centers in Slovakia from 01/2009 to 07/2010. Methods: Forty consecutive pts (28F/12M) with EGFR expressing Kras wild type mCRC (14 pts-rectal cancer, 26 pts-colon cancer) treated with irinotecan-based (29 pts-73%) and oxaliplatin-based (11 pts-27%) chemotherapy were evaluated. Median age was 59 years (44-77).17 pts were pretreated with adjuvant therapy. No of metastatic sites: 1 mts -22 pts (55%), 2 mts-13 pts (32.5%), 3 mts -5pts (12.5%). Median CEA level before therapy 13.5 (1-1,800). Results: 10 pts achieved complete remission (25%), 21 pts partial remission (52.5%), 8pts disease stabilization, 1pt disease progression. Median progression-free survival (mPFS) was 16 months, 1 year survival 65%-95% CI (50-80), median follow-up was 13 months (range 4-20m). The main Gr 3-4 toxicity was skin rash 2pts (5%) and diarrhea 2 pts (5%). Any grade toxicity: rash 32 pts (80%), diarhea 8pts (20%), neuropathy 8pts (20%), weakness 3pts (7.5%), neutropenia 2pts (5%), trombocytopenia 2pts (5%). Conclusions: Our experience confirms the efficacy and acceptable safety profile of combination chemotherapy and cetuximab in first line mCRC patients. No significant financial relationships to disclose.

Retrospective cohort study on the safety and efficacy of bevacizumab for metastatic colorectal cancer patients: The HGCSG0801 study—Efficacy of KRAS mutational status.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 680-680 ◽  
Author(s):  
Susumu Sogabe ◽  
Satoshi Yuki ◽  
Hideyuki Hayashi ◽  
Hirohito Naruse ◽  
Michio Nakamura ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Kras Mutation ◽  
Statistical Tests ◽  
Progression Free Survival ◽  
Wild Type ◽  
Mutation Status ◽  
Free Survival ◽  
Mutational Status ◽  
Kras Mutation Status

680 Background: Mutations of the KRAS gene were identified as a prognostic marker in metastatic colorectal cancer(mCRC). Previously reported data suggests that the longer overall survival (OS) observed with bevacizumab(BV) treatment in mCRC is independent of alterations in the KRAS mutation status. So we analyzed efficacy of bevacizumab combined chemotherapy in mCRC relative to KRAS mutation status. Methods: In the retrospective analysis(n=212) of patients treated with BV(HGCSG0801), additional statistical analyses were done with data from KRAS mutation analyses. The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine Progression-free survival(PFS) and OS. Log-rank test was used to compare with mutant or wild-type KRAS in terms of PFS and OS. All statistical tests were performed using SPSS. Results: KRAS status was assessed in 88 patients (41.5%). Response rate was 58.9% with wild-type and 62.5% with mutant KRAS, that was not significant(p=0.823). The median Progression-free survival was 11.5 months with wild-type and 11.5 months with mutant KRAS, that was not significant(p=0.222). And median OS was 31.8 months with wild-type and 27.5 months with mutant KRAS, that was not significant(p=0.760) as well. Similar results were seen among patients with first-line therapy. Conclusions: Bevacizumab provides clinical benefit in patients with mCRC expressing either mutant or wild-type KRAS.

RAS testing awareness amongst oncologists and panitumumab prescription for metastatic colorectal cancer: A European physician survey and medical records review.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 530-530
Author(s):  
Jorg Trojan ◽  
George Kafatos ◽  
James Bennett ◽  
Gaston Demonty ◽  
Gerry Downey ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Medical Records ◽  
Clinical Information ◽  
Physician Survey ◽  
Wild Type ◽  
Physician Awareness ◽  
Biomarker Testing ◽  
Ras Status ◽  
High Level

530 Background: Patients with metastatic colorectal cancer (mCRC) must have a confirmed RAS wild-type status before starting panitumumab (pmab). Two studies, a physician survey and a medical records review (MRR), were carried out to evaluate physician awareness of the need for biomarker testing in mCRC. Methods: Both studies were carried out in three rounds. Rounds 1 and 2 (2012–14) examined KRAS testing only as they were completed before guidelines changed, and have been published previously. Round 3 (2014–15), reported here, was performed after guidelines changed and covered full RAS testing. Participants were from nine European countries:France, Germany, Italy, Spain, the Czech Republic, the Netherlands, Belgium, Denmark, and Sweden. For the survey, oncologists who had prescribed pmab to mCRC patients in the previous 6 months were interviewed by telephone using a standard questionnaire.For the MRR,oncologists were asked to provide clinical information extracted from their patients’ medical records. Results: 152 oncologists and 131 patients’ records were included in Round 3 of the physician survey and the MMR, respectively, compared with 301 oncologists and 306 records in Rounds 1 and 2. In Round 3 of the physician survey, 95.4% (n = 145) of participants correctly reported that pmab should be prescribed in RAS wild-type mCRC only, compared with 99.0% (n = 298) in Rounds 1 and 2, responding to the same question about KRAS testing. In Round 3 of the MRR, 100% (n = 131) of patients had a confirmed RAS or KRAS wild-type status prior to initiation of pmab. Of those patients, 83.2% (n = 109) were tested for RAS status and 16.8% (n = 22) were tested for KRAS status only. Conclusions: Round 3 of the survey demonstrated a high level of knowledge amongst oncologists about the need for RAS testing in mCRC. The MRR supported these findings, showing that this knowledge is being applied to clinical practice. Comparisons between Round 3 and Rounds 1 and 2 show that physician awareness and adherence to prescribing guidelines remained high over time, despite recommendations changing with RAS testing replacing KRAS testing.

Updated analysis: Observational cohort study of first-line bevacizumab combined with chemotherapy in metastatic colorectal cancer (HGCSG0802)—Sub-group analysis by KRAS Exon2 status.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 522-522
Author(s):  
Michio Nakamura ◽  
Satoshi Yuki ◽  
Kentaro Sawada ◽  
Ayane Oba ◽  
Atsushi Sato ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Multivariate Analysis ◽  
Cohort Study ◽  
Adverse Events ◽  
Metastatic Colorectal Cancer ◽  
Group Analysis ◽  
Observational Cohort Study ◽  
Wild Type ◽  
Mutational Status ◽  
Observational Cohort

522 Background: A few reports have shown the efficacy of bevacizumab (BV) independent of the KRAS Exon2 mutational status (KRAS). We performed a sub-group analysis by KRAS from the HGCSG0802 observational cohort study that investigated 115 patients (pts) treated with 1st line BV for metastatic colorectal cancer (mCRC). Methods: The objective of HGCSG0802 was to evaluate progression-free survival (PFS), overall survival (OS), response rate (RR), and safety. The key eligibility criteria were with evaluable lesions, older than 20 years, ECOG PS 0-2. In this analysis, pts characteristics, RR and safety were compared using Fisher’s exact test. Univariate and multivariate analysis for PFS and OS were performed using patient characteristics. Survival analyses were performed with Kaplan-Meier method and Cox proportional hazards model. Results: Of 108 pts (the full analysis set), 99 pts were evaluable for KRAS. Sixty-two pts (62.6%) had KRAS wild-type (wt) and 37 pts (37.4%) had mutation (mt). The pts characteristics between those with wt and with mt were generally balanced except for PS 0 (91.9% in wt, 75.7% in mt; p = 0.036) and lung metastasis (33.9% in wt, 62.2% in mt; p = 0.007). RR was 70.0% in wt versus 65.7% in mt. Adverse events related to BV were almost balanced except for bleeding (any grade) (30.6% in wt, 13.5% in mt; p = 0.088). The median PFS and OS was 9.9 and 26.8 months in wt versus 7.9 and 17.5 months in mt (PFS ; HR 1.519, p = 0.064 and OS ; HR 1.944, p = 0.005). In Cox multivariate analysis, KRAS mt showed significantly shorter PFS and OS (PFS ; HR 1.637, p = 0.045 and OS ; HR 2.132, p = 0.005). Conclusions: In this cohort, depending on the KRAS Exon2 mutational status, severe adverse events were no significant difference. The multivariate analysis showed that PFS and OS were significantly longer in the KRAS Exon2 wild-type patients. So, KRAS Exon2 mutational status can be a predictive and prognostic marker in bevacizumab combined 1st line chemotherapy. Clinical trial information: UMIN000018935.

Association of SMAD4 gene mutation with incidence of peritoneal involvement in unresectable metastatic colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 772-772
Author(s):  
Diego Vicente ◽  
Takashi Mizuno ◽  
Andrew Loehrer ◽  
Preparim Limani ◽  
Scott Kopetz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Signaling Pathways ◽  
Metastatic Disease ◽  
Peritoneal Metastasis ◽  
Multivariable Analysis ◽  
Wild Type ◽  
Metastatic Sites ◽  
Smad4 Mutation ◽  
Unresectable Metastatic Colorectal Cancer

772 Background: Dorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is involved in TGF- β and Bone Morphogenic Protein (BMP) signaling pathways. Dysregulation in these signaling pathways has been associated with carcinogenesis and poor prognosis in colorectal cancer (CRC). Recent evidence suggests that SMAD4 mutations in CRC may be associated ovarian metastasis, however, the link to peritoneal involvement has not been established. Methods: Patients with next generation sequencing of 50 cancer related genes and unresectable metastatic CRC were identified from a prospectively maintained medical oncology department database. Clinicopathological variables, metastatic sites, and genetic mutations were compared between patients with SMAD4 mutant and SMAD4 wild type patients. Multivariable analysis was then performed to evaluate for factors associated with peritoneal involvement. Results: 324 patients with unresectable metastatic CRC were identified and of these 36 (11%) were SMAD4 mutants. Clinicopathologic variables and additional cancer related gene mutations were similar between SMAD4 mutant and wild type patients. Patients with SMAD4 mutations were more likely to present with peritoneal metastatic disease (50% vs. 24%, p = 0.002) and less likely to present with hepatic metastasis (39% vs 59%, p = 0.021). Metastatic rates to the lungs, distant lymph nodes, and multiple metastatic sites at presentation were similar between the two groups. In patients with metachronous metastatic disease (n = 131), SMAD4 mutation patients demonstrated a trend towards shorter interval to metastatic recurrence (12 vs. 23 months, p = 0.059). During a median follow up of 26 months, SMAD4 mutation patients were more likely to develop peritoneal involvement at either presentation or in progression of disease (58 vs. 35%, p = 0.010). Multivariable analysis showed that compared to other mutations, only the SMAD4 mutation was associated with a higher risk of peritoneal metastasis (OR 2.5, 195% CI 1.2-5.6, p = 0.025). Conclusions: In patients with unresectable metastatic colorectal cancer, SMAD4 mutation is independently associated with peritoneal metastasis.

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