scholarly journals Prognostic impact of additive chemotherapy after curative resection of metachronous colorectal liver metastasis: a single-centre retrospective study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Matthias Kelm ◽  
Julia Schollbach ◽  
Friedrich Anger ◽  
Armin Wiegering ◽  
Ingo Klein ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Curative Resection ◽  
Randomized Clinical Trials ◽  
Cox Regression ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Disease Recurrence ◽  
Prognostic Impact ◽  
Single Centre ◽  
The Impact

Abstract Background A prognostic benefit of additive chemotherapy in patients following resection of metachronous colorectal liver metastases (CRLM) remains controversial. Therefore, the goal of this retrospective study was to investigate the impact of perioperative chemotherapy on disease-free survival (DFS) and overall survival (OS) of patients after curative resection of metachronous CRLM. Methods In a retrospective single-centre study, patients after curative resection of metachronous CRLM were included and analysed for DFS and OS with regard to the administration of additive chemotherapy. The Kaplan-Meier method was applied to compare DFS and OS while Cox regression models were used to identify independent prognostic variables. Results Thirty-four of 75 patients were treated with additive 5-FU based chemotherapy. OS was significantly prolonged in this patient subgroup (62 vs 57 months; p = 0.032). Additive chemotherapy significantly improved 10-year survival rates (42% vs 0%, p = 0.023), but not 5-year survival (58% vs 42%, p = 0.24). Multivariate analysis identified additive chemotherapy (p = 0.016, HR 0.44, 95% CI 0.23–0.86), more than five CRLM (p = 0.026, HR 2.46, 95% CI 1.16–10.32) and disease recurrence (0.009, HR 2.70, 95% CI 1.29–5.65) as independent risk factors for OS. Conclusion Additive chemotherapy significantly prolonged OS and 10-year survival in patients after curative resection of metachronous CRLM. Randomized clinical trials are needed in the future to identify optimal chemotherapy regimens for those patients.

scholarly journals Results of Second-Look Laparotomy in Advanced Ovarian Cancer: One Single Center Experience

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Tarak Damak ◽  
Riadh Chargui ◽  
Jamel Ben Hassouna ◽  
Monia Hechiche ◽  
Khaled Rahal
Keyword(s):  
Cox Regression ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Advanced Ovarian Cancer ◽  
Complete Response ◽  
Disease Recurrence ◽  
Single Center Experience ◽  
Second Look ◽  
Initial Surgery ◽  
Disease Free

Objective. The goal of the study was to analyse the results of 85 cases of second-look laparotomy (SLL) and explore the influence of this procedure on survival. Patients and Methods. We reviewed retrospectively 85 cases of SLL collected and treated in our institute between 1994 and 2003. Results. Complete pathologic response (CPR) was 25.8%, microscopic disease (Rmicro) was 38.8%, and macroscopic disease (Rmacro) was 35.4%. In patients with negative SLL results, disease recurrence was diagnosed in 41%. The 3- and 5-year overall survival rates for the entire population were 91% and 87%, respectively. The 3- and 5-year disease-free survivals were, respectively, 76.3% and 58.5% in negative SLL versus 55.7% and 16% in positive SLL. The difference between the group of patients with complete response (76%) and the patients with residual microscopic disease (72%) was not significant. The tumoral residuum after initial surgery was the only prognostic factor influencing significantly the disease-free survival. On Cox regression model analysis, only initial tumoral residuum () and tumoral residuum after SLL () were independent prognostic factors for survival. Conclusions. The most important advantage of SLL is the early detection of recurrence and thus the early administration of consolidation treatment resulting in a better prognosis.

scholarly journals Impact of Pancreatic Resection on Survival in Locally Advanced Resectable Gastric Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1289
Author(s):  
Shih-Chun Chang ◽  
Chi-Ming Tang ◽  
Puo-Hsien Le ◽  
Chia-Jung Kuo ◽  
Tsung-Hsing Chen ◽  
...  
Keyword(s):  
Lymph Node ◽  
Pancreatic Resection ◽  
Locally Advanced ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Complication Rates ◽  
Lymph Node Yield ◽  
Whipple’S Operation ◽  
Whipple's Operation ◽  
The Impact

Whether gastric adenocarcinoma (GC) patients with adjacent organ invasion (T4b) benefit from aggressive surgery involving pancreatic resection (PR) remains unclear. This study aimed to clarify the impact of PR on survival in patients with locally advanced resectable GC. Between 1995 and 2017, patients with locally advanced GC undergoing radical-intent gastrectomy with and without PR were enrolled and stratified into four groups: group 1 (G1), pT4b without pancreatic resection (PR); group 2 (G2), pT4b with PR; group 3 (G3), positive duodenal margins without Whipple’s operation; and group 4 (G4), cT4b with Whipple’s operation. Demographics, clinicopathological features, and outcomes were compared between G1 and G2 and G3 and G4. G2 patients were more likely to have perineural invasion than G1 patients (80.6% vs. 50%, p < 0.001). G4 patients had higher lymph node yield (40.8 vs. 31.3, p = 0.002), lower nodal status (p = 0.029), lower lymph node ratios (0.20 vs. 0.48, p < 0.0001) and higher complication rates (45.2% vs. 26.3%, p = 0.047) than G3 patients. The 5-year disease-free survival (DFS) and overall survival (OS) rates were significantly longer in G1 than in G2 (28.1% vs. 9.3%, p = 0.003; 32% vs. 13%, p = 0.004, respectively). The 5-year survival rates did not differ between G4 and G3 (DFS: 14% vs. 14.4%, p = 0.384; OS: 12.6% vs. 16.4%, p = 0.321, respectively). In conclusion, patients with T4b lesion who underwent PR had poorer survival than those who underwent resection of other adjacent organs. Further Whipple’s operation did not improve survival in pT3–pT4 GC with positive duodenal margins.

scholarly journals Survival Rate of 1008 Short Dental Implants with 21 Months of Average Follow-Up: A Retrospective Study

2020 ◽  
Vol 9 (12) ◽  
pp. 3943
Author(s):  
João Caramês ◽  
Ana Catarina Pinto ◽  
Gonçalo Caramês ◽  
Helena Francisco ◽  
Joana Fialho ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Survival Rate ◽  
Dental Implants ◽  
Cox Regression ◽  
Survival Rates ◽  
High Survival ◽  
Implant Survival ◽  
Posterior Maxilla ◽  
Clinical Records

This retrospective study evaluated the survival rate of short, sandblasted acid-etched surfaced implants with 6 and 8 mm lengths with at least 120 days of follow-up. Data concerning patient, implant and surgery characteristics were retrieved from clinical records. Sandblasted and acid-etched (SLA)-surfaced tissue-level 6 mm (TL6) or 8 mm (TL8) implants or bone-level tapered 8 mm (BLT8) implants were used. Absolute and relative frequency distributions were calculated for qualitative variables and mean values and standard deviations for quantitative variables. A Cox regression model was performed to verify whether type, length and/or width influence the implant survival. The cumulative implant survival rate was assessed by time-to-event analyses (Kaplan–Meier estimator). In all, 513 patients with a mean age of 58.00 ± 12.44 years received 1008 dental implants with a mean follow-up of 21.57 ± 10.77 months. Most implants (78.17%) presented a 4.1 mm diameter, and the most frequent indication was a partially edentulous arch (44.15%). The most frequent locations were the posterior mandible (53.97%) and the posterior maxilla (31.55%). No significant differences were found in survival rates between groups of type, length and width of implant with the cumulative rate being 97.7% ± 0.5%. Within the limitations of this study, the evaluated short implants are a predictable option with high survival rates during the follow-up without statistical differences between the appraised types, lengths and widths.

H3K27M-mutant Diffuse Midline Gliomas should be Further Molecularly Stratified: An Integrated Analysis of 669 Patients

2021 ◽  
Author(s):  
Huy Gia Vuong ◽  
Hieu Trong Le ◽  
Tam N.M. Ngo ◽  
Kar-Ming Fung ◽  
James D. Battiste ◽  
...  
Keyword(s):  
Cox Regression ◽  
Fatal Outcome ◽  
Extent Of Resection ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Integrated Analysis ◽  
Prognostic Impact ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
The Impact

Abstract Introduction: H3K27M-mutated diffuse midline gliomas (H3-DMGs) are aggressive tumors with a fatal outcome. This study integrating individual patient data (IPD) from published studies aimed to investigate the prognostic impact of different genetic alterations on survival of these patients.Methods: We accessed PubMed and Web of Science to search for relevant articles. Studies were included if they have available data of follow-up and additional molecular investigation of H3-DMGs. For survival analysis, Kaplan-Meier analysis and Cox regression models were utilized, and corresponding hazard ratios (HR) and 95% confidence intervals (CI) were computed to analyze the impact of genetic events on overall survival (OS).Result: We included 30 studies with 669 H3-DMGs. TP53 mutations were the most common second alteration among these neoplasms. In univariate Cox regression model, TP53 mutation was an indicator of shortened survival (HR = 1.446; 95% CI = 1.143-1.829) whereas ACVR1 (HR = 0.712; 95% CI = 0.518-0.976) and FGFR1 mutations (HR = 0.408; 95% CI = 0.208-0.799) conferred prolonged survival. In addition, ATRX loss was also associated with a better OS (HR = 0.620; 95% CI = 0.386-0.996). Adjusted for age, gender, tumor location, and the extent of resection, the presence of TP53 mutations, the absence of ACVR1 or FGFR1 mutations remained significantly poor prognostic factors.Conclusions: We outlined the prognostic importance of additional genetic alterations in H3-DMGs and recommended that these neoplasms should be further molecularly segregated. It could help neuro-oncologists better evaluate the risk stratification of patients and consider pertinent treatments.

Type I Versus Type II Endometrial Cancer: Differential Impact of Comorbidity

2018 ◽  
Vol 28 (3) ◽  
pp. 586-593 ◽  
Author(s):  
Mette Calundann Noer ◽  
Sofie Leisby Antonsen ◽  
Bent Ottesen ◽  
Ib Jarle Christensen ◽  
Claus Høgdall
Keyword(s):  
Cox Regression ◽  
Type I ◽  
Prognostic Impact ◽  
Type Ii ◽  
Regression Analyses ◽  
Differential Impact ◽  
Kaplan Meier ◽  
Prediction Of Survival ◽  
Comorbidity Index ◽  
The Impact

ObjectiveTwo distinct types of endometrial carcinoma (EC) with different etiology, tumor characteristics, and prognosis are recognized. We investigated if the prognostic impact of comorbidity varies between these 2 types of EC. Furthermore, we studied if the recently developed ovarian cancer comorbidity index (OCCI) is useful for prediction of survival in EC.Materials and MethodsThis nationwide register-based cohort study was based on data from 6487 EC patients diagnosed in Denmark between 2005 and 2015. Patients were assigned a comorbidity index score according to the Charlson comorbidity index (CCI) and the OCCI. Kaplan-Meier survival statistics and adjusted multivariate Cox regression analyses were used to investigate the differential association between comorbidity and overall survival in types I and II EC.ResultsThe distribution of comorbidities varied between the 2 EC types. A consistent association between increasing levels of comorbidity and poorer survival was observed for both types. Cox regression analyses revealed a significant interaction between cancer stage and comorbidity indicating that the impact of comorbidity varied with stage. In contrast, the interaction between comorbidity and EC type was not significant. Both the CCI and the OCCI were useful measurements of comorbidity, but the CCI was the strongest predictor in this patient population.ConclusionsComorbidity is an important prognostic factor in type I as well as in type II EC although the overall prognosis differs significantly between the 2 types of EC. The prognostic impact of comorbidity varies with stage but not with type of EC.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictors of outcomes in inflammatory breast cancer

2021 ◽  
Author(s):  
Ouissam Al Jarroudi ◽  
Khalid El Bairi ◽  
Naima Abda ◽  
Adil Zaimi ◽  
Laila Jaouani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Receiver Operating Characteristic ◽  
Inflammatory Breast Cancer ◽  
Operating Characteristic ◽  
Cox Regression ◽  
Menopausal Status ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Receiver Operating

Background: Inflammatory breast cancer (IBC) is uncommon, aggressive and associated with poor survival outcomes. The lack of prognostic biomarkers and therapeutic targets specific to IBC is an added challenge for clinical practice and research. Inflammatory biomarkers such as neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios (NLR and PLR) demonstrated independent prognostic impact for survival in breast cancer. In our study, these biomarkers were investigated in a cohort of patients with nonmetastatic IBC. Methods: A retrospective cohort of 102 IBC patients with nonmetastatic disease was conducted at the Mohammed VI University Hospital (Oujda, Morocco) between January 2010 and December 2014. NLR and PLR were obtained from blood cell count at baseline before neoadjuvant chemotherapy (NACT) from patients’ medical records. The receiver operating characteristic was used to find the optimal cut-off. Correlation between these blood-based biomarkers and response to NACT was analyzed by Chi-squared and Fisher's exact test. Their prognostic value for predicting disease-free survival (DFS) and overall survival (OS) was performed based on Cox regression models. Results: Totally, 102 patients with IBC were included in the analysis. Pathologic complete response (pCR) after NACT, defined by the absence of an invasive tumor in the breast tissues and nodes after surgery (ypT0 ypN0), was observed in eight patients (7.8%). NACT response was found to be associated with menopausal status (p = 0.039) and nodal status (p < 0.001). Patients with a low NLR had a higher pCR rate as compared with the high-NLR group (p = 0.043). However, the pCR rate was not significantly associated with age (p = 0.122), tumor side (p = 0.403), BMI (p = 0.615), histological grade (p = 0.059), hormone receptors status (p = 0.206), human epidermal growth factor receptor 2 (p = 0.491) and PLR (p = 0.096). Pre-treatment blood-based NLR of 2.28 was used as the cut-off value to discriminate between high and low NLR according to the receiver operating characteristic curves. Similarly, a value of 178 was used as the cut off for PLR. Patients with low-NLR had a significantly better 5-year DFS (p < 0.001) and OS (p < 0.001) than the high-NLR group. Moreover, low-PLR was significantly associated with higher DFS (p = 0.001) and OS (p = 0.003). The NLR showed a significant prognostic impact for DFS (HR: 2.57; 95% CI: 1.43–4.61; p = 0.01) and for OS (HR: 2.92; 95% CI: 1.70–5.02; p < 0.001). Similarly, a meaningful association between PLR and 5-year DFS (HR: 1.95; 95% CI: 1.10–3.46; p = 0.021) and OS (HR: 1.82; 95% CI: 1.06–3.14; p = 0.03) was noticed. Conclusions: High NLR and PLR were found associated with reduced DFS and OS in nonmetastatic IBC. Further studies are awaited to confirm these findings.

Increased Expression of Macrophage Migration Inhibitory Factor (MIF) Receptor CD74 Is Associated with Inferior Outcome in Younger Patients (Pts) with Cytogenetically Normal Acute Myeloid Leukemia (CN-AML): a Cancer and Leukemia Group B (CALGB) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1616-1616 ◽  
Author(s):  
Eyal C. Attar ◽  
Kati Maharry ◽  
Krzysztof Mrózek ◽  
Michael D. Radmacher ◽  
Susan P. Whitman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Advanced Pancreatic Cancer ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Free Survival ◽  
Expression Levels ◽  
The Impact ◽  
Disease Free

Abstract Abstract 1616 Poster Board I-642 CD74 is a type II integral membrane protein receptor that binds its ligand MIF to induce phosphorylation of the extracellular signal-regulated kinase-1/2 (ERK-1/2) and drive cellular proliferation via nuclear factor-kappa B (NF-kB) activation. CD74 expression has been identified in human solid tumors, and its expression is associated with adverse prognosis in advanced pancreatic cancer. As CD74 is expressed and NF-kB constitutively activated in myeloblasts, we hypothesized that CD74 expression might also be associated with adverse outcome in AML. To investigate the prognostic impact of CD74 expression in the context of other predictive molecular markers in CN-AML, we assessed CD74 expression levels by Affymetrix HG-U133 Plus 2.0 microarray in 102 younger [<60 years (y)] adults with primary CN-AML, treated on the front-line CALGB 19808 trial with an induction regimen containing daunorubicin, cytarabine, etoposide and, in some cases, the inhibitor of multidrug resistance valspodar, and consolidation with autologous stem cell transplantation. Microarray data were analyzed using the Robust Multichip Average method, making use of a GeneAnnot chip definition file, which resulted in a single probe-set measurement for CD74. At diagnosis, CD74 expression, when assessed as a continuous variable, was significantly associated only with extramedullary disease involvement (P=.006) among clinical features, and with none of the molecular prognostic variables tested, including NPM1, WT1, CEBPA, FLT3 (FLT3-ITD and FLT3-TKD) mutations, MLL partial tandem duplication, or differential BAALC and ERG expression levels. Although CD74 expression levels were not associated with achievement of complete remission (CR; 83% vs 81%), higher levels of CD74 were associated with shorter disease-free survival [DFS; P=.046, hazard ratio (HR) 1.85, 95% confidence interval (CI) 1.12-3.08] and with shorter overall survival (OS; P=.02, HR 1.32, CI 1.04-1.67). In multivariable analyses, higher CD74 expression was independently associated with shorter DFS (P=.045, HR 1.98, CI 1.16-3.40), after adjusting for WT1 mutations (P<.001) and FLT3-TKD (P=.04), and shorter OS (P=.01, HR 1.58, CI 1.11-2.25) after adjusting for FLT3-TKD (P=.02), WT1 mutations (P=.007), BAALC expression levels (P=.02), white blood counts (P=.007), and extramedullary involvement (P=.04). As quartiles 2-4 had similar expression levels distinct from the lowest quartile, to display the impact of CD74 expression levels on clinical outcome only, pts were dichotomized into low (the lowest quartile) and high (the top three quartiles) CD74 expressers. The Kaplan-Meier curves for DFS and OS (Figures 1 and 2) are shown below. In conclusion, our study identifies elevated CD74 expression as associated with adverse prognosis in younger CN-AML pts. Since we previously reported that higher CD74 expression was favorably associated with achievement of CR in AML patients receiving chemotherapy plus bortezomib, an inhibitor of the proteasome and NF-kB (Attar et al., Clin Cancer Res, 2008;14:1446-54), it is possible that in future studies elevated CD74 levels can be used not only for prognostication, but also to stratify CN-AML pts to study of bortezomib-containing chemotherapy regimens. Figure 1 Disease free survival Figure 1. Disease free survival Figure 2 Overall survival Figure 2. Overall survival Disclosures No relevant conflicts of interest to declare.

Adjuvant chemotherapy (ACT) in stage II colon cancer (CC) in patients with Lynch syndrome.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3550-3550
Author(s):  
Karsten Schulmann ◽  
Sven Koepnick ◽  
Christoph Engel ◽  
Christiane Bernhardt ◽  
Verena Steinke ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Prognostic Impact ◽  
Regression Analyses ◽  
Free Survival ◽  
Kaplan Meier ◽  
Stage Ii Colon Cancer ◽  
Disease Free

3550 Background: Previous studies showed conflicting results regarding the value of ACT in MSI-H CC. A recent study reported differential benefits from 5-FU-based ACT comparing suspected sporadic vs suspected hereditary MSI-H CC. We sought to evaluate the prognostic impact of ACT in a large cohort of Lynch syndrome (LS) patients (pts) with stage II CC. Methods: To minimize selection bias diagnoses >2 years prior to registration in the database of the German HNPCC consortium were excluded. 278 patients (61% male, mean age 42.9y, 13% stage IIB, 51% with MMR gene mutation) were eligible. Overall Survival (OS), CC-specific Survival (CSS), and Disease Free Survival (DFS) were analyzed using Kaplan-Meier and Cox Regression analyses. Results: 5y OS, CSS and DFS were 95%, 95% and 93% respectively. Right-sided CC was independently associated with lower DFS in stage II and IIA. Increasing age was associated with lower OS, CSS and DFS in stage IIA, however we observed only trends in the multivariate analysis. Surgery alone (without ACT) was associated with a slightly lower OS in stage IIA (univariate HR 3,659; 95% CI 0,81-16,5; P=0.092); but not with lower DFS and CSS. Prognosis was not different comparing FOLFOX vs. 5-FU-based ACT. Conclusions: Our data suggest that LS pts with stage II CC do not benefit from ACT. FOLFOX was not superior to 5-FU-based ACT. If our results are confirmed, LS pts with stage IIA CC should not receive ACT. The group of stage IIB CC was too small to make definite conclusions. [Table: see text]

The impact of adjuvant delayed radiotheraphy (RT) on survival in patients with resected periampullary adenocarcinomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15168-e15168
Author(s):  
Suayib Yalcin ◽  
Neyran Kertmen ◽  
Deniz Yuce ◽  
Ferah Yildiz ◽  
Erhan Hamaloglu
Keyword(s):  
Cancer Patients ◽  
Survival Rates ◽  
Tumor Resection ◽  
Disease Free Survival ◽  
Ampullary Carcinoma ◽  
Periampullary Cancer ◽  
Periampullary Tumor ◽  
Complete Surgical Resection ◽  
The Difference ◽  
The Impact

e15168 Background: Postoperative prognosis for ampullary carcinoma (AC) is superior to that of pancreatic cancer (PC), the former exhibiting higher complete surgical resection, lower recurrence and longer survival rates (1). Despite all the major recent advances in surgery, chemotherapy (CT) and RT, PC is still one of the most lethal malignancies, overall survival (OS) rates being as low as 5% at 5 years (2). This study was intended to evaluate survival in patients with resected periampullary cancer treated with adjuvant Gemcitabine (Gem) and cisplatin (Cis) with or without delayed RT (with Gem). Methods: This retrospective study involved 91 patients diagnosed and treated with periampullary cancer. Patients with adenocarcinoma of periampullary region with gross total tumor resection and lymph node dissection (R0 and R1 resections only) were included. Of 59 patients with PC, 38 received Gem and Cis for 3 cycles (3 months) before CRT. When delivered after Gem /RT, Gem and Cis were usually given for another 1-3 cycles. Twenty-seven patients received Gem and Cis alone over 6 cycles. Of 32 patients with non-pancreatic periampullary 23 received CT+CRT and 9 patients received CT alone. Results: Patients with non-pancreatic periampullary cancer had better OS (p:0.017) and disease free survival (DFS) ( p<0.001 ) compared to patients with PC. Median OS of patients with PC was 21 months. Both OS and DFS were superior in the RT arm compared to nonRT arm (p: 0.043 and p <0.001). In non-pancreatic periampullary cancer patients OS was 31 months in RT group and 51 months in non-RT group (p: 0.709). DFS was 29 months and 49.8 months respectively, p:0.504). Conclusions: The prognosis of PC was worse than non–pancreatic periampullary tumor. In PC adjuvant delayed RT improved patient outcome. Although OS and DFS were better in patients receiving CT alone, the difference was not statistically significant in non–pancreatic periampullary tumors.

RAS heterogeneity as a prognostic marker in metastatic colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 586-586
Author(s):  
Jonathan M. Loree ◽  
Michael Lam ◽  
Jeffrey Morris ◽  
Michael J. Overman ◽  
Kanwal Pratap Singh Raghav ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Allele Frequency ◽  
Cox Regression ◽  
Rank Test ◽  
Intratumor Heterogeneity ◽  
Prognostic Impact ◽  
Stage At Diagnosis ◽  
Braf Mutations ◽  
The Impact

586 Background: The impact of intratumor heterogeneity on prognosis in metastatic colorectal cancer (mCRC) is unclear, however relative variant allele frequency (rVAF) of key mutations within a tumor may impact outcomes. Therefore, we sought to determine whether rVAF of RAS ( KRAS & NRAS) mutant (mt) clones impacts overall survival (OS) in mCRC patients (pts). Methods: Using a next generation sequencing panel of 201 cancer related genes, we tested 200 mCRC tumors / matched normals. Mutations, indels, and copy number variant (CNV) information were obtained. An rVAF of RAS clones was determined by dividing RAS mt VAF by the VAF of the mutated gene with the highest allele frequency. This truncal gene served as a marker of the total malignant population in a specimen. Pts were stratified at an rVAF of 50%. OS was compared with Kaplan-Meier curves, the log-rank test, and Cox regression. We assessed the impact of CNV on our findings by correcting the rVAF for CNVs in RASand truncal mutations. Results: Of 200 pts, 15% had RAS mt rVAF < 50%, 40.5% had rVAF ≥ 50%, and 44.5% were RAS wild type (WT). Age, gender, MSI status, histology, and stage at diagnosis were similar between groups. More RAS WT pts had BRAF mutations (19.1% vs 1.2% and 3.3%, P< 0.0001), left sided (78.7% vs 56.8% and 60%, P= 0.02), or poorly differentiated tumors (27.3% vs 8.6% and 13.3%, P= 0.003) compared to pts with rVAF ≥ 50% or rVAF < 50%, respectively. Mean coverage was 807x for RAS and 602x for truncal mutations. OS was better in pts with an rVAF < 50% compared to pts with rVAF ≥ 50% regardless of whether rVAF was corrected for CNV (HR 0.6; 95% CI 0.39-0.93, P =0.029) or not (HR 0.48; 95% CI 0.31-0.82, P= 0.010). mOS for pts with WT, rVAF < 50% and rVAF ≥ 50% tumors were 65.8, 55.7, and 38.6 months ( P= 0.0025). In multivariate models controlling for stage at diagnosis and BRAF mutation, pts with rVAF < 50% (HR 1.75; 95% CI 1.03-2.97, P = 0.04) and rVAF ≥ 50% (HR 2.46; 95% CI 1.66-3.65, P< 0.0001) had worse OS compared to WT pts. When rVAF was used as a continuous variable, every 1% increase in rVAF RAS mt resulted in a 1% increased hazard of death ( P <0.0001). Conclusions: Our findings suggest that clonal proportion of a tumor with a RAS mutation may impact OS and suggest the prognostic impact of RAS mutations is not an “all or none” phenomenon.

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