Racial disparity in KRAS mutation frequency and outcomes in colorectal cancer (CRC): A U.S. population based study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 18-18
Author(s):  
Jeffrey Bien ◽  
Mayada Aljehani ◽  
Jerry S.H. Lee ◽  
Albert Y. Lin
Keyword(s):  
Racial Disparity ◽  
Kras Mutation ◽  
Mutation Frequency ◽  
Population Based ◽  
Mutation Status ◽  
Risk Increase ◽  
Kras Status ◽  
Significant Difference ◽  
Hispanic Patients ◽  
Race Ethnicity

18 Background: Racial disparity in CRC survival outcome is well documented. Although the reasons for disparity are unclear, a combination of differences in access to care, quality of care, differential treatment response, and underlying cancer biology are implicated. Further, recent studies have observed differences in KRAS mutation frequency between race/ethnic groups. KRAS mutation in metastatic CRC portends a worse response to EGFR-directed therapy, and predicts a poorer prognosis. In this study, we examined whether racial/ethnic differences in KRAS mutation frequency might impact CRC outcomes on a population-based level. Methods: We examined data from 202,237 CRC patients in the Surveillance, Epidemiology, and End Results (SEER) registry between 2010 and 2015. The differences in tumor mutation status by stage and race/ethnicity were examined by χ2 testing. Cause-specific survival (CSS) and overall survival by mutation status were plotted by Kaplan-Meir curves. A multivariable Cox-proportional hazards model was used to construct hazard ratios and 95% confidence intervals (CI) using patient demographics, tumor characteristics, and KRAS mutation status. Results: Overall, about 9% of patients (n = 18,248) in the SEER registry had KRAS status available. In this cohort, tumors from Non-Hispanic Black (NHB) (48%) or Hispanic patients (44%) carried a greater KRAS mutation (mKRAS) rate when compared against Non-Hispanic White (NHW) (39%) or Asian or Pacific Islander (API) patients (37%) (p < 0.01). The assessment of the impact of mKRAS within each race/ethnic group, comparing patients with mKRAS versus wild-type KRAS (wKRAS) on CSS risk show a 7% risk increase for NHW, (HR = 1.07; 95%CI:1.02-1.12), a 15% risk increase for NHB, (HR = 1.15; 95%CI:1.04-1.26) and no significant increase among API, (HR = 1.02; 95%CI:0.92-1.4). Among patients with wKRAS, with NHW for reference, the risk of CSS is 11% higher among NHB (HR = 1.11; 95%CI:1.00-1.23), 14% higher for Hispanic, (HR = 1.14; 95%CI:1.02-1.26) and no significant difference observed among API, (HR = 1.03; 95%CI:0.91-1.16). Evaluation of the interaction between race/ethnicity and KRAS status on the CSS risk shows an increase of: 11% for mKRAS NHW, (HR = 1.11; 95%CI:1.00-1.23), 13% risk for NHB (HR = 1.13; 95%CI:1.01-1.25), 11% for Hispanic wKRAS, (HR = 1.11; 95%CI:1.04-1.18), 31% for Hispanic mKRAS (HR = 1.31; 95%CI:1.18-1.145), 16% for wKRAS API (HR = 1.16; 95%CI:1.03-1.29). In contrast, no significant difference in risk is seen for NHB nor API patients, HR = 1.02 (95%CI:0.90-1.14) and 1.04 (95%CI:0.91-1.20) respectively. Conclusions: mKRAS, compared to wKRAS, connotes worse CSS among NHW and NHB patients. Among wKRAS, NHB and Hispanic patients still experience higher mortality risk. This data suggests the negative prognosis heretofore associated with mKRAS may be linked to race/ethnicity and worthy of further study.

Awareness of KRAS testing by oncologists and panitumumab use in colorectal cancer patients: A European survey.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 547-547
Author(s):  
Jorg Trojan ◽  
Aliki Taylor ◽  
Jan-Henrik Terwey ◽  
Gerry Downey ◽  
George Kafatos ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Kras Mutation ◽  
Wild Type ◽  
Nras Mutation ◽  
Mutation Status ◽  
Kras Status ◽  
Level Of Knowledge ◽  
High Level ◽  
Colorectal Cancer Patients ◽  
Kras Mutation Status

547 Background: Panitumumab (Pmab) is licensed for treatment in metastatic colorectal cancer (mCRC) patients with wild type KRAS mutation status (US) and wild type RAS (KRAS and NRAS) mutation status (most other countries). To resolve uncertainties about KRAS testing, a survey and medical records review (MRR) are being carried out in Europe in three rounds: the first two rounds (2012-2013) evaluated KRAS testing and round 3 is evaluating RAS testing. These studies are specific obligations in Europe for the conditional marketing authorization for Pmab. Here we present results of rounds 1 and 2. Methods: Eligible oncologists were contacted by telephone in nine European countries (France, Germany, Italy, Spain, Czech Republic, Netherlands, Belgium, Denmark, and Sweden). To be eligible, the physician was required to be a practicing oncologist and have prescribed Pmab to mCRC patients. Results: 299 of 301 (99.3%) oncologists participating in the survey were aware of the need to perform KRAS testing prior to first dose of Pmab and 294 (97.7%) were aware of patients’ KRAS mutation status prior to first dose. 283 of 301 (94.0%) did not prescribe Pmab to mCRC patients with mutant or unknown KRAS status. 164 physicians administered Pmab simultaneously with oxaliplatin-containing chemotherapy to patients and 10 (6.1%) to patients with mutant or unknown KRAS status. 306 patients from 79 participating oncologists were included in the MRR. 302 of 306 mCRC patients (98.7%) were tested for KRAS tumor status, known by the oncologist before first dose of Pmab. 299 of 302 patients (99.0%) had wild-type KRAS tumor status. 83 of 85 patients (97.6%) treated with Pmab and oxaliplatin-containing chemotherapy had wild-type KRAS tumor status. 55 of 56 linked pathology laboratories (98.2%) participated in a Quality Assurance scheme; all used a CE marked or otherwise validated KRAS detection method. Conclusions: Results from both studies show a high level of knowledge among oncologists of the need for KRAS testing in mCRC patients prior to treatment with Pmab and the contraindication with oxaliplatin-containing chemotherapy with mutant or unknown KRAS tumour status. The final round of this study evaluating RAS testing in Europe is currently underway.

Use of the intensity of membranous EGFR staining by immunohistochemistry to predict the efficacy of chemotherapy containing cetuximab in KRAS wild-type patients with metastatic colorectal cancer: A retrospective analysis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 516-516
Author(s):  
Naoki Takahashi ◽  
Yasuhide Yamada ◽  
Hirokazu Taniguchi ◽  
Kohei Akiyoshi ◽  
Yoshitaka Honma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Kras Mutation ◽  
Objective Response ◽  
Endoscopic Biopsy ◽  
Rank Test ◽  
Wild Type ◽  
Mutation Status ◽  
Significant Difference ◽  
Kras Mutation Status

516 Background: KRAS mutation status is a strong predictive factor for anti-EGFR monoclonal antibody therapy efficacy in metastatic colorectal cancer (mCRC). In the BOND trial, objective response rates to cetuximab in irinotecan-refractory mCRC were not significantly different based on the intensity of EGFR staining by immunohistrochemistry (IHC). However, this result was not evaluated by KRAS mutation status, so we retrospectively evaluated the relationship between the efficacy of chemotherapy containing cetuximab and the intensity of membranous EGFR staining in KRAS wild type (KRAS-WT) patients. Methods: Between August 2008 and July 2011, specimens of 391 CRC patients were collected by endoscopic biopsy or surgical resection. EGFR staining by IHC and genetic screening for KRAS status were performed and intensity of EGFR staining was scored by the Guidelines for Interpreting EGFR pharmDx, DAKO. We analyzed 94 KRAS-WT patients who received combination chemotherapy with an irinotecan-regimen plus cetuximab or cetuximab monotherapy and met the following criteria: histologically proven mCRC adenocarcinoma , at least 1 previous regimen of standard fluoropyrimidine - containing chemotherapy , ECOG PS score 0-2, and adequate hepatic and renal function. Patients were classified into 2 groups by intensity of EGFR staining: (A) absence of staining and weakly to moderately positive (IHC 1+ and IHC 2+), (B) strongly positive (IHC 3+). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and compared in Groups A and B by the log-rank test. Results: There was no significant difference in patient characteristics between the 2 groups except for primary site. The median PFS of Groups A (n=76) and B (n=18) were 5.4 months and 9.1 months (p= 0.029), the median OS was 8.1 months and 13.2 months (p=0.054) and response rate was 20.1% and 33.3%, respectively. Conclusions: In KRAS-WT patients with fluoropyrimidine-containing chemotherapy-refractory mCRC, strong intensity of EGFR staining by IHC might be predictive for efficacy of chemotherapy containing cetuximab.

scholarly journals Prognostic value of KRAS mutation status in colorectal cancer patients: a population-based competing risk analysis

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9149
Author(s):  
Dongjun Dai ◽  
Yanmei Wang ◽  
Liyuan Zhu ◽  
Hongchuan Jin ◽  
Xian Wang
Keyword(s):  
Colorectal Cancer ◽  
Kras Mutation ◽  
Prognostic Value ◽  
Proportional Hazards ◽  
Selection Process ◽  
Population Based ◽  
Competing Risk ◽  
Mutation Status ◽  
Model Based ◽  
Kras Mutation Status

Background To use competing analyses to estimate the prognostic value of KRAS mutation status in colorectal cancer (CRC) patients and to build nomogram for CRC patients who had KRAS testing. Method The cohort was selected from the Surveillance, Epidemiology, and End Results database. Cumulative incidence function model and multivariate Fine-Gray regression for proportional hazards modeling of the subdistribution hazard (SH) model were used to estimate the prognosis. An SH model based nomogram was built after a variable selection process. The validation of the nomogram was conducted by discrimination and calibration with 1,000 bootstraps. Results We included 8,983 CRC patients who had KRAS testing. SH model found that KRAS mutant patients had worse CSS than KRAS wild type patients in overall cohort (HR = 1.10 (95% CI [1.04–1.17]), p < 0.05), and in subgroups that comprised stage III CRC (HR = 1.28 (95% CI [1.09–1.49]), p < 0.05) and stage IV CRC (HR = 1.14 (95% CI [1.06–1.23]), p < 0.05), left side colon cancer (HR = 1.28 (95% CI [1.15–1.42]), p < 0.05) and rectal cancer (HR = 1.23 (95% CI [1.07–1.43]), p < 0.05). We built the SH model based nomogram, which showed good accuracy by internal validation of discrimination and calibration. Calibration curves represented good agreement between the nomogram predicted CRC caused death and actual observed CRC caused death. The time dependent area under the curve of receiver operating characteristic curves (AUC) was over 0.75 for the nomogram. Conclusion This is the first population based competing risk study on the association between KRAS mutation status and the CRC prognosis. The mutation of KRAS indicated a poor prognosis of CRC patients. The current competing risk nomogram would help physicians to predict cancer specific death of CRC patients who had KRAS testing.

scholarly journals Exploring Disease Biology in Hispanic Versus Non-Hispanic Patients with Diffuse Large B-Cell Lymphoma (DLBCL) to Explain Survival Disparities

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4867-4867
Author(s):  
Sikander Ailawadhi ◽  
Alvaro J. Alencar ◽  
Madiha Iqbal ◽  
Prachi Jani ◽  
Salman Ahmed ◽  
...  
Keyword(s):  
Ethnic Minorities ◽  
B Cell Lymphoma ◽  
Population Based ◽  
Age At Diagnosis ◽  
Stage Iii ◽  
Disease Stage ◽  
Ki 67 ◽  
Patient Level ◽  
Significant Difference ◽  
Hispanic Patients

Abstract Background: DLBCL is the most common adult NHL and despite significant advancements, outcomes in ethnic minorities remain suboptimal. Factors responsible for these disparities in ethnic minorities, especially variability in clinical and pathological features with evaluation of patient-level data have not been studied. Methods: A multi-institutional database of DLBCL patients seen at Mayo Clinic in Florida, University of Miami and University of Southern California between 1996-2016 was developed. Patient demographics, clinical disease characteristics and details of DLBCL immunophenotype [CD10, MUM1, BCL6 (Han's classification), Ki 67, MYC, BCL2) were reviewed. Comparisons between Hispanic and Non-Hispanic patients were made by Chi-square, Fischer's exact and Signed rank tests, where applicable. Patients with missing data on a certain feature were not included in the statistical analysis of that specific characteristic. Results: A total of 966 DLBCL patients with 69 Hispanics and 752 non-Hispanics were identified. These included 52% males (N=36) and 48% females (N=33) in Hispanics versus 58% males (N=436) and 42% females (N=316) in Non-Hispanics (p=0.35). Median age at diagnosis was significantly lower at 61 years (range 27-89) in Hispanics versus 66 in non-Hispanics (p=0.014). Extranodal disease was seen significantly more commonly in Hispanics (74%) than in non-Hispanics (60%) (p=0.037). There was no significant difference in disease stage at presentation between the two cohorts (p=0.189) although the proportion of patients with stage III and IV disease was higher among Hispanics (80.4%) as compared to non-Hispanics (68.5%). Similarly there was no significant difference in presence of primary CNS DLBCL at diagnosis between the two groups (p=0.74). GCB phenotype per the Hans' classification was seen in 59% (N=29) in both, Hispanics and Non-Hispanics (N=241) (p=0.99). Similarly, the median ki67 index of 80% was seen in both cohorts (p=0.48). MYC was positive in 59% in Hispanics versus only 37.5% in non-Hispanics (p=0.024). BCL2 expression by itself and also combined BCL2 and MYC double expression were not significantly different between the two groups (p=0.58 and p=0.11, respectively). Median overall survival (OS) was 22.5 months in Hispanics compared 54.9 months in Non-Hispanics (p<0.0001) (Figure 1). Conclusion: Survival outcome disparities in racial and ethnic minorities have been previously reported from population-based analyses. Lack of patient-level clinical data makes these analyses hypothesis generating, but not conclusive. We confirmed some prior findings including younger age at diagnosis for Hispanics with DLBCL. We also reported greater incidence of extranodal as well as stage III or IV disease at the time of presentation among Hispanics which may contribute to poor outcomes in this population. From DLBCL pathology standpoint, we found increased expression of MYC among Hispanics but no other significant immunohistochemical differences including double expression or non-GCB phenotype. The inferior OS despite uniform treatment practices at large Cancer Centers suggest multifactorial influences on patient outcomes which may at least in part include some of the differences we report here. Disclosures Ailawadhi: Pharmacyclics: Research Funding; Janssen: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy.

scholarly journals Racial and Ethnic Differences in Clonal Hematopoiesis, Tumor Markers, and Clinical Outcomes of Patients with Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 402-402
Author(s):  
Nancy Gillis ◽  
Lauren C Peres ◽  
Christelle M Colin-Leitzinger ◽  
Mingxiang Teng ◽  
Raghunandan Reddy Alugubelli ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Multivariable Analysis ◽  
Age At Diagnosis ◽  
Advisory Committees ◽  
Black Patients ◽  
Significant Difference ◽  
Hispanic Patients ◽  
Race Ethnicity ◽  
White Patients

Abstract Background: Multiple myeloma (MM) is twice as common in Blacks compared to Non-Hispanic (NH) Whites and Hispanics. While treatment and mortality differences have been reported for Black patients with MM compared to NH White patients, there is limited data on Hispanic populations. Furthermore, the factors driving observed differences in MM presentation and treatment responses by race and ethnicity are largely unknown. We investigated demographic, clinical, and molecular features, including tumor mutations and clonal hematopoiesis (CH), in a diverse population of patients with MM to elucidate mechanisms driving clinical disparities. Methods: Patients diagnosed with MM who consented to our institutional biorepository protocol were eligible for inclusion. Demographic and clinical data were obtained from cancer registry and abstracted from electronic medical records. MM tumor cells were purified from bone marrow aspirates by CD138 affinity chromatography. DNA was isolated from tumor cells and whole blood for each patient, and whole exome sequencing (WES) data was generated. Tumor somatic mutations were characterized using paired tumor-normal (blood) WES. CH was classified based on blood-derived somatic mutations, using paired tumors and reference populations as germline comparators. Outcomes included overall survival (OS; date of diagnosis to death/last contact) and progression-free survival (PFS; 1 st-line treatment start to 1 st disease progression/death). Results: A diverse group of MM patients (n=496) were included: NH White (80%), NH Black (10%) and Hispanic (9%). NH Black and Hispanic MM patients had a younger median age at diagnosis (57 and 53 yrs, respectively) compared to NH Whites (63 yrs, p = 0.0001; Fig A). There was no statistical difference in treatment categories received by race/ethnicity. NH Black patients had a longer time to hematopoietic cell transplant (HCT; 376 days) than NH White or Hispanic patients (248 and 270 days, respectively, p = 0.011). There was an improvement in OS for NH Black (HR 0.49, 95% CI 0.30-0.81) and Hispanic (HR 0.66, 95% CI 0.37-1.18) patients compared to NH White patients, but the association was not statistically significant in Hispanics. In univariable analysis, OS was also associated with age at diagnosis, International Staging System (ISS), treatment with HCT, and treatment regimen category. In multivariable analysis, after adjusting for age, ISS, HCT, and treatment category there was no longer a statistically significant association between OS and race/ethnicity. Although a worse PFS was present among Hispanic patients (adjusted HR 1.45, 95% CI 0.99-2.13), there was no statistically significant difference in PFS by race/ethnicity. The most mutated genes in MM tumors were KRAS (24%), NRAS (17%), TP53 (11%), DIS3 (9%), and BRAF (9%) (Fig B). Genes with significantly higher tumor mutation rates in Black compared to NH White patients were SP140 (12% v 4%, p = 0.026), AUTS2 (8% v 2%, p = 0.04), and SETD2 (6% v 1%, p = 0.037). IRF4 was most commonly mutated in Hispanics (11% v 3% in NH White and 0% in Black, p = 0.019). We identified CH using WES in 60 (12%) patients. The most CH mutations were in ASXL1, DNMT3A, and TET2. There was no difference in the prevalence of CH by race/ethnicity (p=0.8). There was a statistically significant difference in OS by race/ethnicity and CH status (Fig C). For NH Black patients, CH (HR 4.36, 95% CI 1.36-14.0) and age at diagnosis (HR 1.08, 95% CI 1.03-1.14) were associated with inferior OS (Fig C). After adjusting for age in multivariable analysis, the positive association with CH status among Black patients was no longer statistically significant (HR 2.72, 95% CI 0.48-15.4). A positive, but not statistically significant, association for PFS in NH White patients with CH was also noted (adjusted HR 1.38, 95% CI 0.95-2.0). Conclusions: This is the first study to examine differences in tumor mutation profiles, CH, and treatment among different racial and ethnic groups of patients diagnosed with MM. Our data suggest that age at diagnosis, tumor mutations, and CH may all contribute to clinical disparities observed in patients with MM. Efforts to expand our cohort and incorporate additional molecular biomarkers, epidemiologic characteristics, and clinical parameters are ongoing with the ultimate goal of elucidating targetable biological mechanisms to personalize management and optimize outcomes for diverse patients diagnosed with MM. Figure 1 Figure 1. Disclosures Hampton: M2Gen: Current Employment. Blue: WebMD: Consultancy; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Siqueira Silva: AbbVie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Research Funding. Baz: GlaxoSmithKline: Consultancy, Honoraria; BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding; Oncopeptides: Consultancy; Merck: Research Funding. Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Shain: Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm Therapeutics Inc.: Honoraria, Research Funding; Sanofi Genzyme: Consultancy, Speakers Bureau; Novartis Pharmaceuticals Corporation: Consultancy; GlaxoSmithLine, LLC: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 1892: Folate intake and incident colorectal cancer by KRAS mutation status in a population-based cohort of older women

2011 ◽  
Author(s):  
Anthony Razzak ◽  
Robert A. Vierkant ◽  
Alice H. Wang ◽  
Lori S. Tillmans ◽  
Charles F. Lynch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Older Women ◽  
Kras Mutation ◽  
Population Based ◽  
Folate Intake ◽  
Mutation Status ◽  
Kras Mutation Status
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