Pattern of expression of CDX2 in colorectal cancer and its role in prognosis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15115-e15115 ◽  
Author(s):  
JAGDEEP SINGH

e15115 Background: CDX2 (Caudal Type Homeobox 2), a nuclear protein, is essential for the proliferation and development of intestinal epithelial cells and is frequently down-regulated during tumourogenesis. We have evaluated the pattern of expression of CDX2 in all stages of CRC (colorectal cancer) and its association with prognosis. Methods: We performed CDX2 staining by Immunohistochemistry (IHC) on the available biopsy block of patients of CRC registered with Medical Oncology, JIPMER, from January 2014-January 2018. CDX2 scoring was done by semi-quantitative method. Results: 286 patients were registered during study period, of which only 110 biopsy blocks were available for staining. Of 110 patients, 77 (70%) constituted colon cancer and 33 (30%) were rectal cancer. The median age was 54.2 years, 62 (56.4%) being male and 48 (43.6%) female with male to female ratio 1.3:1. In the study cohort, 33 (30%) patients had stage II disease, 30 (27.3%) stage III and 47(42.7%) were stage IV. 73 (66.4%) were positive for CDX2 and 37 (33.4%) were negative. Lack of CDX2 expression was significantly associated with advanced stage, rectal site, poor grade of differentiation, and presence of lympho-vascular invasion (LVSI). With median follow-up of 16 months, PFS (progression free survival) at 2 years was 30% for CDX2 negative patients compared to 67% CDX2 positive (P=0.009), while OS (overall survival) at 2 years was 46% for CDX2 negative versus 77% for positive patients (p=0.01). Conclusions: Lack of CDX2 is associated with significantly worse PFS and OS, serves as a poor prognostic factor in CRC. Lack of CDX2 expression is associated with advanced stage, higher tumor grade and presence of LVSI.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 36-36
Author(s):  
Jagdeep Singh

36 Background: CDX2 (Caudal Homeobox2), a nuclear protein, is essential for the proliferation and development of intestinal epithelial cells and is frequently down-regulated during tumorigenesis. We have evaluated the pattern of expression of CDX2 in all stages of CRC (Colorectal Cancer) and its association with prognosis. Methods: We performed CDX2 staining by immunohistochemistry (IHC) on the available biopsy block of patients of CRC registered with Medical Oncology, JIPMER, from January 2014-January 2018. CDX2 scoring was done in semi-quantitative method. Results: 286 patients were registered during this period, of which only 110 biopsy blocks were available for staining. Of 110 patients, 77 (70%) constituted colon cancer and 33(30%) were rectal cancer. The median age was 54.2 years, 62 (56.4%) being male and 48 (43.6%) female with male to female ratio 1.3:1. In the study cohort, 33(30%) patients had stage II, 30 (27.3%) stage III and 47(42.7%) were stage IV. 73 (66.4%) were positive for CDX2 and 37 (33.4%) were negative. Lack of CDX2 was significantly associated with advanced stage, rectal site, poor grade of differentiation and presence of lympho-vascular invasion (LVSI). With median follow-up of 16 months, PFS (progression free survival) at 2 years was 30% for CDX2 negative compared to 67% for CDX2 positive (P = 0.009), while OS (overall survival) ) at 2 years was 46% for CDX2 negative versus 77% for positive (P = 0.01). Conclusions: Lack of CDX2 is associated with significantly worse PFS and OS, serves as poor prognostic factor in CRC. Lack of CDX2 expression is associated with advanced stage, higher tumor grade and presence of LVSI.


2009 ◽  
Vol 27 (35) ◽  
pp. 5931-5937 ◽  
Author(s):  
Susan D. Richman ◽  
Matthew T. Seymour ◽  
Philip Chambers ◽  
Faye Elliott ◽  
Catherine L. Daly ◽  
...  

PurposeActivating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies.Patients and MethodsThe Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry.ResultsThree hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio [HR], 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012).ConclusionKRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.


Oncoreview ◽  
2016 ◽  
Vol 6 (4) ◽  
pp. 0-0
Author(s):  
Małgorzata Domagała-Haduch ◽  
Marek Jasiówka ◽  
Łukasz Nowak ◽  
Ida Cedrych

Introduction: Bevacizumab is an antiangiogenic drug used in the therapy of numerous solid tumours including colorectal adenocarcinoma. The efficacy and safety of bevacizumab has been demonstrated in many multicenter clinical trials. The scope of this paper is to analyze the safety profile of bevacizumab in patients with stage IV colorectal cancer. Aim of the study: Analysis of toxicity and safety of the treatment with bevacizumab patients with colorectal cancer in the metastatic stage. Material and methods: Retrospective analysis of medical records of 42 patients with advanced colorectal cancer treated in the Department of Systemic and Generalized Malignancies, Maria Skłodowska-Curie Memorial Institute of Oncology, Kraków Branch, in the period 2007–2014. Results: The median time of treatment with bevacizumab was 6 months. The median duration of progression-free survival (PFS) was 8.5 months. Toxicity of treatment with bevacizumab affected 43 percent of patients. The most common adverse events observed was hypertension and bleeding. In 6 patients (14.3%) the treatment with bevacizumab was interrupted due to adverse events (thromboembolic events, bleeding and gastrointestinal perforation). Conclusions: Bevacizumab is a safe therapeutic option in patients with metastatic colorectal cancer, provided that patients are provided close oncological and general medical monitoring.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15096-e15096
Author(s):  
G. Melmed ◽  
C. Becerra ◽  
G. Saracino ◽  
E. Bowman ◽  
A. D. McCollum

e15096 Background: Patients with metastatic colorectal cancer (mCRC) have improved survival due to recent advances in systemic therapy. It remains unclear whether patients responding to initial chemotherapy can be offered a chemotherapy free interval (CFI) without compromising survival. An initial CFI is potentially beneficial from a quality of life and health care economics standpoint. Methods: We studied patients with mCRC treated at Baylor University Medical Center (Dallas, TX) who had a CFI after first-line chemotherapy. Eligible patients had unresectable mCRC and had stable or responding disease after initial chemotherapy. Records were analyzed to record patient characteristics, chemotherapy details, initial response, duration of CFI, progression free survival (PFS), and overall survival (OS). Results: We identified 29 eligible patients treated between 11/02 and 11/08. Analyses are based on data from 8/08. Patient characteristics included: median age 63 (range 34–81), M/F 16/13, ECOG PS 0 (9) or 1 (20), and median number of sites of disease 2 (range 1–7). Initial chemotherapy regimens included mFOLFOX6 with or without bevacizumab (10), FOLFIRI/bevacizumab (12), XELOX/bevacizumab (2), 5-fluorouracil/leucovorin/bevacizumab (3), and capecitabine with or without bevacizumab (2). With a median follow-up of 31.1 months, the median duration of CFI was 8.0 months (95% CI: 4.3–9.6). In addition, the median OS was 33.7 months (95% CI: 27.8 -56.3) and PFS was 15.0 months (95% CI: 9.4–21.4). Conclusions: In this selected group of patients with mCRC, we found a CFI of 8 months. The OS nearing 34 months and PFS of 15 months compares favorably with other studies of patients treated for mCRC. An initial CFI may reduce the medical and financial burden of therapy for patients with mCRC without compromising outcomes and warrants further study. [Table: see text]


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19094-e19094
Author(s):  
B. Han ◽  
J. Shen ◽  
Z. Gao

e19094 Purpose: We investigated whether Treatment Guided by ERCC1,RRM1 and BRCA1 protein expression levels could improve clinical outcomes in Patients With Advanced-Stage NSCLC. Experimental Design: Eligibility: Main inclusion criteria: Stage IV or stage IIIB NSCLC; Eastern Cooperative Oncology Group(ECOG) performance status (PS) 0–1; Measurable disease; Adequate bone marrow, kidney, liver function. Main exclusion criteria: previous NSCLC therapy; Central nervous system metastasis; Requiring immediate intervention or Untreated with radiation within 28 days of study regimen initiation. Previously untreated patients with Stage IV or stage IIIB NSCLC(N=180): Standard chemotherapy group(N=60): Cisplatin 75mg/m2 Day1+Vinorelbine 25mg/m2 Days 1,8 every 28 days; Individualized chemotherapy group (N=120) (ERCC1,RRM1 and BRCA1 protein expression assayed with IHC); Low ERCC1 protein expression subgroup: Cisplatin 75mg/m2 Day1+Vinorelbine 25mg/m2 Days 1,8 every 28 days; High ERCC1 protein subgroup: Vinorelbine 25mg/m2 Days 1,8+Gemcitabine 1250mg/m2 Days 1,8 every 28 days. Description of Current Analysis: ERCC1,RRM1 and BRCA1 protein expression assayed with IHC; Assigned treatment based on ERCC1 protein expression; Primary endpoint: overall response rate; Secondary endpoints: Overall survival (OS), Progression-free survival (PFS). Enrollment progress (As of time Dec-31–2008): See Table . [Table: see text] No significant financial relationships to disclose.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14186-e14186
Author(s):  
Shivi Jain ◽  
Kireet Agrawal ◽  
Shinoj Pattali ◽  
Abhijai Singh ◽  
Kamal Agrawal ◽  
...  

e14186 Background: Overall survival in colorectal cancer is influenced by obesity, age, gender and stage at diagnosis. However, in minority based populations, effect of the above factors on overall survival has not been studied in any detail. Hence, we undertook this retrospective study to evaluate effect of above factors on overall survival in young colorectal cancer patients. Methods: 1,195 subjects with colorectal cancer treated at John H. Stroger Hospital of Cook County between 2000 and 2008 were retrospectively analyzed. 179 subjects with age 50 years and younger were identified. 146 of 179 subjects with available Body Mass Index (BMI) in kg/m2 were included in the study. Effect of BMI, age, sex, race, LDH and CEA levels, stage, site of tumor, smoking and family history on overall survival was evaluated using standard statistical multivariate analysis. Results: In our population, 22 of 146(15%) were underweight (BMI<20), 56 of 146(38.4%) were normal weight (BMI 20-24.9), 46 of 146(31.5%) were overweight (BMI 25-29.9) and 22 of 146(15%) were obese (BMI >30). Male: female ratio was 1.4:1. 75 of 146(51.7%) were African American, 23 of 146(15.9%) were Caucasians. 50 of 146(34.2%) were stage IV colorectal cancer at diagnosis. On univariate analysis, BMI<20(p=0.031, HR 2.1, 95% CI 1.15-3.82), CEA >4ng/ml (p=0.005, HR 1.93, 95% CI 1.21-3.08) and stage IV colorectal cancer (p<0.001, HR 6.1, 95% CI 2.42-15.53) were significantly associated with decreased overall survival. LDH<200 U/L was significantly associated with improved overall survival (p 0.029, HR 0.6, 95% CI 0.391-0.950). On multivariate analysis, stage IV colorectal cancer was a single significant independent predictor of overall survival (p=0.001, 95% CI 2.47-27.78). CEA>4ng/ml was marginally significant for decreased overall survival (p=0.06, 95% CI 0.978-3.015). On the contrary, no statistically significant difference was found on overall survival with age, BMI>20, gender, race, tumor location, smoking and family history. Conclusions: Advanced stage and CEA >4ng/ml are independent prognostic variables for decreased overall survival in minority based population of young colorectal cancer.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15101-e15101
Author(s):  
Yoshifumi Shimada ◽  
Hitoshi Kameyama ◽  
Masayuki Nagahashi ◽  
Hiroshi Ichikawa ◽  
Ryoma Yagi ◽  
...  

e15101 Background: Although the difference in right vs. left sidedness of colorectal cancer (CRC) in response to targeted therapy has been reported, we hypothesized that right-sided colorectal cancer (RCC) is more likely to have genetic alterations associated with resistance of anti-EGFR therapy. We tested this hypothesis using comprehensive genomic sequencing (CGS) on a set of samples from well-characterized CRC patients. Methods: Two-hundred-one primary colon cancer patients with either RCC or left-sided colorectal cancer (LCC) were analyzed. We investigated gene alterations using 415 gene panel, which includes the gene alterations associated with resistance of anti-EGFR therapy: TK receptors ( ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway ( KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway ( PTEN and PIK3CA). We defined the patients who had no alterations in any of the genes as “all wild-type”, who are theoretically considered as responders of anti-EGFR therapy. Other patients with genetic alterations in resistance pathways were defined as “mutant-type”. Results: Fifty-six patients (28%) and 145 patients (72%) had RCC and LCC, respectively. Mutation of PIK3CA, BRAF, ACVR2A, MSH6, and CTNNB1 were significantly associated with RCC. Conversely, mutation of APC and TP53 were significantly associated with LCC. Regarding the gene alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) of RCC were “all wild-type”; in contrast to 41 of 145 patients (28%) of LCC that were “all wild-type” ( P = 0.009). In 45 Stage IV patients treated with anti-EGFR therapy, RCC showed significantly worse progression-free survival (PFS) than LCC ( P = 0.019), and “mutant-type” RCC showed worse PFS compared to the others ( P = 0.018). Conclusions: RCC is more likely to have the genetic alterations associated with resistance of anti-EGFR therapy compared to LCC. Primary tumor sidedness is a surrogate for the non-random distribution of molecular subtypes in CRC.


2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 712-712
Author(s):  
Mahvish Muzaffar ◽  
Abdul Rafeh Naqash

712 Background: 25% of patients with colorectal cancer(CRC) present with synchronous metastatic disease. The incidence of brain metastasis (BM) in CRC is very low (1.2–3.2%) and tend to occur later in the disease course. Synchronous BM(SBM) in CRC is very rare. We sought to explore the impact of primary tumor characteristics on SBM. Methods: Surveillance Epidemiology End Results Program (SEER) 18 registries research data on primary colorectal cancer cases diagnosed during 2010-2015 with brain metastasis at diagnosis were identified. Patients with unlabeled primary site and autopsy alone cases were excluded. Demographic and colorectal cancer characteristics including age, gender, race, tumor grade and primary tumor side were analyzed. Logistic regression model was used to test the association between survival and side of cancer. Results: A total of 475 cases met the inclusion criteria. The mean age was 64.04 yrs. (range 28-95). Majority of the patients (80%) were white, 12% black and others (8%), Male: Female ratio was 1:1.58% patients had primary tumor on left side (splenic flexure, sigmoid, rectosigmoid and rectal) and 42% had right sided (ascending colon, hepatic flexure, cecum, transverse colon) primary tumor. The median overall survival was 5 months with 1-year survival of 26% in the whole cohort. The 1-year overall survival was 21% for patients with right sided primary tumor versus 30% for patients with SBM and left sided primary tumor(p = 0.03). The median disease specific survival was 5 months for right side and 7 months for Left sided tumor with SBM. The regression model showed that higher grade (RR 14, p = 0.003)) and right sided primary tumor (RR 4.2, p = 0.04) were associated with worse outcome among patients with SBM in colorectal cancer. Conclusions: Synchronous brain metastasis is very rare in colorectal cancer. Tumor side seems to be prognostic even in this aggressive disease subset. This differential outcome further indicates that sidedness should be considered in goals of care and treatment discussion.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5518-5518
Author(s):  
D. M. O'Malley ◽  
C. Nagel ◽  
L. A. Cantrell ◽  
L. Havrilesky ◽  
M. Liotta ◽  
...  

5518 Background: There is currently no consensus regarding the management of advanced stage uterine MMT. In an effort to better define postoperative treatment modalities and their associated outcomes, we retrospectively reviewed factors that influence progression and survival. Methods: A retrospective, multi-institution study of women diagnosed from 1997–2007 was performed. Post-operative treatment included either observation (OBS), RT (brachytherapy, whole pelvic, or combination), chemotherapy (CT) alone or with RT (CT+RT). The majority of chemotherapy regimens included carboplatinum/paclitaxel, Ifosfamide/cisplatin, cisplatin/adriamycin, Data collected included time to recurrence, overall survival and sites of recurrence. Statistics included t-test, ANOVA and Kaplan Meier. Results: 119 patients were identified with late stage uterine MMT. 81 had stage III disease and 38 had stage IV disease. The median age at diagnosis was 67 years (range: 30–86). 70 (59%) were Caucasian and 48 (40%) were African-American. 116 (87%) were optimally debulked and their survival further analyzed. 18 (15%) were observed and 9 of these patients recurred. This group had the poorest median progression free survival (PFS) of 3.4 months. The majority (N = 50, 49%) of late stage patients underwent adjuvant CT with a median PFS of 13.3 months and median OS of 15.6 months. Of these patients 33 (66%) recurred. 18 (17 %) patients underwent RT alone with a median PFS of 12.4 months and OS of 14.9 months. 14 (78%) of these patients recurred. 20 patients (19%) underwent a combination of CT and RT and 11 (55%) experienced recurrences . The combination therapy group had the longest median PFS of 14.3 months and OS of 17.2 months (p = 0.27). Conclusions: Chemotherapy had become the standard therapy for advanced stage MMT however the addition of radiation has not been established. Patients diagnosed with advanced stage MMT can achieve long-term DFS in a minority of patients (33%) treated with chemotherapy. We showed that the addition of radiation to adjuvant chemotherapy showed a slight improvement over chemotherapy alone yet the optimal therapy has yet to be defined. This retrospective review highlights the need for prospective trials of new therapeutic agents and treatment regimens for women with advanced stage uterine MMT. No significant financial relationships to disclose.


2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 640-640
Author(s):  
Patrick D. Lorimer ◽  
Kendall K Walsh ◽  
Russell C. Kirks ◽  
Yimei Han ◽  
Jimmy J. Hwang ◽  
...  

640 Background: Patients (pts) with synchronous stage IV colorectal cancer commonly begin palliative chemotherapy while the primary tumor remains. Single institution series report low rates of surgical intervention, but this has not been examined nationally. The present study utilizes a large national dataset to examine the natural history of unplanned surgical intervention in stage IV colorectal cancer pts on palliative chemotherapy. Methods: SEER-Medicare was queried for pts with metastatic colorectal cancer (1998-2009) who underwent resection or diversion (ICD9 procedure/CPT). The cohort was separated into 3 groups: elective (surgery on admission without urgent/emergent flag), urgent (surgery not on day of admission but within hospitalization or with urgent flag) and emergent (emergent flag). Pts who underwent any procedure for curative intent (elective colorectal surgery, liver directed therapy or surgery for pulmonary metastases) at any time were excluded. Demographics, tumor grade and comorbidities were analyzed for effect on intervention rate. Time to event for either urgent or emergent surgical intervention or censorship by death, were measured. Conditional analyses were performed to determine the risk of surgical intervention at 6 months, 1 and 2 years post diagnosis. Results: 3,992 pts met inclusion criteria. Median age=73; 53% male. White 79%, black 11% and other 10%. The overall intervention rate was 6%; 35% emergent, 65% urgent. At 42 months, 90% of the pts had died. The probability of requiring unplanned surgery between 6-12 months was 2.5%; 12-24 months=1.9%, and >24 months=0.8%. Charlson comorbidity score of 1 was a significant predictor of surgical intervention (HR 1.64 [1.24, 2.19]). Sex, age and race had no influence on the likelihood of surgical intervention. Conclusions: This study represents a large series of stage IV colorectal cancer pts and the frequency of unplanned surgery in pts receiving palliative chemotherapy. Pts treated with palliative chemotherapy are unlikely to require urgent or emergent surgery, and therefore prophylactic surgery to reduce the risk of perforation or obstruction should not be routinely performed.


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