Tumor-infiltrating lymphocytes and tumor budding refine prognostication in patients with low- and high-risk stage III colon cancers (NCCTG N0147)[Alliance].

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4065-4065
Author(s):  
Dan Sha ◽  
Hee Eun Lee ◽  
Nathan R. Foster ◽  
Qian Shi ◽  
Steven R Alberts ◽  
...  

4065 Background: Tumor infiltrating lymphocytes (TILs) and tumor budding (linked to epithelial mesenchymal transition) may influence metastatic potential and patient prognosis. We analyzed these features and their relative contribution to survival among low (T1-3 N1) and high (T4 and/or N2) risk groups, defined by the IDEA study, used to inform the duration of adjuvant chemotherapy in stage III colon cancer. Methods: Among 1,532 patients (low risk n=804; high risk n=728) treated in a phase III adjuvant trial of FOLFOX + cetuximab (x 6 months), intraepithelial TIL densities and tumor budding were quantified at microscopy in routine histologic sections. Optimal cutpoints were determined in association with 5-yr disease-free survival (DFS). Relative contribution of variables to DFS was calculated using χ2 from Harrell’s rms R package based on multivariable Cox regression models. Results: In the overall cohort, the tumor budding/TILs combined variable was more robust for predition of DFS than either alone. Budding/TILs was significantly associated with DFS in both low (HRadj, 1.59; 95% CI, 1.02-2.48; p=.0273) and high (HRadj, 2.82; 95% CI, 1.72-4.63; p<.0001) risk patients. We then determined its relative contribution (%) to DFS (Table). Among low risk, budding/TILs ranked second (24.4%) behind KRAS status (45.5%) and ahead of treatment arm (7.2%) and mismatch repair (MMR) status (6.1%). Among high risk, budding/TILs contributed the most to DFS (45.4%) followed by primary tumor sidedness (13.0%), performance status (12.0%), and MMR (10.4%). Conclusions: Tumor budding/TILs provides robust prognostic stratification by risk group to improve anatomic tumor staging. The relative contribution of budding/TILs to DFS was second only to KRAS status in low risk patients, and was the most important predictor of DFS in high risk patients. Evaluation in patients treated with 3 vs 6 mos of adjuvant chemotherapy is warranted. [Table: see text]

Author(s):  
Corinna Lang-Schwarz ◽  
Balint Melcher ◽  
Theresa Dregelies ◽  
Zahra Norouzzadeh ◽  
Stefanie Rund-Küffner ◽  
...  

Abstract Purpose To analyze the influence of adjuvant chemotherapy on the combination of tumor budding and tumor-infiltrating lymphocytes (TILs) in stage II and III colon cancer and to elucidate its potential value for adjuvant treatment decisions. Methods 306 patients with stage II and 205 patients with stage III colon cancer diagnosed between 2005 and 2016 who had undergone surgery in a curative setting were enrolled. Budding and TILs were assessed according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) and the criteria of the International TILs Working Group (ITWG). Combinations of budding and TILs were analyzed, and the influence of adjuvant chemotherapy was assessed. Results In stage II colon cancer, stratification into the four budding/TILs groups showed no significant differences in overall survival (OS) between the chemotherapy and the surgery-alone group, not even in cases with high-risk features. In stage III colon cancer, patients with low budding/high TILs benefited significantly from chemotherapy (p=0.005). Patients with high budding/low TILs as well as high budding/high TILs showed a trend to benefit from adjuvant treatment. However, no chemotherapy benefit was seen for the low budding/low TIL group. Conclusions The budding/TIL combination identified subgroups in stage II and III colon cancer with and without benefit from adjuvant treatment. The results this study suggest that the combination of budding and TILs as tumor-host antagonists might be an additional helpful tool in adjuvant treatment decisions in stage II and III colon cancer.


2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 378-378 ◽  
Author(s):  
Scott Kopetz ◽  
Zhi-Qin Jiang ◽  
Michael J. Overman ◽  
Christa Dreezen ◽  
Sun Tian ◽  
...  

378 Background: Although the benefit of chemotherapy in stage II and III colon cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and has been validated in public datasets, independent European patient cohorts and technical studies (Salazar 2011 JCO, Maak 2012 Ann Surg). Methods: In this study, the commercial ColoPrint test was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center from 2003 to 2009. Frozen tissue specimen, clinical parameters, MSI-status and follow-up data (median follow-up 64 months) were available. The 64-gene MSI-signature developed to identify patients with deficient mismatch repair system (Tian 2012 J Path) was evaluated for its accuracy to identify MSI patients and also for prognosis. Results: In this cohort, ColoPrint classified 56% of stage II and III patients as being at low risk. The 3-year Relapse-Free-Survival (RFS) was 90.6% for Low Risk and 78.4% for High Risk patients with a HR of 2.33 (p=0.025). In uni-and multivariate analysis ColoPrint and stage were the only significant factors to predict outcome. The MSI-signature classified 47 patients (24.6%) as MSI-H and most MSI-H patients were ColoPrint low risk (81%). Patients who were ColoPrint low risk and MSI-H by signature had the best outcome with a 3-year RFS of 95% while patients with ColoPrint high risk had a worse outcome independently of the MSI-status. Low risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (90.1% 3-year RFS for treated patients, 91.4% for untreated patients) while ColoPrint high risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70.1% 3-year RFS in untreated patients (p=0.026). Conclusions: The combination of ColoPrint and MSI-Print improves the prognostic accuracy in stage II and stage III patients and may help the identification of patients at higher risk who are more likely to benefit from additional treatment


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3520-3520 ◽  
Author(s):  
Frank A. Sinicrope ◽  
Lucas J. Huebner ◽  
Pierre Laurent-Puig ◽  
Thomas C. Smyrk ◽  
Josep Tabernero ◽  
...  

3520 Background: Duration of adjuvant FOLFOX or CAPOX for stage III CC is being guided by pt stratification into low (T1-3N1) and high (T4 or N2) risk groups based on the IDEA study. We determined the relative contributions of clinical and molecular features for prediction of time-to-recurrence (TTR) and survival after recurrence (SAR) within each risk group. Methods: Stage III CC (N=5,430) from 2 trials of adjuvant FOLFOX ± cetuximab with similar outcome by study arm [NCCTG N0147 (Alliance), PETACC-8] were used. Tumors were analyzed for mismatch repair (dMMR vs pMMR), mutations in KRAS (exon 2) and BRAFV600E. Median pt follow-up was 83.4 months. Relative contributions to predicting outcome were assessed using χ2 (Harrell’s rms) based on multivariable (MV) Cox models. Results: N (50.8%) and T (31.8%) stage were the top two contributors to prediction of TTR which supports risk grouping. High risk (n=2566) vs low risk (n=2774) pts had poorer TTR (HR 2.7, 95% CI, 2.4-3.0) and SAR [HR 1.6 (1.4-1.9)], both p<.0001. TTR: KRAS contributed the most to predicting TTR among high (58.6%) and low (51.1%) risk pts (Table). Contribution of MMR (16%) to predicting TTR was limited to low risk pts. Contribution of BRAFV600E to TTR was nearly 3-fold increased in high vs low risk pts. SAR: BRAFV600E contributed the most to predicting SAR, especially in high vs low risk pts (2-fold increase). Tumor sidedness and performance status (PS) were key contributors to SAR, but not TTR. MV associations: TTR: low risk, KRAS [HR 1.7 (1.4-2.3], MMR [HR 0.55 (.35-.87), gender (M/F) [HR 1.3 (1.0-1.5)], all p<.04]; high risk: BRAF [HR 1.3 (1.1-1.7)], sidedness (R vs L) [HR 1.14 (1.0-1.3)], KRAS [HR 1.4 (1.2-1.6)], all p<.04]. SAR: BRAF, sidedness, PS (all p<.05). Conclusions: KRAS mutation was the strongest predictor of shorter TTR in both risk groups whereas BRAFV600E was the primary driver of SAR, especially in high risk pts. Support: U10CA180821, U10CA180882, U24CA196171; BMS, Pfizer, Sanofi. NCT00079274.[Table: see text]


2020 ◽  
Author(s):  
Meijiao Zhou ◽  
Trevor D. Thompson ◽  
Hui-Yi Lin ◽  
Vivien W. Chen ◽  
Jordan J. Karlitz ◽  
...  

Abstract Background Clinical trials have indicated high-risk (T4 and/or N2) and low-risk (T1-T3 and N1) stage III colon cancer patients might need different doses of FOLFOX to reserve a similar survival probability. Observational studies have investigated the effect of relative dose intensity (RDI) of FOLFOX on cancer survival for patients with stage III colon cancer, but nonetheless, the studies focused on very specific populations, and none performed stratified analysis by risk profiles. This study aims to identify the optimal RDI of FOLFOX administered for high-risk and low-risk stage III colon cancer patients.Methods Data on 407 eligible patients, diagnosed with stage III colon cancer in 2011 who received FOLFOX, were collected by the eight population-based cancer registries for a CDC National Program of Cancer Registries (NPCR) project focused on Comparative Effectiveness Research. We employed Kaplan-Meier method, cumulative incidence function (CIF), Multivariable Cox model and Fine-Gray competing risks model to explore Optimal Relative Dose Intensity (RDI) defined as the lowest RDI administered without significant differences in either overall or cause-specific death.Results Among the 168 high-risk patients, the optimal RDI cut-off point was 70% where there was no statistically significant difference in overall mortality (HR=1.87; 95% CI: 0.84-4.19) and cause-specific mortality (HR=1.72; 95% CI: 0.61-4.85) when RDI<70% vs. RDI≥70%, adjusting for sociodemographic and clinical covariates. When the RDI cut-off was lower than the optimal one (<55% vs. ≥55%, <60% vs. ≥60%, or <65% vs. ≥65%), the overall and cause-specific mortalities were significantly statistically different between the two groups of each comparison. Among the 239 low-risk patients, none of the evaluated cut-offs were associated with statistically significant differences in overall and cause-specific mortalities between comparison groups. The lowest RDI we assessed was 45%, HR=0.79; 95% CI: 0.23-2.67 for the overall mortality and HR=0.49; 95% CI: 0.05-4.84 for the cause-specific mortality, when RDI<45% vs. RDI≥45%.Conclusions To best utilize health care resources while maintaining efficacy, RDI can be maintained at a minimum of 70% in high-risk stage III colon cancer patients. For low-risk patients, we found that RDI as low as 45% did not impact risk of death.


2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2018-2018
Author(s):  
E. Franceschi ◽  
A. Tosoni ◽  
M. Ermani ◽  
V. Blatt ◽  
P. Amistà ◽  
...  

2018 Background: Due to the rarity of medulloblastoma (MB) in adults, the few studies available on this condition are retrospective, and the follow-up tends to be short. Furthermore, the different therapeutic strategies used in these patients makes it difficult to assess survival rates and prognostic factors. Methods: Between January 1989 and February 2001, a prospective phase II trial was performed to evaluate the efficacy of treatment for adults with medulloblastoma. Patients were completely staged with a neuroradiological examination of the brain and neuraxis and by CSF cytology, according to Chang’s staging system. Low risk patients received radiotherapy alone, while high risk patients were given 2 cycles of upfront chemotherapy followed by radiotherapy and adjuvant chemotherapy. The results of the preliminary analysis of this study at a median follow-up of 3.7 years are reported elsewhere. The present papers reports on the long- term results of the same trial. Results: After a median follow up of 7.6 years, among a total of 36 enrolled adults with medulloblastoma, overall progression free survival (PFS) and overall survival (OS) at 5 years were 72% (range 59% to 84%) and 75% (62% to 91%), respectively. No difference was found between low and high risk patients in terms of PFS and OS at 5 years: in low-risk patients the 5-year PFS was 80% (range, 59–100%) and the 5-year OS, 80% (range, 58 - 100%); in high-risk patients the 5-year PFS was 69% (range, 54 -89%) and the 5-year OS, 73% (range, 58 - 92%). Conclusions: A long-term follow-up is essential to evaluate the real impact of treatments in adult patients with MB. Since there is no significant difference between low-risk and high-risk patients for PFS and OS, the use of chemotherapy is also questionable in low-risk patients. No significant financial relationships to disclose.


2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 465-465 ◽  
Author(s):  
Ramon Salazar ◽  
Jaume Capdevila ◽  
Robert Rosenberg ◽  
Jan Willem de Waard ◽  
Bengt Glimelius ◽  
...  

465 Background: The 18-gene expression profile, ColoPrint, has been developed and validated for identifying risk of recurrence in patients with early-stage colon cancer (CC). In a pooled stage II validation study ColoPrint identified 63% of patients as Low Risk with a 3-yr recurrence-free survival (RFS) of 93% while High Risk patients had a 3-yr RFS of 82% with a HR of 2.7 (p=0.001). PARSC is a prospective study for the assessment of recurrence risk in stage II CC patients using ColoPrint. ColoPrint classification is compared to NCCN risk classification. Methods: The study enrolled 468 patients with histologically proven stage II CC from 31 institutes in Europe, the United States, and Asia between October 2008 and May 2013. Synchronous tumors were excluded. ColoPrint results were not disclosed to the physician and patient. Treatment was at the discretion of the physician, adhering to NCCN approved regimens or a recognized alternative. A McNemars test is performed to compare ColoPrint with NCCN risk classification. A p value ≤ 0.05 indicates the two tests differ significantly. Results: ColoPrint classified 320 (68%) patients as Low Risk and 148 (32%) as High Risk. 89 patients (19%) received adjuvant chemotherapy. In the ColoPrint Low Risk group, 57 (18%) patients received adjuvant chemotherapy while 32 (22%) of ColoPrint High Risk patients received chemotherapy. According to NCCN high risk factors (T4, high grade (exclusive of MSI-H), lymphovascular/perineural invasion, perforation/obstruction, <12 nodes examined, positive margins) 234 (50%) patients were NCCN Low Risk and 234 were NCCN High Risk. 72 (31%) of the NCCN Low Risk patients are ColoPrint High Risk. 158 (68%) of the NCCN High Risk patients are ColoPrint Low Risk. MSI-status was assessed in 86 (18%) patients of which 29 were MSI high and 57 were MSS. All MSI high were classified as ColoPrint Low Risk. Conclusions: The PARSC study is the first prospective study to compare genomic and clinical risk assessment and we observed marked differences between NCCN risk classification and ColoPrint. The clinical validity of these methods will be based on the outcomes at 3 and 5 years. Clinical trial information: NCT00903565. [Table: see text]


2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 845-845
Author(s):  
Ofer Margalit ◽  
Ronac Mamtani ◽  
Yu-Xiao Yang ◽  
Kim Anna Reiss ◽  
Talia Golan ◽  
...  

845 Background: The IDEA pooled analysis compared 3 to 6 months of adjuvant chemotherapy for newly defined low- and high-risk stage III colon cancer patients, suggesting low-risk patients may be offered only 3 months of treatment. We aimed to evaluate the benefit of monotherapy vs doublet chemotherapy in low and high IDEA risk groups. Methods: Using the NCDB (2004-2014) we identified 56,728 and 47,557 individuals as low and high IDEA risk groups, respectively. We used multivariate COX regression to evaluate the magnitude of survival differences between IDEA risk groups, according to treatment intensity (doublet vs monotherapy). In a secondary analysis, we examined the predictive value of subgroups of age. Results: Low and high IDEA risk groups derived similar benefit from doublet chemotherapy compared to monotherapy, with hazard ratios of 0.83 (95%CI 0.79-0.86) and 0.80 (95%CI 0.78-0.83), respectively. The only subpopulations that did not benefit from doublet chemotherapy were low-risk patients above the age of 72 (HR = 0.95, 95%CI 0.90-1.01) and high-risk patients above the age of 85 (HR = 0.90, 95%CI 0.77-1.05). Conclusions: IDEA risk classification does not predict benefit from doublet chemotherapy in stage III colon cancer. However, omission of oxaliplatin can be considered in IDEA low-risk patients above the age of 72.


2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 602-602 ◽  
Author(s):  
R. Salazar ◽  
R. Rosenberg ◽  
M. Lutke Holzik ◽  
J. Marshall ◽  
J. J. Van Der Hoeven ◽  
...  

602 Background: Clinical trials have not yet shown convincingly if adjuvant chemotherapy is justified for stage II CC patients of whom 25% are at risk of recurrence. An 18-gene expression profile, ColoPrint, has been developed for identifying CC cancer patients more likely to develop recurrent disease and who would be candidates for adjuvant chemotherapy. The gene signature has been validated in independent cohorts of 206 CC patients and in in-silico datasets (Salazar et al, JCO in press). The profile classified 63.2% of the stage II patients (n=134) as low risk. The HR for relapse free survival (RFS) was 3.34 (p=0.017) with a 5-year RFS rate of 90.9% (95%CI, 84.0 -97.8%) for low risk patients and 73.9% (95%CI, 59.2-88.6%) for high risk patients. Moreover, the profile stratified patients independent of ASCO clinical risk factors. Methods: A prospective trial, PARSC (Prospective Study for the Assessment of Recurrence Risk in Stage II CC Patients Using ColoPrint) has been initiated. The main objectives are: (1) determine risk assessment by ColoPrint profile versus clinical parameters based on local protocol and ASCO high-risk recommendations in stage II patients; (2) establish proportion of ′good prognosis′ and ′poor prognosis profile′ in various countries; and (3) validate the power of risk assessment and compare performance of ColoPrint and clinical risk assessment in estimating 3 year relapse rate. Inclusion criteria: age ≥ 18 years, adenocarcinoma of the colon, stage II,no neoadjuvant systemic therapy, no synchronous tumors, fresh tumor sample, and written informed consent. The treatment of the patient is at the discretion of the physician. Results: The trial started in Sept. 2008 with currently 26 participating sites in 11 countries. So far, 223 stage II patients have been enrolled of whom 183 are eligible. 11 patients were rejected because of prior malignancies; 24 patients were rejected based on low tumor content of the sample (< 30% tumor cells), 3 patients had rectal cancer and 2 synchronous tumor. Conclusions: The aim is to enroll 600 stage II patients to differentiate between 3 year relapse- free survival predicted by ColoPrint versus clinical factors. [Table: see text]


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3612-3612
Author(s):  
Scott Kopetz ◽  
Zhi-Qin Jiang ◽  
Michael J. Overman ◽  
Robert Rosenberg ◽  
Ramon Salazar ◽  
...  

3612 Background: Although benefit of chemotherapy in stage II and III colorectal cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and validated in independent validation studies (JCO 2011, Ann Surg 2013). Methods: In this study, ColoPrint was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center. Frozen tissue specimen, clinical parameters and follow-up data (median follow-up 64 months) were available. Stage II patients from this study were pooled with patients from previous studies (n=416) and ColoPrint performance was compared to clinical risk factors described in the NCCN Guidelines 2013. Results: In the MDACC patient cohort, ColoPrint classified 56% of stage II and III patients as being at Low Risk. The 3-year Relapse-Free-Survival (RFS) was 90.5% for Low Risk and 78.1% for High Risk patients with a HR of 2.42 (p=0.025). In uni-and multivariate analysis, ColoPrint and stage were the only significant factors to predict outcome. Low Risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (91% 3-year RFS for treated patients, 90% for untreated patients) while ColoPrint High Risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70% 3-year RFS in untreated patients (p=0.037). In the pooled stage II dataset, ColoPrint identified 63% of patients as Low Risk with a 3-year RFS of 93% while High Risk patients had a 3-year RFS of 82.3% with a HR of 2.7 (p=0.001). In the univariate analysis, no clinical factor reached statistical significance. Using clinical high risk factors as described in the NCCN guidelines as classification, 56% of patients were classified as low risk with a 3-year RFS of 90.3% while high risk patients had a 3-year RFS of 87.7% with a HR of 0.6 (p=0.63). Conclusions: ColoPrint significantly improves prognostic accuracy, thereby facilitating the identification of patients at higher risk who might be considered for additional treatment.


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