Fluoropyrimidine-based Adjuvant Chemotherapy Research Articles

PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer: a retrospective study

BackgroundFluoropyrimidine-based postoperative adjuvant chemotherapy is globally recommended for high-risk stage II and stage III colon cancer. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, discovery of novel molecular biomarkers of postoperative adjuvant chemotherapy to identify patients at increased risk of recurrent colorectal cancer is warranted. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between single-nucleotide variants of autophagy-related genes and recurrence rates in order to identify novel biomarkers that predict the effect of adjuvant chemotherapy in colorectal cancer. MethodsWe analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer recurrence rates.ResultsWe detected 560 single-nucleotide variants and insertions/deletions in the target region. The results of Fisher’s exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single-nucleotide variants (c.1018G > A [p < 0.005] or c.1562A > C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1.ConclusionsThe two single-nucleotide variants of PINK1 gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.

Changes in Prescribing Patterns in Stage III Colon Cancer.

For patients with resected stage III colon cancer, 6 months of adjuvant fluoropyrimidine-based chemotherapy has been the standard of care. The IDEA collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Despite failing to meet its primary endpoint, the subgroup analyses demonstrated noninferiority based on regimen and treatment duration when a risk-stratified approach was used. To evaluate the impact of the results of the IDEA collaboration, we evaluated adjuvant chemotherapy prescribing practice patterns, including planned adjuvant treatment regimen and duration from January 1, 2016, to January 31, 2021. The time period was selected to evaluate chemotherapy prescribing patterns prior to the abstract presentation of the IDEA collaboration in June 2017 and after full manuscript publication in March 2018. A total of 399 patients with stage III colon cancer who received adjuvant chemotherapy were included in the analysis. A significant increasing trend for use of 3 months of adjuvant chemotherapy was observed after presentation of the IDEA abstract (P<.001). A significant change in CAPOX (capecitabine/oxaliplatin) prescribing was also observed, increasing from 14% of patients prior to presentation of the IDEA abstract to 48% after presentation (P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX (fluorouracil/leucovorin/oxaliplatin), 3 months of CAPOX use also steadily increased over time (adjusted odds ratio [aOR], 1.28; 95% CI, 1.20-1.37; P<.001). Among subgroups of interest, no differences in adoption of CAPOX were observed. The adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17-1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16-1.47). Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months' duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.

Lessons learned in adjuvant colorectal cancer

SummaryColorectal cancer (CRC) is one of the most frequent malignancies. While adjuvant fluoropyrimidine-based chemotherapy has been established as standard of care for patients with stage III disease, its value and role are still uncertain for stage II disease. This review discusses the usefulness of adjuvant therapy in both stages and highlights the use of liquid biopsy via circulating tumor DNA (ctDNA) for the assessment of minimal residual disease which will shape the therapy decision for adjuvant treatment in future.

Incident Cardiovascular Diseases Among Survivors of High-Risk Stage II-III Colorectal Cancer: A Cluster-Wide Cohort Study.

The incidence and survival of colorectal cancer (CRC) are increasing. There is an increasing number of long-term survivors, many of whom are elderly and have comorbidities. We conducted a population-based study in Hong Kong to assess the long-term cardiovascular disease (CVD) incidence associated with adjuvant fluoropyrimidine-based chemotherapy among CRC survivors. Using the population-based electronic medical database of Hong Kong, we identified adults who were diagnosed with high-risk stage II-III CRC and treated with radical surgery followed by adjuvant fluoropyrimidine-based chemotherapy between 2010 and 2019. We evaluated the cause-specific cumulative incidence of CVD (including ischemic heart disease, heart failure, cardiomyopathy, and stroke) using the flexible parametric competing risk modeling framework. The control group without a history of CVD was selected from among a noncancer random sample from primary care clinics in the same geographic area. We analyzed 1,037 treated patients with CRC and 5,078 noncancer controls. The adjusted cause-specific hazard ratio (HR) for CVD in the cancer cohort compared with the control group was 2.11 (95% CI, 1.39-3.20). The 1-, 5-, and 10-year cause-specific cumulative incidences were 2.0%, 4.5%, and 5.4% in the cancer cohort versus 1.2%, 3.0%, and 3.8% in the control group, respectively. Age at cancer diagnosis (HR per 5-year increase, 1.16; 95% CI, 1.08-1.24), male sex (HR, 1.40; 95% CI, 1.06-1.86), comorbidity (HR, 1.88; 95% CI, 1.36-2.61 for 1 comorbidity vs none, and HR, 6.61; 95% CI, 4.55-9.60 for ≥2 comorbidities vs none), diabetes (HR, 1.38; 95% CI, 1.04-1.84), hypertension (HR, 3.27; 95% CI, 2.39-4.50), and dyslipidemia/hyperlipidemia (HR, 2.53; 95% CI, 1.68-3.81) were associated with incident CVD. Exposure to adjuvant fluoropyrimidine-based chemotherapy was associated with an increased risk of CVD among survivors of high-risk stage II-III CRC. Cardiovascular risk monitoring of this group throughout cancer survivorship is advisable.

Risk of cardiovascular disease among different fluoropyrimidine-based chemotherapy regimens as adjuvant treatment for resected colorectal cancer.

BackgroundPatients with colorectal cancer (CRC) are more likely to develop cardiovascular disease (CVD) than those without cancer. Little is known regarding their CV risk after operative chemotherapy. We aimed to compare the risk of CV disease among different fluoropyrimidine derivatives.MethodsWe assembled a nationwide cohort of patients with newly diagnosed CRC between 2004 and 2015 who received fluoropyrimidine-based adjuvant chemotherapy for resected CRC by linking the Taiwan Cancer Registry (TCR), National Health Insurance Research Database (NHIRD), and Taiwan Death Registry (TDR). All eligible patients were followed from CRC diagnosis (index date) until a CV event, death, loss to follow-up, or December 31st 2018, whichever came first. CV outcomes included acute myocardial infarction (AMI), life-threatening arrhythmia (LTA), congestive heart failure (CHF), and ischemic stroke (IS). We used stabilized inverse probability of treatment weighting using propensity score (SIPTW) to balance all covariates among the three chemotherapy groups: tegafur-uracil (UFT), non-UFT, and mixed. In addition, survival analysis was conducted to examine the association between study outcomes and chemotherapy groups.ResultsFrom 2004 to 2015, 10,615 (32.8%) patients received UFT alone, 14,511 (44.8%) patients received non-UFT, and 7,224 (22.3%) patients received mixed chemotherapy. After SIPTW, the UFT group had significantly lower all-cause mortality and cancer-related death rates than the other two chemotherapy groups. However, the UFT group had significantly higher rates of cancer death, ischemic stroke, and heart failure than those of the other two chemotherapy groups. The UFT group also had a significantly higher AMI rate than the mixed group. There was no significant difference in LTA among the three groups. Similar findings were observed in the subgroup analysis (stage II and age <70 years, stage II and age ≥70 years, stage III and age <70 years, stage III and age ≥70 years) as the overall population was observed.ConclusionHigher heart failure and ischemic stroke rates were found in the UFT group than in the other two chemotherapy groups, especially those with stage III CRC and ≥70 years of age. Careful monitoring of this subset of patients when prescribing UFT is warranted.

P-232 Impact of the IDEA collaboration results on the management of stage II-III colon cancer: 2 years of data from the medical oncology department in Marrakech, Morocco

For many years, adjuvant fluoropyrimidine-based chemotherapy for 6 months has been the standard of care in stage II-III colon cancer with an improved overall survival for stage III and a risk of permanent peripheral neuropathy. However, the benefit of this adjuvant chemotherapy in stage II colon cancer and its duration in stage III were a subject of discussion in different studies. In 2020, the IDEA group collaboration final results were a cornerstone that changed the management of these 2 entities. The aim of this study is to report the impact of IDEA trial on the real-world clinical practice. This is a retrospective study evaluating 44 patients diagnosed with stage II-III colon cancer between 2020 and 2021 at the medical oncology department of the Mohammed VI University Hospital-Marrakech. All patients underwent surgical treatment with curative intent. 44 patients were included in this study, most of our patients were female (56.8%). The average age at diagnosis was 54 years. All patients had a PS of 0-1. All patients had an adenocarcinoma tumor of which (11%) are mucinous. 16 patients (36.3%) had a tumor of the right colon and 28 (63.6%) of the left. Half of the patients had a stage III and the other half a stage II disease. In the stage III group: 11 (50%) had a low-risk and 11(50%) had a high-risk disease. Among patients with a low-risk disease: 7 (70%) received CAPOX for 3 months, 2 (20%) for 6 months and 1 (10%) was lost to follow-up. Among patients with a high-risk disease: 10 (90%) received CAPOX and 1 (10%) FOLFOX for 6 months. In the stage II group: 10 (45,5%) had a low-risk, 4 (18%) had an intermediate-risk and 8 (36,3%) had a high-risk disease. Among patients with a high-risk disease: 6 (75%) received CAPOX, 1 (12%) received CAPECITABINE for 6 months and 1 was lost to follow-up. Among patients with an intermediate-risk disease: 50% received CAPOX and 50% received CAPECITABINE for 6 months. Among patients with low-risk disease: only 1 patient (10%) received adjuvant chemotherapy (CAPECITABINE) for 6 months and the other 90% were put under follow-up without adjuvant chemotherapy. For patients who received 3 months of treatment, 37% had G1 peripheral neuropathy versus 63% of G1-2 for those who received 6 months of treatment. Based on the final results of the IDEA group collaboration, clinicians prefer the use of CAPOX over FOLFOX in the adjuvant sitting especially for the low-risk stage III disease, and they are more likely to use a risk stratification approach for decision making for stage II colon cancer. None of our patients had developed a disabling peripheral neuropathy.

Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer

BackgroundAdjuvant fluoropyrimidine-based chemotherapy substantially reduces recurrence and mortality after resection of stage 3 colon cancer. While standard doses of 5-fluorouracil and capecitabine are safe for most patients, the risk of severe toxicity is increased for the approximately 6% of patients with dihydropyimidine dehydrogenase (DPD) deficiency caused by pathogenic DPYD gene variants. Pre-treatment screening for pathogenic DPYD gene variants reduces severe toxicity but has not been widely adopted in the United States. MethodsWe conducted a cost-effectiveness analysis of DPYD genotyping prior to fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer, covering the c.1129-5923C>G (HapB3), c.1679T>G (*13), c.1905+1G>A (*2A), and c.2846A>T gene variants. We used a Markov model with a 5-year horizon, taking a United States healthcare perspective. Simulated patients with pathogenic DPYD gene variants received reduced-dose fluoropyrimidine chemotherapy. The primary outcome was the incremental cost-effectiveness ratio (ICER) for DPYD genotyping. ResultsCompared with no screening for DPD deficiency, DPYD genotyping increased per-patient costs by $78 and improved survival by 0.0038 quality-adjusted life years (QALYs), leading to an ICER of $20,506/QALY. In 1-way sensitivity analyses, The ICER exceeded $50,000 per QALY when the cost of the DPYD genotyping assay was greater than $286. In probabilistic sensitivity analysis using a willingness-to-pay threshold of $50,000/QALY DPYD genotyping was preferred to no screening in 96.2% of iterations. ConclusionAmong patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe and sometimes fatal toxicities of fluoropyrimidine chemotherapy.

Survival of stage III colon cancer patients with adjuvant chemotherapy: Experience from a specialized cancer institute in Latinoamerica - Peru.

204 Background: In Peru, colon cancer is the 5th most common cause of cancer and the sixth most deadly. Currently, surgery remains as the only curative therapy, however, there is risk of recurrence. Adjuvant chemotherapy has become a useful tool to improve progression-free survival (PFS) and overall survival (OS). In this study, we determine the current survival of our stage III colon cancer patients, submitted to adjuvant chemotherapy, and if this is similar to the evidence seen in large international studies; also, we analyze if delay of adjuvant chemotherapy has impact on survival. Methods: This descriptive cross-sectional study involved 162 patients with stage III colon cancer who underwent a resection surgery and received adjuvant fluoropyrimidine-based chemotherapy. They were evaluated, according to the TNM classification (tumor, nodule), as low risk (T1-T3, N1) and high risk (T4, N2). We also classified patients, according to the weeks of delay from surgery to adjuvant chemotherapy, into subgroups of 6, 8 and 10 weeks. Results: The mean age was 63.7 years, 63 patients were women (38.9%), 99 patients (61.1%) were men. Only 38.3% of patients started adjuvant chemotherapy in the first 6 weeks after surgery, and 85.8% of patients, in the first 10 weeks; the median time from surgery to initiation of adjuvant chemotherapy was 7.0 weeks. We estimated that, at 3 years, the median PFS is 73.5% (95% CI: 65.8-82.1). The 3-year PFS in the low-risk group was 82.9% (95% CI: 72.3-95.0) and 67.3% (95% CI: 57.2-79.2) in the high-risk group. It was estimated that at 3 years, the median OS is 81.1% (95% CI: 75.2-87.5). The 3-year OS in the low-risk group was 87.9% (95% CI: 80.4-96.2) and 76.0% (95% CI: 67.8-85.3) in the high-risk group. Conclusions: The PFS and OS in Peruvian population is similar to data evidenced in international historical studies such as the IDEA trial. This study, also, suggests that starting adjuvant treatment within 10 weeks does not present an impact on OS and PFS in our population.

Expression of astrocyte-elevated gene-1 indicates prognostic value of fluoropyrimidine-based adjuvant chemotherapy in resectable stage III colorectal cancer.

It is unclear which prognostic factor such as pathological features and gene mutation are majorly relevant for stage III disease and whether they aid in determining patients who will be benefit from postoperative adjuvant chemotherapy. The expression of astrocyte-elevated gene-1 (AEG-1), thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) was examined to investigate their role in adjuvant chemotherapy for patients with resectable stage III colorectal cancer (CRC). A significant positive correlation was observed between AEG-1, TS, ERCC1, EGFR, and VEGF gene expression levels in CRC cell lines, and low AEG-1 and TS expression were highly sensitive to 5-fluorouracil treatment. Our results showed that AEG-1 expression was high in T4 and caused CRC recurrence or metastasis. Patients with T4, high AEG-1, TS and VEGF expression had a significantly short disease-free survival and overall survival. In multivariate Cox regression analysis, high AEG-1 expression could be an independent prognostic factor indicating poor survival in patients with resectable stage III CRC treated with adjuvant chemotherapy. In conclusion, AEG-1 expression and tumor grade are potential prognostic factors for recurrence and survival in patients with stage III CRC receiving adjuvant fluoropyrimidine-based chemotherapy.

Cost effectiveness of DPYD genotyping to screen for dihydropyrimidine dehydrogenase (DPD) deficiency prior to adjuvant chemotherapy for colon cancer.

55 Background: Fluoropyrimidine chemotherapy agents, including 5-fluorouracil and capecitabine, are the backbone of adjuvant treatment for colon cancer, and adjuvant chemotherapy substantially reduces recurrence and mortality after surgical resection of stage 3 colon cancer. While fluoropyrimidine chemotherapy is generally safe, the risk of severe, potentially fatal chemotherapy toxicity is substantially increased for the 2-3% of U.S. patients with DPD deficiency caused by pathogenic variants in the DPYD gene. DPYD genotype testing is readily available in the U.S. but has not been widely adopted. We evaluated the cost effectiveness of DPYD genotyping prior to adjuvant chemotherapy for colon cancer in the U.S. Methods: We constructed a Markov model to simulate screening for DPD deficiency with DPYD genotyping (versus no screening) among patients receiving fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer. Screen-positive patients were modeled to receive dose-reduced fluoropyrimidine chemotherapy. Model transition probabilities for treatment-related toxicities were derived from published clinical trial data with annotation of DPYD genotype and chemotherapy dosing strategy. Our analysis is from the healthcare perspective, with a time horizon of five years and an annual discount rate of 3% for future costs and benefits. Direct healthcare costs and health utilities were estimated from published sources and converted to 2020 US dollars, and post-treatment survival was modeled from SEER data. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as dollars per quality-adjusted life year (QALY). We used a value of $100,000/QALY as the cost-effectiveness threshold. One-way sensitivity analyses were used to examine model uncertainty. Results: Compared with no screening, screening for DPD deficiency with DPYD genotyping increased per-patient costs by $106 and improved quality-adjusted survival by 0.0028 QALYs, leading to an ICER of $37,300/QALY. In one-way sensitivity analyses, the ICER exceeded $100,000/QALY when the carrier frequency of pathogenic DPYD gene variants was less than 1.17%, and when the specificity of DPYD genotyping was less than 98.9%. Cost-effectiveness estimates were not sensitive to the cost of DPYD genotyping, the cost of toxicity-related hospitalizations, or the health utility associated with grade 3-4 toxicity. Conclusions: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe, sometimes fatal toxicities of fluoropyrimidine chemotherapy.

The prognostic value of the lymph node ratio for local advanced gastric cancer patients with intensity-modulated radiation therapy and concurrent chemotherapy after radical gastrectomy in China

BackgroundNearly 50% of new gastric cancer cases and gastric cancer-related deaths worldwide occur in China. No global consensus has been reached about the optimal management of locally advanced gastric cancer. Although the Guidelines for the Diagnosis and Treatment of Gastric Cancer from the National Health Commission of China, which has been updated three times since 2010, explicitly emphasize the necessity of adjuvant chemoradiation, few clinical institutions in China routinely adhere to the recommended radiotherapy guidelines. This study aimed to examine the efficacy, in terms of locoregional control and long-term survival, and the safety of adjuvant radiotherapy using intensity-modulated radiation therapy (IMRT) with concurrent and adjuvant fluoropyrimidine-based chemotherapy for gastric cancer.MethodsThis was a retrospective evaluation of 156 patients with high-risk gastric cancer who underwent adjuvant chemoradiotherapy between September 2008 and May 2019. The prescribed planning target volume median dose was 45 Gy in 1.8 Gy daily fractions, and all patients received concurrent and adjuvant fluoropyrimidine-based chemotherapy. Locoregional control, distant metastasis, and overall survival rates were estimated. Clinicopathological characteristics and patterns of failure were retrospectively reviewed to identify factors associated with survival and recurrence.ResultsThe median follow-up duration was 56 months (range 3–130 months) for all patients. Of the patients, 11 (7.1%) were lost to follow-up, and 49 (31.4%) and 104 (66.7%) had stage II or III disease according to the eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging criteria. The frequencies of acute grade 3 or 4 gastrointestinal and hematological toxicity were 9.6% and 10.9%, respectively. In total, 152 patients (97.4%) completed the entire chemoradiation regimen. No toxicity-related deaths occurred. Nineteen patients (12.2%) had locoregional recurrence, 26 (16.7%) had distant metastases, and 12 (7.7%) had peritoneal metastasis. The overall survival (OS) rates were 83.5%, 65.0%, and 59.5%, while the disease-free survival rates were 75.1%, 61.0%, and 55.6% at 1, 3, and 5 years, respectively. In the multivariate analysis, age, pathological T stage and lymph node ratio (LNR) were found to be independent predictors of OS.ConclusionPostoperative concomitant IMRT and chemotherapy were well tolerated, with acceptable toxicities and encouraging locoregional tumor control and long-term survival. The LNR can be used as an important prognostic indicator for OS. Adjuvant chemoradiotherapy should be considered for all patients with a high risk of locoregional recurrence, especially in China.

Sex and Adverse Events of Adjuvant Chemotherapy in Colon Cancer: An Analysis of 34 640 Patients in the ACCENT Database.

Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing. The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin). Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P < .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P < .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P < .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P < .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P < .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P < .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P < .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P < .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P < .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P < .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P < .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P < .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P < .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P < .001]) were observed, with women being consistently at increased risk. Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

Abstract 353: Expression of astrocyte-elevated gene-1 is associated with prognostic value of adjuvant chemotherapy in resectable stage III colorectal cancer

Abstract Background: Administration of postoperative adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival for patients with resected colorectal cancer (CRC). Regarding the prognostic factors, including pathologic features and gene mutation have major relevance for stage III disease, it is not well known whether they might help select patients who would fare favorably when received adjuvant chemotherapy. OBJECTIVE: Expression of astrocyte-elevated gene-1 (AEG-1), thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) were needed to investigate the role involved in adjuvant combination therapy for patients with resectable stage III colon cancer. Methods: AEG-1, TS, ERCC1, EGFR and VEGF were investigated by CRC cell lines and intra-tumor immunohistochemistry stain. Furthermore, this study collected 29 patients with stage III colorectal cancer who underwent surgical resection from 2011 to 2016 and received postoperative adjuvant chemotherapy. The culmination of clinical data registration included surgical procedures, tumor size, number of lymph node metastases, and types of chemotherapy drugs. Result: A significant positive correlation between AEG-1, TS, ERCC1, EGFR, and VEGF gene expression levels were revealed in CRC cell lines. Cell lines with lower AEG-1 and TS expression had higher sensitivity to 5-FU treatment. In clinical studies, we found that higher AEG-1 expression was noted in T4 and also caused CRC recurrence or metastasis. Patients with T4 and stage IIIC CRC had a significantly shorter DFS (T4 v.s. T1-3, DFS, months, median: 4.1 ± 1.2 v.s. non-reach [NR], p &amp;lt; 0.001; IIIC v.s. IIIA or IIIB, DFS, months, median: 10.6 ± 5.3 v.s. NR, p = 0.037; respectively). Patients with higher AEG-1 and TS expression had a shorter DFS (AEG-1, high v.s. low, months, median: 12.8 ± 2.4 v.s. NR, p = 0.003; TS, high v.s. low, months, median: 13.8 ± 2.3 v.s. NR, p = 0.012; respectively). In multivariate Cox Regression analysis, advanced tumor invasion (T4) and high AEG-1 expression could be an independent prognostic factor to cause poor survival in resectable stage III CRC patients treated with adjuvant chemotherapy. Conclusion: Expressions of AEG-1 and tumor grade as a candidate prognostic factor of recurrence in stage III colorectal cancer patients receiving adjuvant fluoropyrimidine-based chemotherapy. A prospective cohort study should be guaranteed to validate these factors to be predictive markers of adjuvant chemotherapy benefit for stage III CRC. Citation Format: Chung-Yu Chen, Peng-Sheng Lai, Ying-Yin Chen, Long-Wei Lin. Expression of astrocyte-elevated gene-1 is associated with prognostic value of adjuvant chemotherapy in resectable stage III colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 353.

Association between adjuvant chemotherapy and survival in patients with rectal cancer and pathological complete response after neoadjuvant chemoradiotherapy and resection

BackgroundFor patients with locally advanced rectal cancer (LARC), it is unclear whether neoadjuvant chemoradiotherapy-induced pathologic complete response (pCR) individuals would further benefit from adjuvant chemotherapy (ACT).MethodsThe pCR individuals who received different ACT cycles were paired by propensity score matching. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated by Kaplan–Meier and log-rank test.ResultsIn total, 1041 pCR individuals were identified from 5567 LARC cases. Specifically, 303 pCR cases had no ACT treatment, and 738 pCR patients received fluoropyrimidine-based ACT (median, 4 cycles) treatment. After 1:3 propensity score matching, 297 cases without ACT treatment were matched to 712 cases who received ACT treatment. Kaplan–Meier analysis showed that pCR individuals treated with or without ACT had the similar 3-year outcome (OS, DFS, LRFS and DMFS) (all P > 0.05). Moreover, the pCR patients received different ACT cycle(s) (0 vs. 1–4 cycles, 0 vs. ≥5 cycles) had comparable 3-year OS, DFS, LRFS and DMFS (all P > 0.05). In stratified analysis, ACT treatment did not improve 3-year survival (OS, DFS, LRFS and DMFS) for the baseline high-risk (cT3–4/cN1–2) subgroup patients (all P > 0.05).ConclusionACT, which did not improve survival, is unnecessary to neoadjuvant treatment-induced pCR LARC patients.Trial registration2019ZSLYEC-136 (24-6-2019).

PNN and KCNQ1OT1 Can Predict the Efficacy of Adjuvant Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer Patients.

The benefit of adjuvant chemotherapy in the early stages of colorectal cancer (CRC) is still disappointing and the prediction of treatment outcome quite difficult. Recently, through a transcriptomic approach, we evidenced a role of PNN and KCNQ1OT1 gene expression in predicting response to fluoropyrimidine-based adjuvant chemotherapy in stage III CRC patients. Thus, the aim of this study was to validate in an independent cohort of stages II–III CRC patients our previous findings. PNN and KCNQ1OT1 mRNA expression levels were evaluated in 74 formalin-fixed paraffin-embedded tumor and matched normal mucosa samples obtained by stages II–III CRC patients treated with fluoropyrimidine-based adjuvant chemotherapy. PININ, the protein encoded by PNN, was immunohistochemically evaluated in 15 tumor and corresponding normal mucosa samples, selected on the basis of a low, medium, or high mRNA expression tumor/mucosa ratio. PNN and KCNQ1OT1 mRNA mean expression levels were significantly higher in tumor compared with normal tissues. Patients with high PNN or KCNQ1OT1 tumor mRNA levels according to ROC-based cutoffs showed a shorter disease-free survival (DFS) compared with patients with low tumor mRNA gene expression. Also, patients with tumor mRNA expression values of both genes below the identified cutoffs had a significantly longer DFS compared with patients with the expression of one or both genes above the cutoffs. In a representative large cohort of stages II–III CRC untreated patients retrieved from GEO datasets, no difference in DFS was observed between patients with high and low PNN or KCNQ1OT1 gene expression levels. These data confirm our previous findings and underscore the relevance of PNN and KCNQ1OT1 expression in predicting DFS in early stages of CRC treated with fluoropyrimidine-based adjuvant chemotherapy. If further validated in a prospective case series, both biomarkers could be used to identify patients who benefit from this treatment and to offer alternative chemotherapy regimens to potential unresponsive patients. In relation to the suggested biological role of PNN and KCNQ1OT1 in CRC, they might also be exploited as potential therapeutic targets.

Translating IDEA to Practice and Beyond: Managing Stage II and III Colon Cancer.

Adjuvant fluoropyrimidine-based chemotherapy has been the standard of care for resected stage III colon cancer since the 1990s; the evolution from 12 to 6 months of fluoropyrimidine therapy and the addition of oxaliplatin to fluoropyrimidine therapy have led to the current accepted standard. However, controversies remain. What is the benefit of adjuvant chemotherapy in stage II disease, and in whom? What is the optimal duration of adjuvant chemotherapy? How should patients with early-stage colon cancer be followed after surgery and adjuvant treatment? Recent evidence has emerged to help inform these important questions, including the International Duration Evaluation of Adjuvant therapy (IDEA) collaboration, which is the largest, prospective study in colon cancer with 12,834 patients. This review discusses current and future risk stratification strategies in stage II disease: the optimal duration of adjuvant oxaliplatin-containing chemotherapy in stage II and III disease according to the IDEA study, and the recent evidence and updated recommendations for surveillance of early-stage colon cancer after resection.

Effects of Adjuvant Chemotherapy on Cognitive Function of Patients With Early-stage Colorectal Cancer

PurposeChemotherapy-related cognitive impairment can occur in cancer survivors after treatment, especially those patients who have undergone chemotherapy for breast cancer. The frequency and to what extent such toxicity develops in colorectal cancer (CRC) survivors is unknown. The present prospective study evaluated the effects of adjuvant chemotherapy on the cognitive performance of patients with localized CRC compared with a control group who had not undergone chemotherapy. Patients and MethodsConsecutive patients with localized stage II and III CRC completed neuropsychological assessments, self-reported cognitive complaint questionnaires, and depressive symptom evaluations before starting fluoropyrimidine-based adjuvant chemotherapy and after 12 months. Blood was collected for apolipoprotein E genotyping. Diffusion tensor imaging data were acquired from a subset of participants at both evaluation points. ResultsFrom December 2012 to December 2014, 137 patients were approached and 85 were included. Of these 85 patients, 49 had undergone chemotherapy and 26 had not, in accordance with the standard recommendations for adjuvant therapy for CRC. The mean age was 62.5 ± 9.4 years, 60% were men, and the mean educational attainment was 7.6 ± 3.7 years. No difference was found in the global composite score (P = .38), attention (P = .84), or memory (P = .97) between the 2 groups during the follow-up period (mean ± standard deviation, 375 ± 29 days). However, a statistically significant difference was found for executive function after adjustment for age, sex, education, and depressive symptoms at baseline (β −1.80; 95% confidence interval, −3.50 to −0.11; P = .04), suggesting worse performance for the chemotherapy group. For the 32 patients who had undergone magnetic resonance imaging, tract-based spatial statistics did not show voxelwise significant differences in structural brain connectivity at baseline or during follow-up. Apolipoprotein E polymorphisms were not predictive of cognitive dysfunction. ConclusionPatients with CRC who received adjuvant 5-fluorouracil with or without oxaliplatin presented with a decline in executive function after 12 months compared with patients with localized disease who had not received chemotherapy.

Abstract 2651: A mesenchymal-associated transcriptomic signature has a prognostic and predictive potential in stage II and III colorectal cancer patients

Abstract Purpose: Clinical decision making for adjuvant chemotherapy, which includes selection of appropriate patients and optimal treatment regimen, remains the most pressing challenge in the management of stage II and III colorectal cancer (CRC) patients. In this study, we attempted to address this issue by developing a clinically actionable mesenchymal-associated transcriptomic signature (MATS) that can accurately predict prognosis and identify CRC patients who could realistically benefit from adjuvant chemotherapy. Experimental Design: To develop a mesenchymal-associated transcriptomic signature, we first performed gene expression profiling in 152 laser capture microdissected CRC tissues, followed by validation of this signature in 1365 CRC patients from various publicly available cohorts (GSE41258, GSE39582, GSE33113, GSE17536 and TCGA). Subsequently, this signature was trained (N=142) and validated (N=286) in two independent clinical cohorts of stage II and III CRC patients, in which Cox's regression analysis was performed to evaluate the recurrence predictive power of this signature. Furthermore, we investigated the clinical significance of MATS in its ability to identify patients who can benefit from fluoropyrimidine-based adjuvant chemotherapy. Results: Through a comprehensive genome-wide expression analysis, we have identified an eight-gene mesenchymal-associated transcriptomic signature that can significantly predict recurrence-free survival (RFS) and identify a mesenchymal CRC subtype with high accuracy. To evaluate its translational potential, we further trained and validated this signature in two independent CRC cohorts consisting of 428 stage II and III CRC patients. Interestingly, MATS successfully stratified patients into low- and high-risk groups with 5-year RFS rates ranging from 87% and 54% in the training cohort [HR: 4.11 (CI: 2.72-15.43)] and 82% and 56% in the validation cohort [HR: 2.66 (CI: 1.66-3.98)], respectively. While the 48 patients with MATS low-risk stage III CRC showed a substantial improvement in survival, the 77 patients with MATS high-risk stage III CRC did not benefit from the fluoropyrimidine-based adjuvant chemotherapy. Furthermore, in multivariate analysis, MATS was significantly associated with RFS along with T-stage and lymphovascular invasion in both training as well as validation cohorts with HRs of 3.80 (CI: 1.85-7.82, p=0.0003) and 2.09 (CI: 1.28-3.42, p=0.003), respectively. Conclusions: Our novel MATS could robustly identify RFS, and this classifier was superior to various clinicopathologic risk factors used in the clinic for risk stratification in CRC patients. In addition, MATS could also predict which stage III CRC patients might benefit from fluoropyrimidine-based adjuvant chemotherapy, which is a significant step forward in the clinical management of these patients. Citation Format: Takatoshi Matsuyama, Raju Kandimalla, Xuan Wang, Toshiaki Ishikawa, Naoki Takahashi, Yasuhide Yamada, Masamichi Yasuno, Yusuke Kinugasa, Hiroyuki Uetake, Ajay Goel. A mesenchymal-associated transcriptomic signature has a prognostic and predictive potential in stage II and III colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2651.

Immunohistochemical Localization of KRAS and BRAF and its Clinical Utility in Patients with Colorectal Cancer

Background: Colorectal cancer (CRC) is a multistep process occurring due to the accumulation of several genetic alterations. The most important ones are RAS and RAF that have been implicated as key intermediates in RAS-mediated signaling cascade. KRAS and BRAF protein expression levels and prognostic evaluation in CRC patients remains unknown. Moreover, minimal evidence exists regarding the predictive role of KRAS and BRAF for fluoropyrimidine-based adjuvant chemotherapy. Hence, present study aimed to investigate the prevalence of KRAS and BRAF protein expressions in CRC patients and further to correlate the results with clinicopathological parameters and prognosis. Methods and findings: A total 82 CRC patients were included in this retrospective study. KRAS and BRAF protein expressions were studied by immunohistochemistry technique using paraffin embedded tumor tissue blocks. The data was analyzed using SPSS software. p value = 0.05 was considered as statistically significant. Immunohistochemical localization of KRAS and BRAF showed cytoplasmic staining in 34% and 63% of patients, respectively. BRAF immunopositivity was found to be significantly higher in patients with positive nodal status (p=0.018), presence of perineural invasion (p=0.039) and = 5.0 ng/mL pre-operative serum CEA levels (p=0.008) as compared to their respective counterparts. Moreover, a trend of higher positive BRAF expression was observed in advanced stage patients as compared to early stage patients (p=0.080). Survival analysis demonstrated a significant reduced relapse-free survival (RFS) with KRAS positive expression in rectal cancer patients (p=0.045). Similar trend of reduced RFS was observed with positive KRAS expression in the subgroup of rectal cancer patients treated with adjuvant therapy (p=0.073). However, BRAF protein expression failed to show any prognostic or predictive value in CRC patients. Conclusion: KRAS and BRAF protein expression might be associated with disease aggressiveness in CRC. Further, KRAS protein expression could be useful prognostic and predictive marker in rectal cancer patients.

Clinicopathologic implications of immune classification by PD-L1 expression and CD8-positive tumor-infiltrating lymphocytes in stage II and III gastric cancer patients

We co-assessed PD-L1 expression and CD8+ tumor-infiltrating lymphocytes in gastric cancer (GC), and categorized into 4 microenvironment immune types. Immunohistochemistry (PD-L1, CD8, Foxp3, E-cadherin, and p53), PD-L1 mRNA in situ hybridization (ISH), microsatellite instability (MSI), and EBV ISH were performed in 392 stage II/III GCs treated with curative surgery and fluoropyrimidine-based adjuvant chemotherapy, and two public genome databases were analyzed for validation. PD-L1+ was found in 98/392 GCs (25.0%). The proportions of immune types are as follows: PD-L1+/CD8High, 22.7%; PD-L1−/CD8Low, 22.7%; PD-L1+/CD8Low, 2.3%; PD-L1−/CD8High, 52.3%. PD-L1+/CD8High type accounted for majority of EBV+ and MSI-high (MSI-H) GCs (92.0% and 66.7%, respectively), and genome analysis from public datasets demonstrated similar pattern. PD-L1−/CD8High showed the best overall survival (OS) and PD-L1−/CD8Low the worst (P < 0.001). PD-L1 expression alone was not associated with OS, however, PD-L1−/CD8High type compared to PD-L1+/CD8High was independent favorable prognostic factor of OS by multivariate analysis (P = 0.042). Adaptation of recent molecular classification based on EBV, MSI, E-cadherin, and p53 showed no significant survival differences. These findings support the close relationship between PD-L1/CD8 status based immune types and EBV+, MSI-H GCs, and their prognostic significance in stage II/III GCs.