Primary Tumor Sidedness Research Articles

Response to Comment on: “Prognostic Relevance of Primary Tumor Sidedness in Early-Stage Colorectal Cancer: An Integrated Analysis of 4 Randomized Controlled Trials (JCOG2003A)”

Response to Comment on: “Prognostic Relevance of Primary Tumor Sidedness in Early-Stage Colorectal Cancer: An Integrated Analysis of 4 Randomized Controlled Trials (JCOG2003A)”

Impact of primary tumor sidedness and sex on prognosis and anti-epidermal growth factor receptor antibody efficacy in BRAF-mutant metastatic colorectal cancer: a pooled analysis of AIO studies FIRE-1, CIOX, FIRE-3, XELAVIRI, and VOLFI

Primary tumor (PT) sidedness is an established prognostic marker in metastatic colorectal cancer (mCRC) and has a predictive impact on the efficacy of anti-epidermal growth factor receptor (anti-EGFR) antibody [monoclonal antibody (mAb)] in patients with RAS wild-type mCRC. This investigation focuses on patients with BRAFV600E-mutated (BRAFmt) mCRC and examines the efficacy of anti-EGFR mAbs in relation to primary tumor sidedness (PTS). This pooled analysis was carried out using individual patient data from five randomized studies in the first-line setting of mCRC. The population of interest was limited to patients with BRAFmt mCRC and known PTS. For analysis, treatment was stratified into two groups: those treated with anti-EGFR mAbs and those without. Dichotomous variables, such as overall response rate and objective response rate (ORR), were compared using chi-square or Fisher's exact test. Time-to-event endpoints [progression-free survival (PFS) and overall survival (OS)] were analyzed using the Kaplan-Meier method, log-rank test, and Cox regression. An interaction test was carried out via Cox regression. A total of 102 patients with BRAFmt mCRC were identified. The type of targeted therapy (anti-EGFR-based versus non-anti-EGFR) did not significantly impact the outcome. However, in patients with left-sided primary tumors, anti-EGFR mAb-based treatment, compared with non-anti-EGFR, was associated with a higher ORR (58% versus 34%; P < 0.01), trended toward improved PFS [hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.34-1.13; P= 0.12], and demonstrated prolonged OS (HR 0.38; 95% CI 0.20-0.72; P < 0.01). In patients with right-sided primary tumors, anti-EGFR-based therapy had no effect on ORR (33% versus 36%; P > 0.99), induced inferior PFS (HR 1.97; 95% CI 1.12-3.47; P= 0.02), and trended toward a worse OS (HR 1.76; 95% CI 0.99-3.13; P= 0.05). This analysis suggests that PTS has predictive value for the efficacy of anti-EGFR mAb in the first-line treatment of BRAFmt mCRC.

Kinetic Profiling of RAS Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of RAS Mutations in Neo-RAS-Wildtype Metastatic Colorectal Cancer Is Transient.

In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable. CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression. Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00). We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.

Primary Tumor Sidedness Associated with Clinical Characteristics and Postoperative Outcomes in Colon Cancer Patients: A Propensity Score Matching Analysis.

Background: Recent investigations have suggested that-sidedness is associated with the prognosis of colon cancer patients. However, the role of sidedness in surgical outcome is unclear. In this study, we tried to demonstrate the real role of sidedness in postoperative results for colon cancer patients receiving surgical intervention. Methods: This is a propensity score matching study using the database of the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) from 2009 to 2013. Sidedness groups including right-sided and left-sided colon cancer were created according to the associated diagnosis and procedure codes. Postoperative 30-day mortality, morbidity, overall complications, and total length of hospital stay were analyzed after performing propensity score matching. Results: Out of a total of 24,436 colon cancer patients who received associated operations, 15,945 patients had right-sided cancer and 8941 patients had left-sided cancer. Right-sided colon cancer patients were accompanied by more preoperative comorbidities including old age, female sex, hypertension, dyspnea, anemia, hypoalbuminemia, and a high American Society of Anesthesiologists grade (SMD > 0.1). Postoperative mortality, morbidities including re-intubation, bleeding, urinary tract infection and deep vein thrombosis, postoperative overall complications, and total length of hospital stay were significantly associated with right-sided cancer (p < 0.05). After 1:1 propensity score matching, postoperative mortality was not significantly different between right-sided cancer (2.3%) and left-sided cancer (2.4%) patients. The patients with left-sided colon cancer had significantly more postoperative morbidities, more overall complications, and longer total length of hospital stay. Conclusions: Poor clinical characteristics and postoperative outcomes were noted in right-sided cancer patients. After propensity score matching, left-sided cancer patients had worse postoperative outcomes than those with right-sided cancer.

Comment on Prognostic Relevance of Primary Tumor Sidedness in Early-Stage Colorectal Cancer: An Integrated Analysis of Four Randomized Controlled Trials (JCOG2003A).

Comment on Prognostic Relevance of Primary Tumor Sidedness in Early-Stage Colorectal Cancer: An Integrated Analysis of Four Randomized Controlled Trials (JCOG2003A).

Distinctive clinical and molecular aberrations of colorectal cancer patients with ovarian metastases.

e15595 Background: Ovarian metastases (OM) from colorectal cancer (CRC) are a rare phenomenon. There are limited data detailing outcomes from surgical interventions on OM. However, there is a lack of studies integrating genetic aberrations identified in these patients with clinical characteristics. Methods: We conducted a retrospective review of CRC patients with OM. Demographic variables of interest included age and stage at diagnosis, time from diagnosis to discovery of OM, laterality of OM, primary tumor sidedness, and choice of chemotherapy. Next Generation Sequencing was utilized to collect solid tumor DNA sequencing, in addition to cell-free DNA (cfDNA). Results: A cohort of 12 MSI-S patients was identified between December 2023 and January 2024. Median age of diagnosis was 42.5 y/o. Demographics noted: Primary tumor sidedness included descending colon [58%; 86% of these sigmoid] and ascending colon (42%). AJCC T4 (50%) with OM at presentation (83%); unilateral (58%); 57% in the left ovary. 67% of patients underwent bilateral salpingo-oophorectomy (BSO), 25% unilateral resection, and 8.3% had no resection. 9 patients continue to receive treatment; 3 patients are deceased. Tissue NGS data was available for 75% of patients. The most common mutations were p53 (100%), APC (88%), KRAS (G12A, G12C and G12D; 38%), and PIK3CA (25%). cfDNA data was available for 58% of patients; common mutations were APC (86%), p53 (71%), KRAS [G12C (2); G12D; 43%), PMS2 (29%), BRAF V600E (14%) and BRAF amplification (14%). Conclusions: In our cohort, CRC patients with OM were of early age onset with sigmoid &gt; ascending colon cancer with similar molecular alterations by tissue and cfDNA noting increased KRAS aberrations. Hence, NGS should be completed in all CRC as an opportunity to further characterize potentially actionable mutations in patients with OM, expanding precision oncology availability to this select patient population.

Survival impact of KRAS mutation in metastatic colorectal cancer (mCCR) under first-line treatment.

3547 Background: Activating mutations in the MAPK pathway are predictive biomarkers in mCCR and 50% of patients (pts) present KRAS mutations. There is a large spectrum of molecular aberrations with a lack of data regarding tumor side correlations and their impact on treatment response and overall survival. Methods: Retrospective cohort of mCRC pts and KRAS activating mutations treated between 2019-2022 in a tertiary cancer center in Brazil. KRAS gene was analyzed by next-generation sequencing in tumor tissue samples. Electronic medical records were reviewed with case report forms registered in RedCap software. The primary endpoint was Overall survival (OS), estimated using Kaplan-Meir and compared with the log-rank test. Cox proportional models were applied to estimate hazard ratios (HR). Results: We included 490 patients with a mean age of 59 years (y), mostly male, 51.4%. Primary left-side location was present in 65.5% and liver metastasis in 66.7%. The spectrum of KRAS mutations found were G12D (31.2%), G12V (20.2%), G13D (15.1%), G12C (9.4%), G12A (4.9%), G12S (3.5%), and G12R (2%). First line regimen was 5-FU and Oxaliplatin (mFLOX) in 84.9% (n=388), with a median PFS of 9.2 months (95%CI 7.8 - 11.6) and OS of 21 months (95%CI;19-23) in this group. Treatment related outcomes in first-line therapy at first evaluation were 40% partial response, 20.4% stable disease, 30,9% disease progression and 1.3% complete response. G12S mutation was associated with better PFS 18.62 vs. 8.75m compared with other codon mutations (HR:0.52;95%CI 0.28-0.98) and OS NR vs. 21.58m HR (HR:0.48;95%CI;0.24-0.97). G12R was associated with worse PFS 5.31 vs. 9.90 m (HR:2.2;95%CI;1.09-4.47) and OS 17.89 vs. 21.88m (HR:1.61;0.79-3.24). Sideness was not associated with prolonged response or overall survival right-sided tumors 20.72 vs. vs. left-sided tumors 22.14m (HR:1.04;95%CI;0.82-1.31). Conclusions: Specific mutated codons in the KRAS gene impact PFS and OS independently of primary tumor sidedness. G12S mutation demonstrated an improved OS and PFS. [Table: see text]

Phase II randomized study of maintenance therapy with regorafenib (REGO) versus placebo after first-line platinum and fluoropyrimidines-based chemotherapy in HER2 negative locally advanced/metastatic gastric (GC) or gastroesophageal junction (GEJ) cancer: Results of a-MANTRA study (GOIRC-05-2016).

4056 Background: REGO is an oral multi-targeted TKI that showed promising activity in advanced HER2-neg gastric cancer pts. The a-MANTRA study aimed to evaluate the efficacy and safety of REGO as maintenance after first-line (1L) therapy in advanced GC/GEJ tumors. Methods: This is a randomized, double-blind, placebo-controlled, multicenter Phase-II study in which HER2 neg advanced GC/GEJ pts with disease control after 1L platinum and fluoropyrimidines-based therapy, were randomized (1:1 ratio) to receive maintenance placebo (ARM A) or REGO (ARM B) starting at 80 mg with an escalation up to 160 mg (once daily on d1-21 q28 days), until intolerance or PD. The primary endpoint was Progression Free Survival 1 (PFS1). Two-sided 80% CIs were calculated to detect HR of 0.57, using a one-sided α=0.10 to have 90% power, translating to 3 months of improvement in mPFS. 118 subjects were required to observe 88 events. The interim analysis (IA) was planned after 44 events. Results: 67 pts were randomized in 18 Italian Cancer Centers; 64 pts (33 in ARM A and 31 in ARM B) received treatment. Most of the pts were male (64.1%), Caucasian (96.8%), ECOG PS 0 (81.2%), and median age 66 (40-80) yrs; the main primary tumor side was proximal (64.1%) with intestinal subtype (54.7%). Peritoneum metastases were present in 42.2%. IA showed a 98% probability of achieving a positive and statistically significant result for mPFS1. The study was stopped early due to the introduction of ICIs as 1L in PD-L1-positive pts. The objective responses to 1L chemotherapy were RP (50.0%), SD (42.2%), and CR (7.8%). At a median follow-up of 31 months (IQR 19.1-33-8), 28 (84.8%) and 26 (83.8%) events for each arm were reported. The main reason for discontinuation was PD (66.7% and 35.5%). The mPFS was 3.91 (80% CI, 2.27-5.98) and 5.19 months (80% CI, 4.0-7.26) with HR= 0.736 (80%CI, 0.51-1.04; p=0.1318). The mOS was 11.25 and 16.97 months (80%CI, HR=0.596 [0.318-1.103], p=0.1003). The most common G3-4 toxicities in ARM A and B were fatigue (3.0 vs 6.4%), thrombocytopenia (3.0 vs 3.2%), hand-foot syndrome (0 vs 12.9%), diarrhea and skin rash (0 vs 3,2%, respectively). Conclusions: Despite the promising trend, considering the sample was not sized for the statistical study hypothesis, REGO maintenance therapy after 1L chemotherapy did not reach statistically significant results in mPFS1. No significant safety concerns were raised. New study designs following the REGO with ICIs are currently underway. Clinical trial information: NCT03627728 .

Abstract 925: Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection

Abstract Introduction: Anti-EGFR monoclonal antibody plus doublet chemotherapy is the mainstay of first-line treatment of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Some of these patients might undergo secondary resection. However, there is no standardized suggestion on whether colorectal cancer liver metastasis patients should keep target therapy after secondary resection. NCCN guidelines suggest chemotherapy only in patients receiving primary liver resection. Whether we could spare the use of target therapy after secondary resection is the main aim of our study. Methods: Using Taiwan's National Health Insurance Research Database, we established a cohort of KRAS wild-type mCRC patients treated with first-line anti-EGFR therapy plus doublet chemotherapy between 2013 and 2018. Secondary surgery was defined as either resection of liver metastases or radiofrequency ablation. Results: 5694 stage IV mCRC patients received anti-EGFR MAb plus doublet chemotherapy as a first-line treatment between 2013 and 2018. 174 patients were enrolled in the final analysis, with 153 continuing anti-EGFR MAb after secondary resection and 21 patients without anti-EGFR MAb. Compared with those who without anti-EGFR therapy after secondary resection, patients who continued anti-EGFR MAb exhibited significantly longer overall survival (OS; median, 43.8 vs. 31.9 months, p = 0.031) but not in time to treatment failure (TTF; median, 22.2 vs. 26.6 months, p = 0.841). The OS benefits of continuing anti-EGFR MAb remained regardless of left-sided or right-sided primary tumors (40.9 vs. 43.0 months, p = 0.980). The patient cohort from 2016 to 2018 showed more prolonged survival than from 2012 to 2015 (not reached vs. 40.450, p = 0.0305). TTF has no statistical difference when considering patient cohort or primary tumor location. In multivariate analyses, continuing first-line anti-EGFR MAb therapy after secondary resection remained an independent predictor of longer OS. Conclusion: For mCRC patients who received secondary resection after first-line anti-EGFR and doublet chemotherapy, continuing anti-EGFR MAb after resection was associated with significantly longer OS regardless of primary tumor sidedness. Citation Format: Yao-Yu Hsieh, Chin-Wen Tsai, T-CARE Group, Yi-Hsieh Liang. Continuing anti-EGFR treatment prolonged survival in mCRC patients receiving conversion liver resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 925.

Refining first-line treatment decision in RAS wildtype (RAS-WT) metastatic colorectal cancer (mCRC) by combining clinical biomarkers: Results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).

13 Background: Optimal patient selection for first-line treatment targeting epithelial growth factor receptor (EGFR) in RAS-WT mCRC is based on primary tumor sidedness (PTS) with anti-EGFR being the preferred option for patients with left-sided mCRC (LC). Right-sided mCRCs (RC) are preferentially treated in combination with bevacizumab targeting vascular endothelial growth factor (VEGF). Here, improvement in patient selection was evaluated by combining clinical biomarkers beyond PTS using the randomized phase III trial FIRE-3. Methods: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC. Besides PTS, further clinical biomarkers were evaluated in pairwise combinations using Cox regression models and model-based recursive partitioning with Weibull models to predict treatment benefit of either treatment arm regarding overall survival (OS): age, sex, liver-limited disease status (LLD) and baseline carcinoembryonic antigen serum level (CEA). The resulting P-values of second-order interactions were adjusted using Holm-Bonferroni correction. The model with the best test statistics and P-value was chosen for further evaluations. Results: In 400 patients with RAS-WT mCRC, a model combining PTS and LLD status best predicted treatment outcome of either treatment arm (c-index = 0.603, p=0.005). Here, a significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was evident in patients with LC/non-LLD (HR 0.62, p=0.02) compared to LC/LLD (HR 0.83, p=0.40). In patients with RC, FOLFIRI/Bev was significantly associated with increased OS compared to FOLFIRI/Cet when patients suffered from non-LLD (HR 2.09, p=0.010). However, patients with RC/LLD rather had a benefit from FOLFIRI/Cet compared to FOLFIRI/Bev (HR 0.59, p=0.218). Conclusions: Combining clinical biomarkers PTS and LLD status might improve optimal patient selection for targeted first-line treatment in RAS-WT mCRC. Validation in further data sets is warranted. Clinical trial information: NCT00433927 .

Understanding causes of racial/ethnic survival disparity in 47,178 patients with colorectal cancer: A quantitative evaluation of molecular, socioeconomic, and clinical covariates.

20 Background: A disparity in overall survival (OS) of colorectal cancer (CRC) patients based on self-reported race has been observed. Separately, differing frequencies of driver gene mutations among racial groups have been observed. The contribution of these molecular differences to disparity in outcomes is not well understood. We conducted a systematic investigation of molecular, socioeconomic (SES) and clinical covariates to quantitate the degree to which each influences the OS disparity. Methods: The Foundry software platform was used to query electronic health records to identify CRC patients and extract clinical and molecular data. The relative contribution of each variable to OS disparity was determined using mediation analysis consisting of sequential multivariate Cox regression models. Results: 47,178 patients with CRC diagnosed between 1973 and 2023 with self-reported race were identified. Relative to Non-Hispanic white (NHW), African American (AA) had worse OS (HR=1.16, P= 1.5E-6), while Asians and Hispanics had better OS (HR=0.66, P=4.2E-13 and HR=0.86, P=3.4E-6, respectively). The magnitude of disparity between AA and NHW was greater in metastatic disease (HR 1.2, P=1.7E-4). Among 7,628 patients with clinical molecular testing, five genes differed significantly in mutation frequencies; APC (54% NHW, 62% AA, 57% Hispanics, 46% Asian, FDR= 0.01), KRAS (45%, 58%, 50%, 44%, FDR=8.4E-9), PIK3CA (17%, 23%, 17%, 12%, FDR=0.006) were higher in AA, while BRAF (8%, 3%, 4%, 7%, FDR=2.4E-8), KIT (4%, 1%, 2%, 3%, FDR=0.013) were higher in NHW. In multivariate analysis mutations of BRAF (HR= 1.9, P=1.2E-8), KRAS (HR= 1.39, P=1.7E-7), and APC (HR= 0.81, P= 5E-4) were significantly associated with OS as was national area deprivation index (HR= 1.07, P=0.004), marital status (HR= 1.16, P=0.03), performance status (HR= 1.42, P= 5.3E-29), disease stage (HR= 1.502, P=4.4E-26), right sided tumors (HR= 1.23, P=0.003), tumor differentiation (HR= 1.22, P=0.004) and MSI-high (HR= 0.37, P=1.8E-7). Mediation analysis identified neighborhood SES as the greatest contributor to disparity (38%), followed by primary tumor side (10%), and molecular characteristics (MSI-status, KRAS and BRAF mutations, 10%). After including all covariates, 39% of disparity remained unaccounted. Conclusions: Systematic evaluation of a large cohort from a single institution confirmed substantial racial disparity in survival and frequencies of driver mutations. SES factors have the largest contribution but account only for forty percent of the disparity, with tumor molecular features also contributing. Molecular characteristics should be incorporated in multicentric studies of racial survival disparity. Future clinical studies should ideally account for genetic ancestry and molecular features when evaluating chemotherapy outcomes.

Initial efficacy evaluation of fruquintinib plus capecitabine versus capecitabine as maintenance treatment for metastatic colorectal cancer (mCRC): A randomized, controlled, phase Ib/II study.

119 Background: The standard first-line therapy followed by maintenance treatment is an optional approach to balance the efficacy and toxicity for mCRC. Fruquintinib (Fru), a highly specific inhibitor of VEGFR1/2/3, has demonstrated favorable safety and efficacy outcomes in the treatment of mCRC. In this study, we present findings from an investigation into the comparative efficacy and safety of Fru in combination with capecitabine (Cap) versus Cap as a maintenance therapy for patients (pts) with mCRC. Methods: Pts with histologically confirmed mCRC who achieved disease control (including CR/PR and SD) after at least six cycles of first-line standard chemotherapy were included in the study. During phase Ib, pts received Fru (4 mg p.o. qd, 3 weeks on/1 week off, q4w]) plus Cap (850 mg/m2, p.o. bid, d1-7 and d15-21, q4w). In phase II, pts were randomized in a 1:1 ratio to receive either Fru (RP2D, 3mg, 3 weeks on/1 week off) plus Cap or Cap alone. The primary outcome was progression-free survival (PFS). Results: By Sep 10, 2023, a total of 34 pts were enrolled in the study, and 26 pts were considered evaluable for efficacy. During Fru plus Cap (n=14) and Cap (n=12), the median age was 61.5 (39-78) and 57.5 (32-75) years. The main primary tumor side was left (64.3% / 66.7%) and approximately half of the pts harbored a RAS mutation (50.0% / 58.3%). Most pts had previously received bevacizumab therapy (57.1% /58.3%) or cetuximab (35.7% /25.0%), respectively. The mPFS was significantly improved in Fru plus Cap vs Cap (9.1 vs 3.8 months, HR: 0.289, 95% CI 0.083 to 1.01, p=0.039). Consistently, ORR (21.4% vs 0%) and DCR (92.9% vs 66.7%) were improved with Fru plus Cap. Grades 3 and 4 treatment-emergent adverse events (TEAEs) were hypertension (11.1%), oral mucositis (5.6%), voice alteration (5.6%), small intestinal obstruction (5.6%), acrodynia (5.6%) and blood bilirubin increased (5.6%) in Fru plus Cap, and diarrhea (6.3%), oral mucositis (6.3%) and acrodynia (6.3%) in Cap therapy. Conclusions: The findings suggest that Fruquintinib plus Capecitabine can be considered as a first-line maintenance therapy for metastatic colorectal cancer, as it demonstrated a promising improvement in mPFS by 5.3 months while maintaining a controlled level of safety. Clinical trial information: NCT05451719 .

Primary tumor sidedness is not prognostic factor in resectable colorectal cancer liver metastasis: a retrospective observational cohort study

Primary tumor sidedness is not prognostic factor in resectable colorectal cancer liver metastasis: a retrospective observational cohort study

Sustained Disease Control in Immune Checkpoint Blockade Responders with Microsatellite Instability-high Colorectal Cancer after Treatment Termination.

Outcomes for patients with MSI-H colorectal cancer stopping immunotherapy after disease control remain unknown. Sixty-four patients with MSI-H colorectal cancer from our institution stopping treatment for sustained benefit or toxicity were retrospectively assessed. After median follow up of 22 months and median immunotherapy exposure of 18 months, 88% patients remained without progression. All patients who recurred or progressed and were rechallenged with immunotherapy have continued to experience disease control.

Prognostic Impact of Primary Tumor Sidedness in Stage III Colorectal Cancer: Real-World Evidence from a Brazilian Cohort

BackgroundPrimary tumor sidedness (PTS) is an independent prognostic factor in patients with metastatic colorectal cancer (CRC), with a worse prognosis for right-sided tumors. There are limited data on the prognostic impact of PTS in stage III CRC. The main objective of this study was to analyze the prognostic impact of PTS in stage III CRC. Patients and MethodsA retrospective and uni-institutional cohort study was performed in an oncology reference center. Patients with stage III CRC treated with a 5-fluorouracil and oxaliplatin-based chemotherapy regimen (mFLOX regimen) from October 2007 to February 2013 were included. The primary outcome was the probability of overall survival (OS) at 5 years stratified by PTS. Secondary outcomes were the probability of disease-free survival (DFS) at 5 years and an analysis of the prognostic impact of clinical and molecular biomarkers. Kaplan‒Meier curves were used, and Cox models were used to evaluate prognostic factors associated with OS and DFS. ResultsOverall, 265 patients were evaluated. Transverse colon tumors, multicentric tumors, and undetermined primary subsites were excluded, resulting in 234 patients classified according to PTS: 95 with right sidedness (40.6%) and 139 with left sidedness (59.4%). The median follow-up time was 66 months [interquartile range (IQR): 39-81]. The 5-year OS probabilities for right-sided and left-sided tumors were 67% (95% CI: 58%-77%) and 82% (75%-89%), respectively [hazard ratio (HR): 2.02, 95% CI: 1.18-3.46; P = .010]. The 5-year probabilities of DFS for right-sided and left-sided tumors were 58% (49%-69%) and 65% (58%-74%), respectively (HR: 1.29, 0.84-1.97; P = 0.248). ConclusionThese data suggest that there may be a worse prognosis (inferior OS at 5 years) for resected right-sided stage III CRC patients treated in the real world. However, these data need to be confirmed by prospective studies with a larger number of participants.

Analysis of an Unselected Patient Cohort With Advanced Colorectal Carcinoma from a Maximum Care Center.

Systemic treatment for metastatic colorectal cancer (CRC) includes chemotherapy in combination with a targeted antibody. Novel targeted therapies and immunotherapies are introduced for specific molecular subgroups. Prognostic relevant determinants are still under investigation. Systemic therapies of an unselected patient cohort with metastatic CRC were retrospectively analyzed. Treatment outcome was evaluated according to time-to-next-treatment (TTNT) and frequency of conversion surgery and compared between subgroups stratified by primary tumor side, molecular profile, sex and age, and metastases sites. More than 50% of patients with locally advanced or metastatic CRC underwent secondary resection after first-line systemic therapy. Rectum carcinoma had the best prognosis under anti-EGFR-antibody treatment. Female patients had a worse prognosis than male patients in late disease stage. Young patients demonstrated poor response to systemic therapy, but a high rate of conversion surgeries. Conversely, elderly patients benefited from systemic therapy but underwent surgery less frequently. Liver and lung metastases had a worse prognosis than other metastases sites, whereas lung metastases were more likely to be resected than liver metastases in early disease stage. Patient age, sex, primary tumor localization, and metastatic sites are prognostic factors that could guide future treatment decisions for the therapy of metastatic CRC.

Prognostic impact of colorectal cancer patients with bone metastases: a single-center experience.

The incidence of bone metastasis (BM) in colorectal cancer (CRC) patients is low and the prognosis is poor. There is no clear conclusion on the risk factors affecting the survival of CRC patients with BM. The aim of this study was to investigate the factors that may affect the prognosis of CRC patients with BM. The clinical and pathological data of CRC patients with BM were retrospectively analyzed. The overall survival after BM diagnosis was estimated using the Kaplan-Meier method and Log-rank test, and a multivariable cox regression model was used to identify the prognostic factors of overall survival. This study included 178 CRC patients with BM, of whom 151 had left-sided CRC and 27 had right-sided colon cancer. 1124 CRC patients with BM from the SEER database were included to perform a sensitivity analysis of the primary outcome. Multivariate analysis showed that the N staging, site of BM, and primary tumor sidedness (PTS) were independent prognostic factors for CRC with BM. Among them, right-sided colon cancer patients with BM had a poorer prognosis. Sensitivity analyses showed that PTS was an independent prognostic factor in CRC patients with BM. Primary tumor sidedness and N stage may be potential prognostic markers for BM of CRC. The prognosis of N0 stage CRC with BM is better, while the prognosis of right-sided colon cancer is poor.

Negative hyperselection of elderly patients with RAS and BRAF wild-type metastatic colorectal cancer receiving initial panitumumab plus FOLFOX or 5-FU/LV

BackgroundUpfront anti-EGFR therapy represents the standard of care for patients with left-sided, MSS/pMMR, RAS and BRAF wild-type mCRC. Molecular ‘hyperselection’ may optimize EGFR inhibition by detecting additional resistance alterations. Materials and methodsWe used comprehensive genomic profiling on archival samples of elderly patients enrolled in the PANDA trial to detect: HER2 amplification/mutations; MET amplification; NTRK/ROS1/ALK/RET rearrangements; PIK3CA exon 20 mutations; PTEN alterations; AKT1 mutations; MAP2K1 mutations. We defined ‘Gene Altered’ (GA) patients whose tumour harboured at least one alteration, and ‘Hyperselected’ (HS) those without. Survival and tumour response outcomes were correlated to hyperselection status alone or combined with primary tumour sidedness or treatment arm. ResultsGenomic alterations were detected in 41/147 patients (27.9%). PFS, OS and ORR were inferior in GA versus HS (median PFS: 7.6 versus 12.8 months, HR = 2.08, 95% CI: 1.43–3.03, p < 0.001; median OS: 20.0 versus 29.5 months, HR = 1.82, 95% CI:1.23–2.69, p = 0.002; ORR: 51% versus 71%; OR = 0.43, 95% CI: 0.21–0.91, p = 0.02). In the multivariable models, the impact of hyperselection on PFS and OS was confirmed. Lower ORR was observed with 5-FU/LV/panitumumab in GA (40% versus 62%), but not in HS (70% versus 72%). GA was associated with worse survival and response regardless of primary tumour sidedness, whereas in the HS subgroup, right-and left sided tumours had similar outcomes. ConclusionsMolecular hyperselection and comprehensive genomic profiling have a potential usefulness in elderly patients with RAS/BRAF wild-type, pMMR/MSS mCRC, eligible for upfront EGFR inhibition.

607P Impact of primary tumour sidedness (PTS) on demographics, resectability, and outcome after metastasectomy +/- local ablative therapy (LAT), or systemic therapy in metastatic colorectal cancer patients (a RAXO substudy)

607P Impact of primary tumour sidedness (PTS) on demographics, resectability, and outcome after metastasectomy +/- local ablative therapy (LAT), or systemic therapy in metastatic colorectal cancer patients (a RAXO substudy)

Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer

The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated. To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy. The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022. After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen. The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile. Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]). The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC. ClinicalTrials.gov Identifier: NCT02404935.