Tumor Sidedness Research Articles

Survival Outcome in Early-Onset Metastatic Colorectal Cancer: A Multicenter-Matched Pair Analysis

Introduction: Survival of patients suffering from metastatic colorectal cancer (mCRC) has increased over the last decades. These benefits appear to be restricted to patients aged 50 and above. However, among the population aged <50, colorectal cancer incidence and mortality rates are significantly rising. The clinical benefit of treatment in this population still is a matter of debate. We aim to compare the clinical outcome between patients aged 50 and younger. Methods: In this retrospective, observational study, we analyzed data from 1,077 patients treated for mCRC at three cancer centers in Austria from January 2005 to December 2019. Patients were divided into two groups based on age at diagnosis: <50 years (eo-CRC) and >50 years (regular-onset CRC, ro-CRC). Propensity score matching was used to control for potential biases, and survival outcomes were compared between the two groups. Results: The differences in tumor characteristics between eo-CRC and ro-CRC in the overall population were primarily related to tumor sidedness and disease-free survival following intended curative resection. Our data show that eo-CRC patients underwent metastases resection more often and received significantly more lines of treatment in the palliative setting. Overall survival was superior in eo-CRC compared to ro-CRC, even after adjusting for sidedness, timing of metastases, sex, number of treatment lines, and resection of metastases by propensity scoring. Conclusion: Our study suggests that younger patients benefit at least to the same magnitude or even more from mCRC-treatment than patients aged 50 or above.

The Impact of Sidedness on the Efficacy of Anti-EGFR-Based First-Line Chemotherapy in Advanced Colorectal Cancer Patients in Real-Life Setting-A Nation-Wide Retrospective Analysis (RACER).

Anti-EGFR antibodies combined with chemotherapy doublets are a cornerstone of the upfront treatment of colorectal cancer. RAS and BRAF mutations are established negative predictive factors for such therapy. The primary tumour located in the proximal colon has recently emerged as another negative predictive factor. We have conducted a retrospective multicentre study to collect data on real-world population characteristics, practice patterns, and outcomes in patients with metastatic colorectal cancer treated in a first-line setting with either cetuximab or panitumumab in combination with either FOLFOX or FOLFIRI chemotherapy. The presented analysis focuses on the impact of the primary tumour location. 126 of 842 patients analysed (15.0%) had proximal primary. It was associated with a lower BMI at diagnosis, mucinous histology, and peritoneal metastases. It was also associated with inferior treatment outcomes in terms of response ratio: 59.4% vs. 74.22% (odds ratio [OR] 0.51, 95% CI 0.33-0.78, p = 0.010), and median depth of response: -36.7% vs. -50.0% (p = 0.038). There was only a borderline non-significant trend for inferior PFS in patients with proximal tumours. OS data was incomplete. The presented analysis confirms the negative impact of tumour sidedness on the efficacy of an upfront anti-EGFR-chemotherapy combination and provides valuable data on real-world population characteristics.

Prognostic Relevance of Primary Tumor Sidedness in Early-stage Colorectal Cancer: An Integrated Analysis of 4 Randomized Controlled Trials (JCOG2003A).

The aim of this study was to determine the genuine prognostic relevance of primary tumor sidedness (PTS) in patients with early-stage colorectal cancer (CRC). The prognostic relevance of PTS in early-stage CRC remains a topic of debate. Several large epidemiological studies investigated survival only and did not consider the risk of recurrence so far. Patients with stage II/III adenocarcinoma of the colon and upper rectum from 4 randomized controlled trials were analyzed. Survival outcomes were compared according to the tumor location: right-sided (cecum to transverse colon) or left-sided (descending colon to upper rectum). A total of 4113 patients were divided into a right-sided group (N=1349) and a left-sided group (N=2764). Relapse-free survival after primary surgery was not associated with PTS in all patients and each stage [hazard ratio (HR) adjusted =1.024 (95% CI: 0.886-1.183) in all patients; 1.327 (0.852-2.067) in stage II; and 0.990 (0.850-1.154) in stage III]. Also, overall survival after primary surgery was not associated with PTS in all patients and each stage [HR adjusted =0.879 (95% CI: 0.726-1.064) in all patients; 1.517 (0.738-3.115) in stage II; and 0.840 (0.689-1.024) in stage III]. In total, 795 patients (right-sided, N=257; left-sided, N=538) developed recurrence after primary surgery. PTS was significantly associated with overall survival after recurrence (HR adjusted =0.773, 95% CI: 0.627-0.954). PTS had no impact on the risk of recurrence for stage II/III CRC. Treatment stratification based on PTS is unnecessary for early-stage CRC.

First-line (1L) panitumumab (PAN) vs bevacizumab (BEV) in patients (pts) with HER2 amplification (HER2amp+), RAS wild type (WT) metastatic colorectal cancer (mCRC) according to tumor sidedness.

53 Background: HER2 gene alterations occur in 3%–5% of pts with mCRC and may be associated with aggressive tumor behavior. Gene amplification is a frequent HER2 alteration in mCRC, often leading to HER2 protein overexpression. Preclinical and retrospective studies suggest HER2 alterations may predict anti–epidermal growth factor receptor (EGFR) therapy resistance in mCRC; however, there is limited information regarding the efficacy of 1L anti-EGFR therapy in mCRC pts with HER2 alterations. The PARADIGM trial demonstrated longer median OS with 1L PAN (anti-EGFR) vs BEV (anti–vascular endothelial growth factor), with mFOLFOX6, in RAS WT mCRC (NCT02394795). We evaluated the efficacy of PAN vs BEV in pts with HER2amp + and HER2amp−, RAS WT mCRC from PARADIGM, taking into account primary tumor sidedness. Methods: Baseline plasma ctDNA was obtained from pts with RAS WT mCRC enrolled in PARADIGM; pts with evaluable pretreatment ctDNA were included in the biomarker analysis (NCT02394834). A custom panel (PlasmaSELECT-R 91, PGDx) was used to detect HER2amp+ and HER2amp− samples. OS, PFS, and response rate (RR) were compared in pts with HER2amp+ vs pts with HER2amp−. Results: Of 802 pts with RAS WT mCRC, 733 (91%) had evaluable pretreatment samples; 32 (4%) had HER2amp + (PAN, n=19; BEV, n=13). A lack of a survival benefit with PAN vs BEV was suggested in pts with HER2amp+, regardless of tumor-sidedness (median OS: overall population, PAN, 23.0 mo; BEV, 26.7 mo; HR, 0.96; 95% CI: 0.45–2.04; left-sided population, PAN, 25.1 mo; BEV, 26.7 mo; HR, 0.89; 95% CI: 0.39–2.04]). Data in the right-sided population are not shown for pts with HER2amp+ due to the small sample size. In the overall population, there was a trend toward shorter OS for HER2amp + vs HER2amp− pts (PAN: 23.0 vs 36.3 mo; HR, 1.57; 95% CI: 0.96–2.57; BEV: 26.7 vs 31.6 mo; HR, 1.41; 95% CI: 0.79–2.52). Median PFS and RR were similar between pts with HER2amp + and HER2amp− in PAN or BEV arms (Table). Conclusions: HER2 amplification appears to be prognostic in pts with RAS WT mCRC but may not be predictive of a survival benefit of 1L PAN treatment over BEV. Clinical trial information: NCT02394834 . [Table: see text]

Impact of Colorectal Cancer Sidedness and Location on Therapy and Clinical Outcomes: Role of Blood-Based Biopsy for Personalized Treatment.

Colorectal cancer is one of the most common malignant diseases in the United States and worldwide, and it remains among the top three causes of cancer-related death. A new understanding of molecular characteristics has changed the profile of colorectal cancer and its treatment. Even controlling for known mutational differences, tumor side of origin has emerged as an independent prognostic factor, and one that impacts response to therapy. Left- and right-sided colon cancers differ in a number of key ways, including histology, mutational profile, carcinogenesis pathways, and microbiomes. Moreover, the frequency of certain molecular features gradually changes from the ascending colon to rectum. These, as well as features yet to be identified, are likely responsible for the ongoing role of tumor sidedness and colorectal subsites in treatment response and prognosis. Along with tumor molecular profiling, blood-based biopsy enables the identification of targetable mutations and predictive biomarkers of treatment response. With the application of known tumor characteristics including sidedness and subsites as well as the utilization of blood-based biopsy, along with the development of biomarkers and targeted therapies, the field of colorectal cancer continues to evolve towards the personalized management of a heterogeneous cancer.

China special issue on gastrointestinal tumor-radiological features of pathological complete response in mismatch repair deficient colorectal cancer after neoadjuvant PD-1 blockade: A post hoc analysis of the PICC phase II trial.

Neoadjuvant programmed cell death protein 1 (PD-1) blockade exhibits promising efficacy in patients with mismatch repair deficient (dMMR) colorectal cancer (CRC). However, discrepancies between radiological and histological findings have been reported in the PICC phase II trial (NCT03926338). Therefore, we strived to discern radiological features associated with pathological complete response (pCR) based on computed tomography (CT) images. Data were obtained from the PICC trial that included 36 tumors from 34 locally advanced dMMR CRC patients, who received neoadjuvant PD-1 blockade for 3 months. Among the 36 tumors, 28 (77.8%) tumors achieved pCR. There were no statistically significant differences in tumor longitudinal diameter, the percentage change in tumor longitudinal diameter from baseline, primary tumor sidedness, clinical stage, extramural venous invasion status, intratumoral calcification, peritumoral fat infiltration, intestinal fistula and tumor necrosis between the pCR and non-pCR tumors. Otherwise, tumors with pCR had smaller posttreatment tumor maximum thickness (median: 10 mm vs 13 mm, P = .004) and higher percentage decrease in tumor maximum thickness from baseline (52.9% vs 21.6%, P = .005) compared to non-pCR tumors. Additionally, a higher proportion of the absence of vascular sign (P = .003, odds ratio [OR] = 25.870 [95% CI, 1.357-493.110]), nodular sign (P < .001, OR = 189.000 [95% CI, 10.464-3413.803]) and extramural enhancement sign (P = .003, OR = 21.667 [2.848-164.830]) was observed in tumors with pCR. In conclusion, these CT-defined radiological features may have the potential to serve as valuable tools for clinicians in identifying patients who have achieved pCR after neoadjuvant PD-1 blockade, particularly in individuals who are willing to adopt a watch-and-wait strategy.

Transcriptional Profiling and Consensus Molecular Subtype Assignment to Understand Response and Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Colorectal Cancer.

Activating mutations in KRAS, NRAS, and BRAF are known to cause resistance to anti-epidermal growth factor receptor (EGFR) therapy; however, only approximately 40% of patients with colorectal cancer (CRC) with RASWT tumors respond to anti-EGFR treatment. We sought to discover novel biomarkers to predict response to anti-EGFR antibody treatment in CRC and to understand mechanisms of resistance to anti-EGFR therapy. Transcriptomic profiles from three clinical and two preclinical cohorts treated with cetuximab were used to assign consensus molecular subtypes (CMS) to each sample and correlated with outcomes. Restricting to RASWT patients, we observed that CMS2 tumors (canonical subtype) had significantly higher response rates relative to other CMS when treated with cetuximab combination with doublet chemotherapy (Okita et al cohort: 92% disease control rate (DCR) for CMS2, chi-square P = .04; CALGB/SWOG 80405 cohort: 90% objective response rate (ORR) for CMS2, chi-square P < .001) and with single-agent cetuximab (68%, chi-square P = .01). CMS2 tumors showed best response among right-sided (ORR = 80%) and left-sided (ORR = 92%) tumors in the CALGB/SWOG 80405 cohort. CMS2 cells lines were most likely to be sensitive to cetuximab (60%) and CMS2 patient-derived xenograft had the highest DCR (84%). We found Myc, E2F, and mammalian target of rapamycin pathways were consistently upregulated in resistant samples (enrichment score >1, false discovery rate <0.25). Inhibitors of these pathways in resistant cell lines exhibited additive effects with cetuximab. These data suggest that CRC transcriptional profiles, when used to assign CMS, provide additional ability to predict response to anti-EGFR therapy relative to using tumor sidedness alone. Notably both right-sided and left-sided CMS2 tumors had excellent response, suggesting that anti-EGFR therapy be included as a treatment option for right-sided CMS2 tumors.

Real-world comparison of triplet- versus doublet-chemotherapy with bevacizumab in patients with newly diagnosed metastatic colorectal cancer (mCRC).

3574 Background: Meta-analysis of five randomized intensification trials in mCRC demonstrated an overall survival (OS) benefit of triplet chemotherapy (5FU/leucovorin, oxaliplatin, irinotecan) plus bevacizumab (Triplet/Bev) compared to doublet chemotherapy plus bevacizumab (Doublet/Bev) (HR 0.81). Guidelines recommend first-line Triplet/Bev for patients with excellent performance status and normal organ function who can withstand increased toxicity, but such patients are less represented in the real world. In this retrospective cohort study, we examine the real-world effectiveness of Triplet/Bev compared to Doublet/Bev in the U.S. Methods: We used the nationwide Flatiron Health electronic health record-derived database, comprising de-identified patient-level structured and unstructured data curated via technology-enabled abstraction from ~ 280 cancer clinics. Included were mCRC patients treated with first-line Triplet/Bev or Doublet/Bev between 10/23/14 and 10/31/22. OS by treatment was assessed using the Kaplan Meier method and adjustment for confounding variables was performed using Cox proportional hazards modeling with stabilized inverse probability of treatment weighting (IPTW). Pre-specified confounding variables included age, gender, race/ethnicity, year of metastatic diagnosis, health insurance, practice setting, KRAS/NRAS/BRAF mutation status, MMR/MSI status, synchronous/metachronous metastases, primary tumor sidedness, CEA, renal dysfunction, hepatic dysfunction, and ECOG performance status. Missing data were imputed using multiple imputation with chained equations. Results: Among 10,016 patients, 391 (3.9%) received Triplet/Bev and 9,625 (96.1%) received Doublet/Bev. Patients who received Triplet/Bev were younger (median age 52 vs 63 years) and were more likely to be treated at academic practices (27% vs 8%), to have synchronous metastatic disease (83% vs 65%), and to have KRAS/NRAS/BRAF wild-type disease (30% vs 17%). In the univariate analysis, median OS was 30.0 months (95% CI 24.7 – 34.7) in the Triplet/Bev cohort versus 23.4 months (95% CI 22.8 – 24.1) in the Doublet/Bev cohort (HR 0.73; 95% CI 0.62 – 0.85; p &lt; 0.001). In Cox proportional hazards modeling with IPTW, there was no significant difference in hazard of death between Triplet/Bev and Doublet/Bev (HR 0.92; 95% CI 0.75 – 1.12; p = 0.4). Conclusions: In this large, national, real-world population of patients with mCRC, first-line treatment with Triplet/Bev was not associated with improved survival compared to Doublet/Bev after accounting for differences in baseline patient characteristics. The benefit to Triplet/Bev observed in randomized trials does not translate well to a more heterogeneous, real-world population. Sub-group analyses including by age, tumor sidedness, KRAS/NRAS/BRAF status, and baseline CEA level will be performed.

Overall survival of patients with BRAF-mutant metastatic colorectal cancer treated with encorafenib-cetuximab in a real-world nationwide study in the Netherlands.

3589 Background: Approximately 10-15% of patients with metastatic colorectal cancer (mCRC) have BRAFV600E mutated tumors. Encorafenib plus cetuximab (EC) combination treatment was approved following the results of the randomized phase III BEACON trial and is currently recommended for all pretreated patients with BRAFV600E-mutant mCRC. Selection of patients in randomized controlled trials is based on restrictive eligibility criteria and often not representative of the patient population in daily clinical practice. Complementary real-world effectiveness studies can improve knowledge on the generalizability of trial results, and support decision making in clinical practice. Methods: This population-based study included all mCRC patients in the Netherlands treated with EC since approval in October 2020 until June 2022. Individual patient data and original pathology reports were collected. Primary endpoint was overall survival (OS), defined as time from EC initiation until death by any cause, analyzed by Kaplan-Meier curves. WebPlotDigitizer was used to reconstruct the Kaplan-Meier survival curve of the BEACON trial. Uni- and multivariable analyses were performed. Subgroup analyses were conducted for patients who would have been eligible for the BEACON trial based on key eligibility criteria: BRAFV600E mutation, 1-2 prior regimens, world health organization performance status (WHO PS) of 0-1, normal neutrophil count, absence of brain metastases, no prior RAS/RAF/MEK treatment, and no concurrent malignancies. Results: 155 patients were included with a median follow-up time of 11.1 months. Patient characteristics differed from BEACON in mean age (64 versus 60 years), primary tumor sidedness (69% versus 50% right-sided) and WHO PS (23% versus 51% WHO 0). Median OS of the total real-world cohort was 6.6 months (95% CI: 6.0-8.3) and differed significantly from BEACON (9.3 months; 95% CI: 8.0-11.3; p = 0.003). 35% of real-world patients treated with EC would not have been eligible for the BEACON trial, showing an inferior median OS of 6.0 months (95% CI: 4.6-9.2) compared to 7.0 months (95% CI: 6.4-9.8) in trial eligible real-world patients. WHO PS was independently associated with poor survival in multivariable analysis. Patients with WHO PS≥2 had a median OS of 3.9 months (95% CI: 2.4-NA) with a hazard rate of 2.5 (95% CI: 1.1-5.5; p = 0.003). Conclusions: This largest to date - unselected - population-based cohort of mCRC patients treated with EC showed an efficacy-effectiveness gap for OS. These outcomes should be considered in clinical practice for treatment decision making. Omitting EC for subgroups demonstrating very short OS, such as patients with WHO PS ≥2, needs to be considered. Further research is warranted to adapt treatment guidelines towards a more personalized approach for patients with BRAFV600E-mutated mCRC.

Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis.

3554 Background: Approximately 30% of patients (pts) diagnosed with colorectal cancer (CRC) develop liver metastases (LM). Liver is the most common organ of metastasis of CRC. The ARCAD database contains individual patient data of randomized trials that included CRC pts with initially unresectable metastases treated with systemic therapy. The aim of this study was to assess the response and survival outcomes in non-LM (NLM) vs LM across different lines of treatment. Methods: We analyzed survival outcomes of mCRC pts with either single site (SS) or multiple sites (MS) according to LM status in the following treatment groups: A: chemotherapy (CT) alone, B: CT + VEGF-antibodies, C: CT + EGFR-antibodies in KRAS wild-type tumors, within first-line (1L) and second line (2L) of therapy and D: pts enrolled on third line (≥3L) trials treated with trifluridine/tipiracil or regorafenib and placebo. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) which were assessed using Kaplan-Meier estimates and adjusted Cox models on ECOG PS, age, and gender. Results: We included 26 trials with 17924 pts. 14066 pts had LM. Pts with LM had a higher rate of colon vs rectum as primary tumor (72 vs 62%; P &lt; .001) and less SS (31 vs 47%; P &lt; .001) than those with NLM. OS and PFS results in subgroups are reported in the table. In groups A and B, we found better OS and PFS outcomes in NLM pts as either SS or MS in 1L and 2L. In group C from 1L, we found better survival outcomes in pts with SS LM. In pts with MS, NLM superiority was observed in OS but not in PFS. However, these results were influenced by primary tumor sidedness. In group D, better OS and PFS was observed in pts without LM than those with LM whether in pts with SS or MS. Response rates were higher in LM than in NLM in most 1L and 2L subgroups. Conclusions: LM is a poor prognostic factor for mCRC increasing from the 1L to ≥3L. Survival with CT alone and CT + anti-VEGF according to LM and NLM differs significantly in 1L and 2L but not with CT + anti-EGFR. This data justifies using LM as a stratification factor at least in ≥3L trials. [Table: see text]

Prognostic impact of primary tumor sidedness in stage III colorectal cancer.

e15622 Background: Primary tumor sidedness (PTS) has been shown to be an independent prognostic factor for patients with metastatic colorectal cancer (CRC), with worse prognosis for right-sided tumors. There are limited data regarding the prognostic impact of PTS in stage III CRC. Objective: The main objective of this study was to analyze the prognostic impact of PTS in stage III CRC. Methods: A retrospective and uni-institutional cohort study was performed in a reference center in São Paulo-SP, Brazil. All consecutive patients with stage III CRC and treated with a 5-fluorouracil and oxaliplatin-based chemotherapy regimen (mFLOX regimen) from October 2007 to February 2013 were included. The primary outcome was probability of overall survival (OS) at 5 years stratified by PTS. Secondary outcomes were probability of disease-free survival (DFS) at 5 years stratified by PTS, and analysis of the prognostic impact of clinical and molecular biomarkers. The time-to-event variables were reported by the Kaplan Meier estimation method and prognostic factors associated with OS and DFS were assessed by Cox models. Results: 265 patients were included. Transverse colon tumors, multicentric tumors and undetermined primary subsite were later excluded, totaling 234 patients who were classified according to PTS: 95 on the right side (40.6%) and 139 on the left side (59.4%). Median age was 58 and 59 years for right- and left-sided tumors, respectively. For both groups, approximately 67% had stage IIIB. The median follow-up time was 66 months (range: 0-149). 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=0.010). The 5-year probability 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). Of the 234 patients, 61 patients (26%) had tissue samples available for DNA sequencing by NGS and immunohistochemical analysis. Of these, 12 patients (19.7%) had a RAS mutation, no patient had a BRAF mutation (V600E) and 6 patients (9.8%) had DNA repair enzyme deficiency (dMMR). No statistically significant difference was identified in the probability of OS and DFS at 5 years when comparing patients with right-sided and left-sided tumors when stratified by RAS mutation status and MMR status. Among patients with right-sided tumors, age &gt;70 years (HR=4.11, 1.67-10.1; p=0.002), pN2 (HR=2.52, 1.23-5.17; p=0.012) and high-risk stage III according to the IDEA trial (HR=2.95, 1.35-6.44; p=0.002) were predictors of worse OS at 5 years. Among patients with left-sided tumors, poorly differentiated histology (HR=3.93, 1.44-10.7; p=0.007) and angiolymphatic invasion (HR=5.23, 1.54-17.8; p=0.008) were predictors of worse OS in 5 years. Conclusions: Data indicate a worse prognosis (inferior OS at 5 years) for resected right-sided stage III CRC treated with adjuvant mFLOX regimen.

Factors Affecting the Efficacy of Regorafenib in Metastatic Colorectal Cancer: Is Tumour Sidedness Important?

Factors Affecting the Efficacy of Regorafenib in Metastatic Colorectal Cancer: Is Tumour Sidedness Important?

SEOM-GEMCAD-TTD clinical guidelines for the systemic treatment of metastatic colorectal cancer (2022)

Colorectal cancer (CRC) is the second leading cause of cancer deaths in Spain. Metastatic disease is present in 15–30% of patients at diagnosis and up to 20–50% of those with initially localized disease eventually develop metastases. Recent scientific knowledge acknowledges that this is a clinically and biologically heterogeneous disease. As treatment options increase, prognosis for individuals with metastatic disease has steadily improved over recent decades. Disease management should be discussed among experienced, multidisciplinary teams to select the most appropriate systemic treatment (chemotherapy and targeted agents) and to integrate surgical or ablative procedures, when indicated. Clinical presentation, tumor sidedness, molecular profile, disease extension, comorbidities, and patient preferences are key factors when designing a customized treatment plan. These guidelines seek to provide succinct recommendations for managing metastatic CRC.

Profiling estrogen, progesterone, and androgen receptors in colorectal cancer in relation to gender, menopausal status, clinical stage, and tumour sidedness.

Although estrogen (ERα/ERβ), progesterone (PGR), and androgen (AR) receptors are pathologically altered in colorectal cancer (CRC), their simultaneous expression within the same cohort of patients was not previously measured. ERα/ERβ/PGR/AR proteins were measured in archived paired normal and malignant colon specimens (n =120 patients) by immunohistochemistry, and results were analyzed by gender, age (≤50 vs. ≥60 years), clinical stages (early-stage I/II vs. late-stage III/IV), and anatomical location (right; RSCs vs. left; LSCs). Effects of 17β-estradiol (E2), progesterone (P4), and testosterone alone or combined with the specific blockers of ERα (MPP dihydrochloride), ERβ (PHTPP), PGR (mifepristone), and AR (bicalutamide) on cell cycle and apoptosis were also measured in the SW480 male and HT29 female CRC cell lines. ERα and AR proteins increased, whilst ERβ and PGR declined markedly in malignant specimens. Moreover, male neoplastic tissues showed highest AR expression, whilst ERβ and PGR weakest alongside ERα strongest expression was seen in cancerous tissues from women aged ≥60 years. Late-stage neoplasms also revealed maximal alterations in the expression of sex steroid receptors. By tumor location, LSCs disclosed significant elevations in ERα with marked declines in PGR compared with RSCs, and ERα strongest alongside PGR weakest expression was detected in advanced LSCs from women aged ≥60 years. Late-stage LSCs from females aged ≥60 years also showed weakest ERβ and strongest AR expression. In contrast, male RSC and LSC tissues exhibited equal ERβ and AR expression in all clinical stages. ERα and AR proteins also correlated positively, whereas ERβ and PGR inversely, with tumor characteristics. Concomitantly, E2 and P4 monotherapies triggered cell cycle arrest and apoptosis in the SW480 and HT29 cells, and while pre-treatment with ERα-blocker enhanced the effects of E2, ERβ-blocker and PGR-blocker suppressed the E2 and P4 anti-cancer actions, respectively. In contrast, treatment with the AR-blocker induced apoptosis, whilst co-treatment with testosterone hindered the effects. This study advocates that protein expression of sex steroid receptors in malignant tissues could represent prognostic markers, as well as hormonal therapy could provide an alternative strategy against CRC, and their efficacies could be dependent on gender, clinical stage, and tumor location.

RETRO-TAS, a Retrospective Observational Study of Trifluridine/Tipiracil in Chemorefractory Metastatic Colorectal Cancer.

Trifluridine/tipiracil (FTD/TPI) is an oral antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue that inhibits cell proliferation following its incorporation into DNA, and tipiracil that helps maintain the blood concentration of trifluridine by inhibiting the enzyme thymidine phosphorylase which inactivates trifluridine. It is approved as a third-line treatment option for patients with metastatic colorectal cancer (mCRC) and is administered at 35 mg/m2 two times daily from day 1 to 5 and from day 8 to 12 every 28 days. The aim of this investigator-initiated retrospective study (RETRO-TAS; NCT04965870) was to document real-world data on the clinical efficacy of FTD/TPI in patients with chemorefractory mCRC. The clinical characteristics of patients with mCRC treated with FTD/TPI in 8 Cancer Centres were collected to assess physician's choice in the third or beyond line of treatment as well as the duration of treatment, dose modification, and toxicity. In addition, other important prognostic features related to mCRC such as molecular profile, performance status (PS), and primary site were analyzed. Statistical analysis for progression-free survival (PFS), overall survival (OS), 6-/8-month PFS rate and disease control rate (DCR) along with Cox regression model, Kaplan-Meier curves, and log-rank tests were carried out by using Stata/MP 16.0 for Windows. From October 2018 to October 2021, a total of 200 patients with mCRC and a median age of 67.0 (IQR 58.0, 75.0) years were treated with FTD/TPI. Τhe median follow-up time was 14 months (IQR 7, 23), 158 PDs and 106 deaths were reported at the time of this analysis. Of all the patients, 58% were males and 58% had mCRC at diagnosis. The molecular analysis identified mutations in KRAS (52%), NRAS (5%), HER2 (3.5%), BRAF (3.5%), and MSI (9%). Previous treatments included radical surgery in 51.5% and adjuvant chemotherapy in 39.5% of patients. FTD/TPI was administered in the third- (70.5%), fourth- (17.0%), or fifth-line (12.5%) treatment setting. Serious adverse events related to FTD/TPI included neutropenia (2%), anaemia (1%), thrombocytopenia (0.5%), diarrhoea (0.5%), nausea (0.5%), and fatigue (4%). A reduction of FTD/TPI dose, delay of next cycle initiation, and shorter duration were reported in 25%, 31%, and 14.5% of patients, respectively. Of all the patients 71.5% received FTD/TPI as monotherapy, 24.5% in combination with bevacizumab, and 4.0% with an anti-EGFR agent. The median FTD/TPI treatment duration was 119.5 days and 81% of patients discontinued treatment due to progressive disease. The DCR recorded by investigators' assessment was 45.5%. The median PFS was 4.8 and the median OS was 11.4 months. The 6- and the 8-month PFS rate was 41.4% and 31.5%, respectively. In the multivariate analysis, PS > 1 and presence of liver and lung metastasis were adversely associated with PFS and OS whereas mutational status and tumor sidedness were not. RETRO-TAS is a real-world observational study that confirms and adds on the findings of the pivotal RECOURSE Phase III study in relation to the efficacy of FTD/TPI in the third-line setting and in all subgroups of patients regardless of mutational status and sidedness.

Impact of Primary Tumor Location and Genomic Alterations on Survival Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Colorectal Peritoneal Metastases.

Colorectal cancer leads to peritoneal metastases (CRPM) in 10% of cases. Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) improves survival. Primary tumor location and abnormalities in RAS, BRAF, and mismatch repair/microsatellite stability (MMR/MSI) may affect post-CRS-HIPEC survival, but studies have not been consistent. We estimated the effects of primary tumor site and genomic alterations on post-CRS-HIPEC survival. This retrospective cohort study included CRS-HIPEC cases for CRPM at a high-volume center from 2001 to 2020. Next-generation sequencing and microsatellite testing defined the RAS, BRAF, and MMR/MSI genotypes. Adjusted effects of tumor sidedness and genomics on survival were evaluated using a multivariable Cox proportional hazards model. We analyzed these variables' effects on progression-free survival and the effects of immune checkpoint-inhibitors. A total of 250 patients underwent CRS-HIPEC with testing for RAS, BRAF, and MMR/MSI; 50.8% of patients were RAS-mutated, 12.4% were BRAF-mutated, and 6.8% were deficient-MMR/MSI-high (dMMR/MSI-H). Genomic alterations predominated in right-sided cancers. After adjustment for comorbidities and oncological and perioperative variables, rectal origin [hazard ratio (HR) 1.9, p = 0.01], RAS mutation (HR 1.6, p = 0.01), and BRAF mutation (HR 1.7, p = 0.05) were associated with worse survival. RAS mutation was also associated with shorter progression-free survival (HR 1.6, p = 0.01 at 6 months post-operatively), and dMMR/MSI-H status was associated with superior survival (HR 0.3, p = 0.01 at 2 years). dMMR/MSI-H patients receiving immune checkpoint-inhibitors trended toward superior survival. Rectal origin, RAS mutations, and BRAF mutations are each associated with poorer survival after CRS-HIPEC for CRPM. Patients with CRPM and dMMR/MSI-H status have superior survival. Further research should evaluate benefits of immune checkpoint-inhibitors in this subgroup.

Impact of primary tumor side on clinical outcomes of first-line cetuximab plus FOLFOX-4 in RAS wild-type metastatic colorectal cancer.

Aim: To examine the impact of tumor sidedness on clinical outcomes in Chinese patients with metastatic colorectal cancer treated with folinic acid/fluorouracil/oxaliplatin (FOLFOX-4)±cetuximab in the TAILOR trial. Patients & methods: Clinical data from 391 patients were evaluated for tumor sidedness. Results: Patients with left-sided tumors who received cetuximab plus FOLFOX-4 had a significantly longer overall survival (medians: 22.0 vs 18.3months; p=0.007) and progression-free survival (medians: 9.3 vs 7.9months; p=0.006) compared with FOLFOX-4 alone. Overall survival (medians: 11.5 vs 9.4months; p=0.664) and progression-free survival (medians: 7.4 vs 4.5months; p=0.068) also improved in patients with right-sided tumors. Conclusion: Adding cetuximab to first-line FOLFOX-4 in patients with metastatic colorectal cancer improved clinical outcomes irrespective of primary tumor side.

Abstract 1177: Genomic characteristics and clinical outcomes of early onset colorectal cancer (EOCRC): Findings from AACR Project GENIE Biopharma Collaborative registry

Abstract Background: By 2030, the incidence of EOCRC is predicted to increase by more than 140%. A better understanding of the molecular features of EOCRC is needed. Methods: The AACR GENIE Biopharma Collaborative CRC 1.2-consortium dataset consists of clinical and genomic data from a cohort of CRC patients (pts) with next generation tumor sequencing (55-500 genes) from 2015 to 2017 at three academic centers. Imaging reports and medical oncology notes were retrospectively curated. EOCRC was defined as age at diagnosis &amp;lt; 50 years; while later onset CRC (LOCRC) as ≥ 50 years. Association with clinical variables was analyzed using Chi-Square or Fisher’s exact test. Associations with genomic alterations were analyzed using the Benjamini-Hochberg procedure for multiple testing; the associations were evaluated among the overall study population and by stage. Kaplan-Meier method was used to estimate the median overall survival (OS) and was adjusted to left truncation bias introduced by the inclusion criteria for this project. Results: A total of 1507 pts with CRC, 519 (34%) with EOCRC, were analyzed. EOCRC pts were more likely to be diagnosed with Stage IV than LOCRC (51% vs 44%, p&amp;lt;0.01). Left-sided primary tumors were more frequent in EOCRC (73% vs 57%, p&amp;lt;0.01). Among stage I-III, EOCRC was associated with longer OS compared to LOCRC (HR:1.43, 95%CI 1.07-1.91, p=0.01). Among stage IV CRC, no differences were observed in OS between EOCRC and LOCRC in a multivariate analysis including RAS/BRAF mutation (mt), MSI and liver, lung and peritoneal metastasis (HR: 1.01, 95% CI 0.8-1.28, p=0.92). The proportion of BRAF mt was higher in LOCRC (15 vs 7%, p&amp;lt;0.01), mainly in stage I-III (17% vs 7%, p=0.01). This association is significant after adjusting for tumor sidedness (OR: 1.77 95% CI 1.19-2.63, p&amp;lt;0.01). BRAF V600E mt is more frequent in LOCRC (11 vs 3%, p&amp;lt;0.01). APC and PI3KCA mt are more common in EOCRC, but only among right-sided tumors. There were not significant differences in copy number alterations or structural variants. APC, TP53, KRAS, BRAF and PI3KCA were analyzed according to stage. Among EOCRC, TP53 mt was more frequent in stage IV vs I-III (79 vs 70%, p=0.02). In LOCRC, both TP53 (76% vs 69%, p=0.01) and KRAS mt (47 vs 38%, p&amp;lt;0.01) were more frequent in stage IV vs I-III. Effect modification of the association between these genes and OS by age of onset was explored using an interaction test in stage IV and I-III. APC mt in stage I-III conferred better prognosis in EOCRC (HR 0.31 (0.18-0.51) for EOCRC; HR 0.72 (0.51-1.01) for LOCRC; interaction p&amp;lt;0.01). Conclusions: EOCRC does not show significant genomic differences from LOCRC except for lower frequency of BRAF mt. For right-sided tumors, APC and PI3KCA mt are more common in EOCRC. APC mt in stage I-III is associated with a better prognosis in EOCRC. Further characterization of the biology of EOCRC beyond genomic profiling is needed. Citation Format: Enrique Sanz Garcia, Eric Chen, Marios Giannakis, Gregory J. Riely, Jeremy L. Warner, Michele L. LeNoue-Newton, Jessica Weiss, Katrina Hueniken, Kenneth L. Kehl, Deborah Schrag, Andrea Cercek, Kimmie Ng, AACR GENIE BPC Core Team . Genomic characteristics and clinical outcomes of early onset colorectal cancer (EOCRC): Findings from AACR Project GENIE Biopharma Collaborative registry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1177.

SCOT: Tumor Sidedness and the Influence of Adjuvant Chemotherapy Duration on Disease Free Survival (DFS)

AimPatients with loco-regional right-sided colorectal tumors have a worse overall survival (OS). Here we investigate the difference in disease free survival (DFS) between colorectal patients with right and left sided tumors in the SCOT study. MethodsThe SCOT study showed 3-months of oxaliplatin-containing adjuvant chemotherapy (OxFp) is non-inferior to 6-months for patients with stage III and high-risk stage II colorectal cancer. We divided the cohort into patients with left and right sided tumors, and evaluated the effect on DFS and the principle 3 versus 6-months analysis. Results6088 patients with Stage III/high risk Stage II colorectal cancers were randomized between 27th March 2008 and 29th November 2013 from 244 centers internationally. In February 2017 (3-years FU) information on sidedness was available for 3309 patients (1238 R-sided, 2071 L-sided). Patients with right-sided tumors had a significantly worse DFS (3-year DFS right: 73.3% (se = 1.3%), left: 80.2% (se = 0.9%) HR 1.423 (95% CI 1.237-1.637; P < .0001). Adjusting for T and N-stage reduced the HR to 1.230 (95% CI 1.066-1.420, P = .005). The data did not suggest that sidedness affected the impact of chemotherapy duration on 3-year DFS (R: HR 1.024 [0.831-1.261], L: HR 0.944 [0.783-1.139]). Test for heterogeneity, P = .571. Further sub-set analysis was limited due to cohort size. ConclusionsThis is the first study to show that unselected patients with right-sided tumors had a worse DFS compared to left-sided tumors. Tumor sidedness did not impact upon the 3-months versus 6-months comparison in SCOT.

A Real-World Comparison of Regorafenib and Trifluridine/Tipiracil in Refractory Metastatic Colorectal Cancer in the United States.

Trifluridine/Tipiracil (TAS-102) and regorafenib are FDA-approved in the United States for treatment of refractory metastatic colorectal cancer (mCRC). FDA approvals of these agents were based on modest improvements in overall survival (OS) compared with best supportive care + placebo in the RECOURSE and CORRECT trials, respectively. This study compared real-world clinical outcomes with the use of these agents. A nationwide deidentified electronic health record-derived database was reviewed for patients diagnosed with mCRC between 2015 and 2020. Patients who received at least 2 lines of standard systemic therapy followed by treatment with either TAS-102 or regorafenib were included for analysis. Kaplan-Meier and propensity score-weighted proportional hazards models were used to compare survival outcomes between groups. The records of 22,078 patients with mCRC were reviewed. Of these, 1,937 patients received at least 2 lines of standard therapy followed by regorafenib and/or TAS-102. Median OS for the TAS-102 alone or prior regorafenib group (n=1,016) was 6.66 months (95% CI, 6.16-7.18 months) compared with 6.30 months (95% CI, 5.80-6.79 months) for regorafenib alone or prior to TAS-102 (n=921; P=.36). A propensity score-weighted analysis controlling for potential confounders did not demonstrate a significant difference in survival between groups (hazard ratio, 0.99; 95% CI, 0.90-1.09; P=.82). A subgroup analysis did not identify any significant differences in outcomes regarding age, performance status, tumor sidedness, microsatellite instability status, or RAS/RAF status. This analysis of real-world data found that OS was similar for patients with mCRC who were treated with TAS-102 compared with regorafenib. Median OS with both agents in a real-world setting was similar to that shown in the clinical trials that led to their approvals. A prospective trial comparing TAS-102 and regorafenib would unlikely change current management of patients with refractory mCRC.