Management Of Metastatic Colorectal Cancer Research Articles

Arfolitixorin: An unmet need in the management of metastatic colorectal cancer

Arfolitixorin [6R]-5,10-methylenetetrahydrofolate (6R-MTHF) is a folate-based contemporary prodrug that FDA has approved for Phase III study [1]. It is a refined form of folate, which boosts cytotoxic 5-fluorouracil (5-FU) competence, thereby enhancing tumor mortality in carcinoma cells. This drug is currently used in patients who underwent therapeutic regimens with advanced colorectal cancer (CRC) as reported by Isofol Medical AB [2]. Conventional treatment for advanced colorectal cancer relies on cytotoxic drugs initially, but drug resistance poses challenges. Chemotherapy, has systemic toxicity and lacks tumor specificity, driving the exploration of targeted therapies like monoclonal antibodies and immunotherapeutic approaches (ACT, vaccines, cytokines) to address limitations and enhance outcomes, thus this is where Arfolitixorin emerge as a potential treatment option [3]. Unlike traditional folate-based prodrugs like leucovorin and levoleucovorin, Arfolitixorin doesn't need multi-step metabolic activation, making it highly beneficial for advanced colorectal cancer patients. A genomic analysis at Östra Hospital in Gothenburg found that ~75% of metastatic colorectal cancer patients lack the potential to effectively metabolize folate-based drugs, rendering them ineffective, but Arfolitixorin provides a new ray of hope for these patients [2]. In a developing country like Pakistan, the prevalence of colorectal cancer is 5.6% [4]. Moreover, advanced mCRC with liver and lung involvement has a five-year survival of only 10-15%. Thus most patients with mCRC are treated with 5-FU. Following therapy, they become susceptible to the side-effects including anemia, diarrhea, bruising, bleeding, and mucositis etc. To counter such effects folinic acid is co-administered. Despite this regimen, the conversion of folinic acid to MTHF is inefficient, leading to suboptimal levels of MTHF. In such cases, a drug such as Arfolitixorin can be beneficial as it does not require conversion leading to a concurrent rise in MTHF levels in tumor cells thus causing efficient regression of tumor cells. Some potential adverse effects of Arfolitixorin include diarrhea, nausea, vomiting, stomatitis, leucopenia, neutropenia, thrombocytopenia, ocular toxicity, paresthesia, fatigue, and neuropathy, which seemed to be the equivalent of conventional folate based prodrugs and not more pronounced, eliciting it as a better treatment candidate due to its effectiveness [5]. Arfolitixorin can be considered a broad-spectrum medication for the standard-care treatment for metastasized & non-metastasized CRC as well as other cancers including breast cancer, pancreatic cancer, head and neck cancers, and stomach cancers because in such cancers conventional folate-based drugs are also administered. Further clinical trials must be conducted to predict the safety and efficiency of Arfolitixorin.

Early changes in circulating tumor DNA (ctDNA) predict treatment response in metastatic KRAS-mutated colorectal cancer (mCRC) patients

The detection of RAS mutations and co-mutations in liquid biopsy offers a novel paradigm for the dynamic management of metastatic colorectal cancer (mCRC) patients.Expanding the results of the prospective OMITERC (OMIcs application from solid to liquid biopsy for a personalized ThERapy of Cancer) project, we collected blood samples at specific time points from patients who received a first-line chemotherapy (CT) for KRAS-mutated mCRC. CTC quantification was performed by CellSearch® system. Libraries from cfDNA were prepared using the Oncomine™ Colon cfDNA Assay to detect tumour-derived DNA in cfDNA. The analysis involved >240 hotspots in 14 genes.Twenty patients with KRAS-mutated mCRC treated at the Medical Oncology Unit of Careggi University Hospital were prospectively enrolled. Nine patients had available data for longitudinal monitoring of cfDNA. After 6 weeks of first-line CT an increase of KRAS-mutated clone was reported in the only patient who did not obtain disease control, while all patients with decrease of KRAS clones obtained disease control. Overall, in patients with a short (<9 months) progression-free survival (PFS) we registered, at 6 weeks, an increase in cfDNA levels and in KRAS mutations or other co-mutations, i.e. PIK3CA, FBXW7, GNAS, and TP53. In selected cases, co-mutations were able to better anticipate radiological progressive disease (PD) than the increase of KRAS-mutated clones.In conclusion, our study confirms plasma ctDNA as a crucial tool for anticipating PD at an early time point and highlights the value of a comprehensive assessment of clonal dynamics to improve the management of patients with mCRC.

Preventive effect of a traditional Japanese Kampo medicine, shakuyakukanzoto, against neurotoxicity of FOLFOX plus bevacizumab used for metastatic colorectal cancer management: A single‐arm phase II study

AbstractAim5‐Fluorouracil/folinic acid and oxaliplatin plus bevacizumab (FOLFOX + BV) is a standard chemotherapy regimen for metastatic colorectal cancer (mCRC). This study was aimed at evaluating the preventive effects of shakuyakukanzoto against oxaliplatin‐induced neurotoxicity associated with FOLFOX + BV administration.MethodsIn this single‐arm, open‐label, phase II clinical trial, we enrolled patients with previously untreated, histologically confirmed mCRC from six hospitals in Japan who were aged 20 years and older and had an Eastern Cooperative Oncology Group performance status of 0–1. The patients received shakuyakukanzoto 2.5 g thrice daily, orally, until disease progression and/or unacceptable toxicity was noted. The primary endpoint was the incidence of neurotoxicity following oxaliplatin administration at a dose of 500 mg/m2. Neurotoxicity was evaluated according to the Neurotoxicity Criteria of Debiopharm (DEB‐NTC). The trial was registered in the UMIN Clinical Trials Registry of Japan (UMIN000001853).ResultsForty‐one non‐pretreated mCRC patients were included between April 2009 and September 2013. At an oxaliplatin dose of 500 mg/m2, neurotoxicity of DEB‐NTC grade 1–2 developed in 25.0% of patients; no patient had DEB‐NTC grade 3 neurotoxicity. The most common grade 3/4 adverse events were neutropenia (34.1%), hypertension (24.4%), and fatigue (9.8%). The response rate of the 38 patients with measurable lesions was 55.2%. The median progression‐free and overall survival was 14.9 and 35.2 months respectively.ConclusionShakuyakukanzoto substantially reduced oxaliplatin‐induced neurotoxicity without negatively affecting tumor response or survival in FOLFOX + BV‐treated patients with CRC.

Management of metastatic colorectal cancer in patients ≥70 years - a single center experience.

Age-standardized mortality rates for metastatic colorectal cancer (mCRC) are highest among elderly patients. In current clinical guidelines, treatment recommendations for this patient population are based on a limited number of clinical trials. In this monocentric, retrospective analysis we characterized patients aged ≥70 years undergoing systemic therapy for mCRC and overall survival (OS) was investigated. We included 117 unselected, consecutive mCRC patients aged ≥70 years undergoing systemic therapy for mCRC between February 2009 and July 2022. Median OS was 25.6 months (95% CI: 21.8-29.4). The median age was 78 years (range: 70-90) and 21%, 48%, 26% and 5% had an ECOG performance score of 0, 1, 2, and 3, respectively. The median number of systemic therapy lines was 2 (range: 1-5). The choice of first-line chemotherapy backbone (doublet/triplet versus mono) did not impact OS (HR: 0.83, p=0.50) or the probability of receiving subsequent therapy (p=0.697). Metastasectomy and/or local ablative treatment in the liver, lung, peritoneum and/or other organs were applied in 26 patients (22%) with curative intent. First-line anti-EGFR-based therapy showed a trend towards longer OS compared to anti-VEGF-based therapy or chemotherapy alone in left-sided mCRC (anti-EGFR: 39.3 months versus anti-VEGF: 27.3 months versus chemotherapy alone: 13.8 months, p=0.105). In multivariable analysis, metastasectomy and/or local ablative treatment with curative intent (yes versus no, HR: 0.22, p<0.001), the ECOG performance score (2 versus 0, HR: 3.07, p=0.007; 3 versus 0, HR: 3.66, p=0.053) and the presence of liver metastases (yes versus no, HR: 1.79, p=0.049) were independently associated with OS. Our findings corroborate front-line monochemotherapy in combination with targeted therapy as the treatment of choice for elderly mCRC patients with palliative treatment intent. Metastasectomy and/or local ablative treatment with curative intent are feasible and may improve OS in selected elderly mCRC patients.

Angiogenesis inhibition in metastatic colorectal cancer continuum of care

Current treatment for most patients with metastatic colorectal cancer consists of sequential lines of different systemic therapies, including chemotherapy combinations (5-fluorouracil plus irinotecan or oxaliplatin) with the addition of molecular-targeted drugs, such as anti-angiogenic drugs (independently of the molecular characterisation of the tumour) or anti-epidermal growth factor receptor drugs (for patients whose tumours are wild type for KRAS and NRAS genes). More recently, for the subgroup of patients with high microsatellite instable or mismatch repair deficient tumours (approximately 5% of patients), immune checkpoint inhibitors (pembrolizumab or nivolumab plus ipilimumab) have been shown to be highly effective as first-line or second-line therapies. 1 Ciardiello F Ciardiello D Martini G Napolitano S Tabernero J Cervantes A Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022; 72: 372-401 Crossref PubMed Scopus (49) Google Scholar , 2 Cervantes A Adam R Roselló S et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34: 10-32 Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar Furthermore, in patients whose tumours show HER2 gene amplification, BRAFV600E mutation, or KRASG12C mutation, current treatment options also incorporate the corresponding appropriate molecular-targeted drugs. 1 Ciardiello F Ciardiello D Martini G Napolitano S Tabernero J Cervantes A Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022; 72: 372-401 Crossref PubMed Scopus (49) Google Scholar , 2 Cervantes A Adam R Roselló S et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34: 10-32 Summary Full Text Full Text PDF PubMed Scopus (70) Google Scholar Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 studyFruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. Full-Text PDF

P-13 Management of metastatic colorectal cancer in patients ≥70 years: A single-center experience

P-13 Management of metastatic colorectal cancer in patients ≥70 years: A single-center experience

Prediction models for overall and cancer-specific survival in patients with metastatic early-onset colorectal cancer: a population-based study

Metastatic early-onset colorectal cancer (EO-CRC) is on the rise, yet there is a dearth of predictive models for this disease. Therefore, it is crucial to develop a nomogram to aid in the early detection and management of metastatic colorectal cancer in young patients. We retrieved data from the SEER database on patients with metastatic colorectal cancer aged 50 or younger between 2010 and 2017. The data were randomly allocated in a 7:3 ratio to training and validation cohorts, and univariate and multivariate Cox regression analyses were used to identify independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS) at 1, 3, and 5years. The nomograms were developed based on these factors, and their discriminatory and calibration capabilities were validated. Using the nomogram risk scores, patients were stratified into low-risk and high-risk groups. The study included 2470 patients with metastatic EO-CRC. Univariate and multivariate Cox regression analysis identified 12 independent risk factors that were included in the nomogram. The training cohort had a consistency index (C-index) of 0.71, while the validation cohort had a C-index of 0.70, demonstrating good predictive accuracy. Calibration plots showed a high level of consistency between the observed and predicted values, with overlapping plots along the diagonal. The decision curve analysis (DCA) revealed that the nomogram had a high clinical application value. The novel nomograms were created to predict the prognosis of patients with metastatic EO-CRC, which can aid clinicians in developing more effective treatment strategies and contribute to more accurate prognostic assessments.

SB8, an approved bevacizumab biosimilar based on totality of evidence: scientific justification of extrapolation.

SB8 is a biosimilar of bevacizumab based on its similarity demonstrated by physicochemical, functional, non-clinicaland clinical studies. Supported by the concept of extrapolation, SB8 was authorized and is used in a similar manner across all types of tumors as reference bevacizumab. Furthermore, SB8 offers convenience with prolonged stability compared with reference bevacizumab in diluted form. Although a biosimilar must demonstrate biosimilarity to a reference product with the 'totality of evidence' in a stringent regulatory process for marketing authorization, some concerns remain among healthcare practitioners, particularly about extrapolation. This review summarizes the concepts of the totality of evidence and extrapolation in biosimilar development and the role of bevacizumab biosimilars in the management of metastatic colorectal cancer as an extrapolated indication.

Association between artificial intelligence (AI) -assisted tumor AREG and EREG immunohistochemistry (IHC) and outcomes from anti-EGFR therapy during the routine management of metastatic colorectal cancer (mCRC): An observational cohort study.

203 Background: AREG and EREG are ligands of EGFR. AI assisted IHC evaluation of tumor AREG/EREG expression predicted benefit from anti-EGFR therapy in a retrospective analysis of the PICCOLO trial of second-line irinotecan ± panitumumab. Here, we sought to validate those findings through an analysis of patients who received anti-EGFR therapy during routine care for mCRC. Methods: Patients (pts) with available archival FFPE tumor tissue who received panitumumab or cetuximab ± chemotherapy at any time for treatment of mCRC at 8 UK cancer centers were eligible. Central RAS testing by next generation sequencing (NGS) was performed for pts where extended RAS testing had not been previously undertaken. RAS-mutant (mut) and RAS-unknown pts were excluded from the primary analysis population. AREG and EREG positive tumor cells were identified by IHC, performed locally at 6 of 8 sites. Pathologists annotated tumor areas on digital images of glass slides. AI algorithms calculated the percentage of tumor cells staining positive for AREG and EREG within tumor areas. More than 20% AREG and/or EREG tumor cell positivity was regarded as high biomarker expression, the optimal cut-point identified in PICCOLO. Study endpoints were progression-free survival (PFS), overall survival (OS), and locally reported response rate (RR) and disease control rate (DCR). Results: Of 541 pts recruited, 494 (91.3%) had adequate archival tissue for analysis. Central RAS testing was successfully performed in 255 of 393 (64.9%) pts without existing extended RAS results, leading to 45 exclusions, leaving 449 pts in the primary analysis population. 26 (5.8%) pts were BRAF-mut. 110 (24.5%) received concomitant FOLFOX and 304 (67.7%) FOLFIRI. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS (HR 0.73; 95% CI, 0.56-0.95; p = 0.02), OS (HR 0.66 [0.50-0.86]; p = 0.002), and DCR (OR 1.92 [1.05-3.54]; p = 0.04), but not RR (unadjusted OR 1.39 [0.83-2.33]; p = 0.21). Median PFS in the high vs low biomarker groups was 8.5 vs 4.4 months; median OS 16.4 vs 8.9 months. The significant difference in OS (high vs low) was maintained in the subgroup with right-sided primary tumor location (n = 107; 23.8%) (HR 0.56 [0.37-0.86]; p = 0.007). Conclusions: High tumor AREG/EREG expression was associated with significantly prolonged PFS, OS and DCR among a cohort of pts treated with anti-EGFR therapy during routine care of mCRC. The prognostic effect observed validates the predictive effect of AREG/EREG seen in the PICCOLO trial, where AREG/EREG had no prognostic effect in patients receiving chemotherapy alone. A prospective biomarker-led trial is in set-up to support the use of AREG/EREG IHC in clinical practice.

Peribiliary gland injury by floxuridine may be an early mechanistic insult en route to sclerosis

Background: Hepatic artery infusion pumps (HAIP) are being increasingly employed in the management of metastatic colorectal cancer and cholangiocarcinoma secondary to encouraging response rates in most patients. However, efficacy is limited in many patients by biliary toxicity, which requires vigilant monitoring of hepatic biochemistry and frequent dose reductions to avoid secondary sclerosing cholangitis. Although dexamethasone is employed to limit this drug-induced adverse event, little is known about the early (and possibly intervenable) mechanism(s) of toxicity. We hypothesize that mitigation of biliary sensitivity to floxuridine (FUDR) will allow patients to receive more FUDR, increasing the oncologic efficacy of therapy while simultaneously minimizing morbidity.

Anti-Epithelial Growth Factor Receptors for Prognosis in Management of Metastatic Colorectal Cancer

Anti-Epithelial Growth Factor Receptors for Prognosis in Management of Metastatic Colorectal Cancer

499 A 15-Year Experience of Colorectal Pulmonary Metastasectomy in a High-Volume Tertiary Referral Centre

Abstract Aim PulMiCC trial results have challenged the role of pulmonary metastasectomy as part of the management of metastatic colorectal cancer in contemporary practice. We aimed to review short and long-term outcomes for patients undergoing surgical resection of pulmonary colorectal metastases. Method Retrospective analysis of electronic-patient-record data was performed. All patients undergoing lung resection for pathologically confirmed colorectal pulmonary metastatic disease from November-2005 to May-2021 were included. In-hospital, 90-day, 1-year, 2-year, 5-year and 10-year mortality rates were analysed. Cox proportional hazards regression analysis was used to identify factors associated with reduced overall survival. Statistical analysis was undertaken using SPSS version-28. Results 619 patients underwent surgery during the study period. Mean age was 66.0 years (±10.0) and 61.2%(n=379) were male. 68.7%(n=425) underwent open surgery. 151(24.4%) had multiple metastases resected. Median follow-up time was 45(IQR 23–87) months. In-hospital mortality was 0.3%(n=2) and median post-operative length of stay was 4(IQR 3–5) days. 90-day, 1-year, 5-year and 10-year mortality rates were 1.1%(n=7/619), 4.5%(n=26/580), 40.6%(n=165/406) and 74.0%(n=208/281), respectively. After multivariable analysis, advanced age (HR 1.026, 95% CI 1.011–1.043, p&amp;lt;0.001) and resection of more than one metastasis (HR 1.524, 95% CI 1.108–2.097, p=0.010) were independently associated with reduced overall survival. Conclusions Although there is inherent selection bias associated with patients referred for surgical management of colorectal cancer, our results demonstrate extremely low short-term mortality and encouraging longer-term outcomes for these patients. Advanced age and the presence of more than one metastasis at the time of surgery were associated with worse prognosis.

Prognostic and Predictive Value of PIK3CA Mutations in Metastatic Colorectal Cancer

Comprehensive genomic profiling is used to guide the management of metastatic colorectal cancer (mCRC); however, the role of PIK3CA mutations, present in up to 20% of mCRCs, is unclear. This study aimed to evaluate the association of PIK3CA mutations with other common mutations in mCRC and determine the prognostic and predictive value of PIK3CA mutations. A retrospective chart review was performed on patients in the Moffitt Clinical Genomic Database with mCRC. A meta-analysis was performed to further evaluate the predictive value of PIK3CA mutations to the response to anti-epidermal growth factor receptor (EGFR) therapy. Among 639 patients, PIK3CA was positively correlated with KRAS mutation (r=0.11, p=0.006) and negatively correlated with TP53 mutation (r=- 0.18, p≤0.001) and ERBB2 amplification (r=- 0.08, p=0.046). The median overall survival (OS) of patients with PIK3CA-mutant mCRC (n=49) was 35.5 (95% confidence interval [CI] 18.7-48.1) months vs. 55.3 (95% CI 47.5-65.6) months for PIK3CA wild-type mCRC (n=286) [p=0.003]. This OS difference remained significant with exon 9 and exon 20 subset analyses. There was no significant difference in response rate between patients with PIK3CA wild-type (n=97) versus mutant (n=9) mCRC who received anti-EGFR therapy (43% vs. 56%, p=0.61) and no significant difference in median progression-free survival (PFS) of 10.3 versus 7.2 months (p=0.60). However, our meta-analysis of 12 studies, including ours, using a common effect model identified that PIK3CA mutations are associated with reduced response to anti-EGFR therapy, with a relative risk of 0.56 (95% CI 0.38-0.82). Our study identified PIK3CA mutations as a poor prognostic factor, and our meta-analysis identified PIK3CA mutations as predictive of decreased response to anti-EGFR therapy in patients with mCRC.

P-171 Prognostic value of conversion from RAS-mutated to RAS wild-type during treatment of metastatic colorectal cancer using liquid biopsies – real-world data of two Portuguese institutions

Determination of RAS and BRAF mutational status is standard-of-care in the management of metastatic colorectal cancer (mCRC). Liquid biopsy (LB) is a powerful technology to evaluate tumor genetic heterogeneity in a noninvasive manner. Because RAS-mutations (mut) play a major role in resistance to anti-EGFR-therapy in mCRC, serial monitoring of RAS-mut with LB may be useful to guide treatment. A retrospective observational multicenter study was conducted in patients (pts) with mCRC between January/2018-December/2021. RAS and BRAF mutations were examined in the tissue biopsy at the time of metastatic diagnosis (TMD), and by LB throughout treatment (according to physician’s choice of timing), using the Idylla™ test (Biocartis). Our aim was to evaluate the prognostic impact of loss of RAS-mut status (conversion to RAS wild-type (wt) in LB) during treatment of mCRC, and to identify pts and tumor characteristics that correlate with RAS-conversion. A total of 58 LB were done in mCRC patients. Forty-one pts initially with RAS-mut tumors were studied, median (MED) age was 65 years (41-86), 26 (63%) were men. The majority had stage IV disease at diagnosis (N=25, 61%), MED 1 site of metastases (1-4), mostly hepatic (N=26, 63%) and pulmonary (N=13, 32%). Primary tumor of right-colon occurred in 18 pts (44%). Forty-pts (97,5%) underwent surgery of primary tumor, 13 (32%) complemented with metastasectomy. Curative-intent strategies were performed in 30 pts (73,2%), all receiving perioperative systemic therapy. LB was performed after a MED of 3 lines (0-7) of systemic treatment and all pts were previously treated with anti-VEGF antibodies (Abs). Conversion to RAS-wt occurred in 13 pts (32%); 8 of them (61,5%) received further treatment with anti-EGFR-Abs and 3 obtained a response (2 ongoing after 2 and 41 months). None had BRAF mutations in LB. MED follow-up after LB is 12 months, 1-year-OS is 58% (50-66) and MED OS is 15 months (11-19). A non-statistically significant numerical difference in MED OS was found between RAS-wt conversion and persistent RAS-mut pts (23 (4-40) vs 11 (5-17) months; log rank 3,8; p=0,05). Multivariate Cox regression analysis identified RAS-wt conversion as an independent prognostic factor for OS (HR 0,27; CI95 0,09-0,80; p=0,02), as well as presence of peritoneal metastases (HR 2,7; CI95 1,0-7,0; p=0,04). Moreover, more than one site of metastases at TMD was associated with RAS-conversion. This study confirms RAS-wt conversion as an independent prognostic factor for OS, with a potencial 12 months improvement in OS and a 73% relative-risk reduction of death in heavily pretreated pts with RAS-wt conversion. Although it was a retrospective study, with a small sample, these results are promising, with a rate of RAS conversion to wt superior to published data (32% versus 20% ). Several clinicopathological factors were correlated with RAS-wt conversion, which may help select pts most likely to benefit from LB during treatment. Doing LB in pts with Ras-mut tumors should be considered, preferentially early in the disease-course, since loss of mutation represents an opportunity for treatment with anti-EGFR-therapy otherwise unlikely.

Clinical management of metastatic colorectal cancer in the era of precision medicine.

Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC. CA Cancer J Clin. 2022;72:000-000.

Surgical Management of Metastatic Colorectal Cancer

Surgical Management of Metastatic Colorectal Cancer

Impact of the evolution in RAS mutation analysis in Australian patients with metastatic colorectal cancer.

RAS mutation testing now routinely informs the optimal management of metastatic colorectal cancer (mCRC), specifically the finding of a RAS mutation defines patients who will not benefit from treatment with an epidermal growth factor receptor inhibitor. Over time more RAS genes have been tested and more sensitive techniques used. To review routine care RAS testing and results over time. A retrospective analysis of the molecular data collected prospectively in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry from 2009 to 2018 was undertaken. Patients with RAS data were further analyzed. In parallel, the RAS mutation status of patients enrolled in the Test Tailor Treat (TTT) program was examined for 2011-2018. Of 2908 patients in the TRACC registry, 1892 (65%) were tested, with 898 (47%) of tested patients found to be RAS mutant (RASmt). RAS data were available for 5935 TTT patients. Of the tested TRACC patients diagnosed in 2009 and 2010, 38% were RASmt. For each 2-year period from 2011/2012 through to 2017/2018, the prevalence of RASmt in TRACC and TTT was 42% and 40% (2011/2012), 52% and 40% (2013/2014), 47% and 49% (2015/2016), and 47% and 49% (2017/2018). Based on both TRACC and TTT data, the proportion of patients reported to have a RAS mutation increased from 2009 to 2015 but has remained relatively stable in recent years. The increased proportion of RASmt patients observed over time is likely largely driven by the uptake of extended RAS testing.

Exact Primary Tumor Location in mCRC: Prognostic Value and Predictive Impact on Anti-EGFR mAb Efficacy.

Simple SummarySidedness of primary tumor is a well-established prognostic marker and is predictive for anti-EGFR efficacy in RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. As molecular markers change rather continuously throughout the colon, we ask whether the exact primary tumor location (PTL) is a better prognostic marker than sidedness and predictive for anti-EGFR efficacy in RAS/BRAF wild-type mCRC. We retrospectively analyzed five studies containing various therapy protocols concerning primary tumor location, dividing the colorectal frame into six segments. In our cohort, PTL has a prognostic impact on disease spread and overall survival. Only distal segments benefitted when receiving anti-EGFR containing therapy regarding overall survival. Intermediate segments were indifferent and caecal primaries had a detrimental effect receiving anti-EGFR based therapy. Being a retrospective analysis and challenging the standard of basing anti-EGFR treatment on sidedness in RAS/BRAF wild-type mCRC, future studies are necessary to confirm and further investigate our hypothesis-generating results.Primary tumor sidedness (left vs. right) has prognostic and predictive impact on anti-EGFR agent efficacy and thus management of metastatic colorectal cancer (mCRC). This analysis evaluates the relevance of primary tumor location (PTL) in RAS/BRAF wild-type mCRC patients, when dividing the colorectal frame into six segments. This pooled analysis, performed on a single-patient basis of five randomized first-line therapy trials, evaluates the impact of exact PTL classification on baseline characteristics, prognosis and prediction of anti-EGFR antibody efficacy by chi-square and log-rank tests, the Kaplan–Meier method, Cox and logistic regressions. The PTL was significantly associated with metastatic spread: liver (p = 0.001), lung (p = 0.047), peritoneal (p < 0.001) and lymph nodes (p = 0.048). A multivariate analysis indicated an impact on anti-EGFR agent efficacy in terms of overall survival depending on the exact primary tumor location: from detrimental in caecal (HR 2.63), rather neutral effects in the ascending colon (HR 1.24), right flexure/transverse colon (HR 0.99) and left flexure/descending colon (HR 0.91) to clear benefit in sigmoid (HR 0.71) and rectal (HR 0.58) primaries. Exact primary tumor location affects anti-EGFR antibody efficacy in a rather continuous than a dichotomous fashion in RAS/BRAF wild-type mCRC patients. This perspective might help to support clinical decisions when anti-EGFR antibodies are considered.

Tumor Biomarker Testing for Metastatic Colorectal Cancer: a Canadian Consensus Practice Guideline.

The systemic therapy management of metastatic colorectal cancer (mCRC) has evolved from primarily cytotoxic chemotherapies to now include targeted agents given alone or in combination with chemotherapy, and immune checkpoint inhibitors. A better understanding of the pathogenesis and molecular drivers of colorectal cancer not only aided the development of novel targeted therapies but led to the discovery of tumor mutations which act as predictive biomarkers for therapeutic response. Mutational status of the KRAS gene became the first genomic biomarker to be established as part of standard of care molecular testing, where KRAS mutations within exons 2, 3, and 4 predict a lack of response to anti- epidermal growth factor receptor therapies. Since then, several other biomarkers have become relevant to inform mCRC treatment; however, there are no published Canadian guidelines which reflect the current standards for biomarker testing. This guideline was developed by a pan-Canadian advisory group to provide contemporary, evidence-based recommendations on the minimum acceptable standards for biomarker testing in mCRC, and to describe additional biomarkers for consideration.

More than FOLFOX and FOLFIRI: The Management of Metastatic Colorectal Cancer in the Era of Precision Oncology

Metastatic colorectal cancer (mCRC) is a markedly heterogeneous disease, which portends a poor prognosis, with an estimated 5-year overall survival rate of approximately 15%. The standard of care of systemic therapy remains fluoropyrimidine-based chemotherapy, with modest results, despite improvements with the combination with anti-angiogenics and anti-epidermal growth factor receptor therapy. Significant advances in cancer therapy have been observed in the past two decades. The enhanced appreciation of molecular biology in oncology has allowed for the identification of specific molecular subtypes and novel therapeutic targets. Nevertheless, meaningful precision-based advancements in the therapeutic options for mCRC have been challenging and slow to realisation. Comprehensive molecular profiling and circulating tumour DNA highlight a heterogeneous disease at the genomic, epigenomic, and transcriptomic levels, and with a low frequency of actionable alterations. In the present review, the authors describe the current and emerging predictive biomarkers in mCRC, as well as present landmark clinical trials that have allowed for evolving precision in the therapeutic management. The understanding of the benefit of immune checkpoint inhibitors in patients with high microsatellite instability cancer and in those with POLE mutations or high tumour mutational burden, the combination of BRAF with epidermal growth factor receptor inhibition in BRAF V600-mutated patients, the use of allele-specific KRAS G12C inhibitors, the promising findings of dual anti-HER2 therapy in HER2-positive mCRC, and the possibility to offer targeted therapy for patients harbouring gene fusions NTRK/ALK/ROS1 have ushered in a new era of precision oncology for mCRC, providing personalised treatments and sustaining hope for patients affected by this challenging disease.