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Colorectal Cancer Research Roundup

Every two weeks, a critical review of the most significant colorectal cancer research indexed in PubMed, with key findings, methodological appraisal, and clinical implications.

Issue of September 1, 2026 · covering August 15-31, 2026

1. Long-course chemoradiotherapy versus short-course radiotherapy for response-adapted organ preservation in early rectal cancer: 12-month results (STAR-TREC, The Lancet Oncology)

Simon P. Bach (Division of Surgery and Interventional Science, University College London), David Sebag-Montefiore (University of Leeds), Victoria Homer, Alexandra Gilbert, Ane Appelt, Geerard L. Beets, Anna Martling, Nicholas P. West, et al., Corrie A. M. Marijnen, Johannes H. W. de Wilt, and the STAR-TREC Collaborative; corresponding author Simon P. Bach

Key points

  • International, open-label, phase 2/3 trial enrolling 503 participants at 37 sites in five European countries; the 12-month analysis included 409 patients (163 long-course chemoradiotherapy [LCCRT], 168 short-course radiotherapy [SCRT], 78 primary total mesorectal excision [TME]) with rectal adenocarcinoma of 40 mm or less staged mrT1-T3bN0.
  • Among patients choosing organ preservation, 12-month TME-free survival was 78.5% (95% CI 72.4-85.1) with LCCRT versus 60.6% (95% CI 53.6-68.4) with SCRT; HR 1.90 (95% CI 1.29-2.81), with a posterior probability of LCCRT superiority above 99.5%.
  • Clinical complete response at 16-20 weeks: 104 (64%) with LCCRT versus 61 (36%) with SCRT; watch-and-wait without further treatment: 93 (57%) versus 53 (32%); transanal local excision: 32 (20%) versus 52 (31%).
  • Grade 3 or worse serious adverse events over 12 months: 28 of 331 (8%) in the organ-preservation groups versus 15 of 78 (19%) with primary TME; the only death followed an anastomotic leak in the TME group.
  • The primary endpoint, organ preservation at 30 months, has not yet been reported; 36-month and definitive 60-month analyses are planned.

Key limitations

  • Only 12-month results are available; local regrowth, distant metastasis and survival outcomes are immature.
  • Phase 3 used a partially randomized patient-preference design, so the comparison with primary TME is not fully randomized.
  • Open-label design, and bowel function and quality-of-life findings were reported mainly descriptively in available sources.

Future directions

  • Report the prespecified 30-month organ-preservation endpoint, expected in mid-2027.
  • Confirm oncological safety of response-adapted organ preservation in the 36-month and 60-month analyses.
  • Define which patients with early rectal cancer benefit most from LCCRT versus SCRT within an organ-preservation pathway.

Radical total mesorectal excision (TME) has long been the standard treatment for early-stage rectal cancer and achieves good oncological control, but it carries substantial costs in morbidity: anastomotic complications, the possibility of a permanent stoma, and long-term bowel, urinary and sexual dysfunction. For patients with small, node-negative tumors, the question is increasingly whether rectal removal is necessary at all. Organ-preserving strategies, in which radiotherapy is used to shrink the tumor and surgery is reserved for residual or regrowing disease, have gained ground, but the optimal radiotherapy approach for this purpose has been unclear.

Watch-and-wait and local excision after neoadjuvant therapy have been adopted in selected centers, mainly on the basis of cohort data and smaller trials. Two radiotherapy schedules are in common use for rectal cancer: long-course chemoradiotherapy over five weeks with a fluoropyrimidine, and short-course radiotherapy over five days. The two differ in convenience, toxicity profile and, potentially, in the depth of tumor response they achieve, which matters more when the aim is to avoid surgery rather than to prepare for it. STAR-TREC was designed to test response-adapted organ preservation against standard TME and to compare the two radiotherapy schedules head to head.

STAR-TREC is an international, multicentre, open-label, phase 2/3 trial conducted in England, the Netherlands, Denmark, Belgium and Sweden (ISRCTN14240288). Eligible patients had biopsy-confirmed rectal adenocarcinoma of 40 mm or less, MRI-staged mrT1-T3bN0, and ECOG performance status 0-1. In phase 2, patients were randomized 1:1:1 to LCCRT (50 Gy in 25 fractions with capecitabine 825 mg/m2 twice daily), SCRT (25 Gy in 5 fractions, without subsequent chemotherapy) or primary TME. Phase 3 used a partially randomized patient-preference design in which patients choosing organ preservation were randomized 1:1 between LCCRT and SCRT. Patients with a clinical complete response entered surveillance, small residual lesions were removed by transanal local excision, and radical surgery was reserved for inadequate response. Overall, 503 participants were enrolled at 37 sites between June 2017 and April 2024.

The expanded 12-month analysis included 426 participants recruited before August 8, 2023; after 17 withdrew before treatment, the modified intention-to-treat population comprised 409 patients (163 LCCRT, 168 SCRT, 78 TME). Among those choosing organ preservation, 12-month TME-free survival was 78.5% (95% CI 72.4-85.1) with LCCRT and 60.6% (95% CI 53.6-68.4) with SCRT, a hazard ratio of 1.90 (95% CI 1.29-2.81); the posterior probability that LCCRT was superior exceeded 99.5%. In the interim phase 2 analysis, median TME-free survival was not reached with LCCRT versus 7.6 months with SCRT (HR 3.7, 95% CI 1.7-8.0). A clinical complete response at 16-20 weeks occurred in 104 patients (64%) after LCCRT and 61 (36%) after SCRT.

The deeper responses with LCCRT translated into more patients managed without further intervention: 93 (57%) entered watch-and-wait versus 53 (32%) after SCRT, while transanal local excision was used in 32 (20%) and 52 (31%), respectively. Rectal removal before surveillance began was required in 27 (17%) versus 55 (33%). Grade 3 or worse serious adverse events over 12 months occurred in 28 of 331 patients (8%) in the organ-preservation groups and 15 of 78 (19%) after primary TME, where anastomotic leak with perforation occurred in 12 patients (15%); one patient in the TME group died after a leak. Grade 3 or worse events within four weeks of radiotherapy were more frequent after LCCRT (9 of 163, 6%) than SCRT (2 of 168, 1%). Bowel function was reported to be better in organ-preservation patients without a stoma.

The trial's strengths are its multinational design, a randomized comparison of the two radiotherapy schedules, and a pragmatic response-adapted pathway that mirrors how organ preservation is delivered in practice. However, the present report covers only 12 months. Organ preservation at 30 months is the prespecified primary endpoint, and the durability of a clinical complete response, the risk of local regrowth, and the possibility that deferred surgery affects distant control cannot yet be assessed. The phase 3 component allowed patients to choose surgery, so comparisons with the TME group are partly non-randomized and susceptible to selection effects. The open-label design and the descriptive reporting of functional outcomes in available summaries also limit firm conclusions about quality of life.

The authors conclude that LCCRT appears more effective than SCRT at 12 months and that a response-adapted organ-preservation approach is supported by these early results, with avoidance of unnecessary rectal removal potentially the more appropriate strategy in early-stage disease. For clinicians discussing options with patients who have small, node-negative rectal cancers, the data offer the first randomized estimates of how often each radiotherapy schedule allows the rectum to be kept. The 30-month organ-preservation analysis, expected in mid-2027, followed by 36-month cancer outcomes and a definitive 60-month analysis, will determine whether this early advantage holds and whether organ preservation is oncologically safe.

Source: Bach et al. (STAR-TREC), "Chemoradiotherapy versus short-course radiotherapy for response-adapted organ preservation in early-stage and intermediate-stage rectal cancer (STAR-TREC): 12-month results of an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial," The Lancet Oncology, published online August 23, 2026 (vol. 27, issue 9). Read the paper

2. Ifebemtinib plus garsorasib in previously treated KRAS G12C-mutated metastatic colorectal cancer (randomized phase 1b/2 trial, The Lancet Oncology)

Zhengbo Song (institutional affiliation not confirmed in available sources), Liming Zhu, Ying Liu, Rongbo Lin, Xingya Li, Yongzhong Luo, Yuan Yuan, et al.; corresponding author Xiangdong Cheng (Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou)

Key points

  • Multicentre phase 1b/2 trial in China (NCT06166836 and NCT05379946) combining the FAK inhibitor ifebemtinib (100 mg once daily) with the KRAS G12C inhibitor garsorasib (600 mg twice daily) in previously treated KRAS G12C-mutated metastatic colorectal cancer.
  • Single-arm phase 2 cohort (n=15): confirmed ORR 46.7% (95% CI 21.3-73.4); median PFS 6.9 months; median OS 14.3 months; median follow-up 23.8 months.
  • Randomized phase 2 (n=36, 1:1): confirmed ORR 38.9% (95% CI 17.3-64.3) with the combination versus 16.7% (95% CI 3.6-41.4) with garsorasib alone; difference 22.2% (95% CI -7.7 to 49.1), one-sided P=0.068 (primary endpoint not met).
  • Median PFS 7.7 versus 4.0 months (HR 0.48, 95% CI 0.22-1.04); median OS not estimable versus 7.5 months (HR 0.34, 95% CI 0.11-1.12); disease control 100% versus 77.8%.
  • Grade 3 treatment-related adverse events 30% versus 28%; most common treatment-related events with the combination were diarrhea (64%), proteinuria (64%) and nausea (52%); no grade 4 events or treatment-related deaths.

Key limitations

  • Very small randomized cohort (18 patients per arm), and the primary ORR comparison did not reach statistical significance.
  • Open-label design without masked independent central review; PFS and OS comparisons were descriptive.
  • All patients were enrolled in China, so generalizability to other populations and to regimens built on anti-EGFR antibodies is uncertain.

Future directions

  • A larger randomized trial powered for PFS to confirm whether FAK inhibition adds to KRAS G12C blockade.
  • Head-to-head or combination strategies with anti-EGFR antibodies, the current backbone for KRAS G12C inhibitors in colorectal cancer.
  • Use of baseline cfDNA KRAS G12C detection and other biomarkers to select patients and track resistance.

KRAS G12C mutations occur in a small subset of metastatic colorectal cancers and have historically conferred a poor prognosis with limited treatment options after standard chemotherapy. Covalent KRAS G12C inhibitors have transformed management of KRAS G12C-mutated lung cancer, but in colorectal cancer their activity as single agents has been modest, largely because tumors rapidly reactivate upstream signaling. The search for rational partners that blunt this adaptive resistance has therefore become a central question for this molecular subgroup.

In colorectal cancer, adaptive feedback through receptor tyrosine kinases such as EGFR has been the main explanation for the limited efficacy of KRAS G12C inhibitor monotherapy, which is why current combinations pair these agents with anti-EGFR antibodies. Focal adhesion kinase (FAK) offers a different, orally available target: it mediates signaling from the tumor microenvironment and has been implicated in resistance to MAPK pathway inhibition. Ifebemtinib (IN10018) is a FAK inhibitor and garsorasib (D-1553) a KRAS G12C inhibitor. An all-oral doublet that improves on garsorasib monotherapy would offer a practical alternative for patients after chemotherapy.

This multicentre phase 1b/2 study enrolled patients with previously treated KRAS G12C-mutated locally advanced or metastatic colorectal cancer, ECOG performance status 0-1, and progression after irinotecan- or oxaliplatin-based therapy. Phase 1b, in six patients with KRAS G12C-mutated non-small-cell lung cancer, observed no dose-limiting toxicities and established the recommended phase 2 dose of ifebemtinib 100 mg once daily plus garsorasib 600 mg twice daily. Phase 2 began with a 15-patient single-arm cohort; seven partial responses met the threshold to proceed to a randomized portion in which 36 patients were assigned 1:1 to the combination or garsorasib alone. The primary endpoint was investigator-assessed confirmed objective response rate. The data cutoff was June 30, 2025.

In the single-arm cohort (median age 53 years, median follow-up 23.8 months), the confirmed ORR was 46.7% (95% CI 21.3-73.4) in the safety set and 50.0% (95% CI 23.0-77.0) among response-evaluable patients, with seven partial responses, six cases of stable disease and one of progressive disease. Median duration of response was 5.4 months, median PFS 6.9 months and median OS 14.3 months. In the randomized portion, the confirmed ORR was 38.9% (95% CI 17.3-64.3) with the combination and 16.7% (95% CI 3.6-41.4) with garsorasib alone, a difference of 22.2% (95% CI -7.7 to 49.1) that did not reach statistical significance (one-sided P=0.068).

Secondary endpoints favored the combination numerically. Disease control was 100% versus 77.8%, median duration of response 15.4 months versus not estimable, and median PFS 7.7 versus 4.0 months (HR 0.48, 95% CI 0.22-1.04; nominal one-sided P=0.029). Median OS was not estimable with the combination versus 7.5 months with monotherapy (HR 0.34, 95% CI 0.11-1.12; nominal one-sided P=0.032). Among the 33 patients who received the combination, the most common treatment-related adverse events were diarrhea (64%), proteinuria (64%) and nausea (52%); grade 3 events included diarrhea (18%), proteinuria (6%) and intestinal obstruction (6%). Grade 3 treatment-related events occurred in 30% versus 28%, serious adverse events in 30% versus 22%, and dose reductions in 24% versus 6%. There were no grade 4 treatment-related events or treatment-related deaths.

The trial is small, and its randomized comparison was not powered to detect moderate differences: the primary endpoint was missed and the confidence intervals for PFS and OS hazard ratios cross 1.0, so these should be read as trends rather than established benefits. The open-label design and investigator assessment without masked central review add potential bias to response and progression endpoints. All patients were Asian and treated in China, and the investigators cautioned against cross-trial comparisons. The comparator was garsorasib monotherapy rather than a KRAS G12C inhibitor plus an anti-EGFR antibody, which is now the reference combination in colorectal cancer, so the regimen's place relative to established doublets remains undefined.

The study provides proof of concept that adding FAK inhibition to KRAS G12C blockade is tolerable and may deepen and prolong responses in colorectal cancer, with a toxicity profile dominated by gastrointestinal events and proteinuria. An all-oral regimen is attractive, but its value will depend on confirmation in an adequately powered randomized trial with PFS as the primary endpoint and, ideally, comparison against or combination with anti-EGFR-based approaches. Exploratory cfDNA analyses, in which KRAS G12C was detected in 35 of 48 baseline samples, suggest that liquid biopsy could support patient selection and monitoring of resistance in future studies.

Source: Song et al., "Ifebemtinib plus garsorasib in previously treated metastatic colorectal cancer with KRASG12C mutation: a multicentre, randomised, phase 1b/2 trial," The Lancet Oncology, published online late August 2026 (publication announced August 28, 2026; September 2026 issue). Read the paper

3. Fecal occult blood screening and colorectal cancer mortality adjusted for contamination and nonadherence (Stockholm-Gotland screening program, JAMA Network Open)

Johannes Blom (Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet), Lennarth Nyström, and Håkan Jonsson (Karolinska Institutet and Umeå University, Sweden); corresponding author Johannes Blom

Key points

  • Re-analysis of the Stockholm-Gotland biennial fecal occult blood test (FOBT) program (ages 60-69 randomized by birth year to first invitation): 376,511 people, 203,692 invited 2008-2012 versus 172,819 controls; up to 14 years of follow-up and 1,668 colorectal cancer deaths (856 vs 812).
  • The original 2024 evaluation had estimated a 14% reduction in colorectal cancer mortality with invitation to screening.
  • Adjusting for loss of exposure (cancers diagnosed more than 2 years after invitations ended): risk ratio 0.81 (95% CI 0.69-0.94).
  • Additionally adjusting for contamination of the control group, about two-thirds of whom were eventually invited: RR 0.74 (95% CI 0.58-0.94), a 26% reduction with invitation.
  • Adjusting for nonadherence and control-group screening to estimate the effect of actual participation: RR 0.57 (95% CI 0.40-0.80), a 43% reduction; about one-third of invitees never submit a sample.

Key limitations

  • Estimates rely on statistical adjustments for several biases, so some uncertainty remains, as the authors acknowledge.
  • Residual confounding is possible because covariates such as age and follow-up time were merged into broader intervals.
  • Birth-cohort allocation within an ongoing program is not equivalent to an individually randomized trial.

Future directions

  • Further development of methods for evaluating ongoing screening programs that lack truly unexposed controls.
  • Strategies to raise participation, given that roughly a third of invitees do not return a sample.
  • Similar contamination- and adherence-adjusted analyses of FIT-based programs.

Stool-based screening is the backbone of organized colorectal cancer screening in many countries, including Sweden, which offers testing every two years to people aged 60 to 74; a positive home test usually leads to colonoscopy. The Stockholm-Gotland region introduced routine screening in 2008, and its rollout created a natural comparison group because birth cohorts were assigned to different years of first invitation. Evaluating the real-world impact of such programs matters for policy, yet doing so rigorously is difficult once screening becomes widely available.

A 2024 evaluation of the Stockholm-Gotland program found that people invited to FOBT screening had a 14% lower risk of dying from colorectal cancer over up to 14 years of follow-up. That figure is an intention-to-screen estimate and is likely diluted by several factors: about two-thirds of the control group were eventually invited to screening themselves, some cancer deaths in the invited group came from cancers diagnosed after invitations had ended, and roughly one-third of invitees never submitted a sample. Few studies evaluate ongoing programs precisely because valid unexposed controls are hard to identify, which motivated this re-analysis.

Blom, Nyström and Jonsson re-analysed the cohort using Swedish health registers. The study group comprised 203,692 people (48.8% men; mean age 63.6 years at the start of follow-up) invited to FOBT screening between 2008 and 2012; the control group comprised 172,819 people (49% men; mean age 62.8 years) who were not invited or were invited between 2013 and 2015. The analysis used the same data as the 2024 publication, with 40 additional deaths identified from a national database, for a total of 1,668 colorectal cancer deaths (856 in the study group, 812 in controls). Sequential adjustments addressed loss of exposure, contamination of the control group, and nonadherence among invitees.

Adjusting for colorectal cancers diagnosed more than two years after invitations ended in the study group gave a risk ratio for colorectal cancer death of 0.81 (95% CI 0.69-0.94), a 19% reduction. Further excluding control-group deaths among people who were eventually invited, to correct for contamination, gave a risk ratio of 0.74 (95% CI 0.58-0.94), a 26% reduction associated with invitation to screening. Adjusting additionally for participation, that is, nonadherence in the study group and screening in the control group, yielded a risk ratio of 0.57 (95% CI 0.40-0.80), a 43% reduction in colorectal cancer mortality associated with actually taking part in screening.

Intermediate estimates from partial participation adjustments, of 30% and 38% reductions, were cited in an accompanying perspective by Arielle Elmaleh-Sachs of NYU Langone Health, illustrating how the effect estimate grows as each source of dilution is addressed. The sequence of estimates, from 14% in the original intention-to-screen analysis to 43% for participation, is the central message of the paper: conventional evaluations of organized programs can substantially understate their benefit. The study population was large, follow-up was long, and outcomes came from comprehensive national registers, which reduces loss to follow-up and misclassification of cause of death.

The authors note that the results depend on statistical adjustment for multiple biases, so some uncertainty remains. Participants and nonparticipants differ in health behaviors and baseline risk, and although the participation-adjusted method was designed to address this, residual confounding is possible, particularly as covariates such as age and follow-up time were grouped into broad intervals. Allocation by birth year within an operating program is not equivalent to individual randomization. The confidence interval around the participation estimate is also wide, and the analysis concerns a fecal occult blood testing program, so its applicability to fecal immunochemical test-based programs requires separate confirmation.

The findings strengthen the case that organized stool-based screening reduces colorectal cancer deaths substantially among those who take part, and that conventional evaluations may underestimate its value. Blom summarized the main message as screening working better than many people realize, and emphasized the importance of participation, given that around a third of people invited do not submit a sample. The work also provides a methodological template for evaluating other ongoing programs where contamination and nonadherence complicate comparisons, and it underlines the potential gains from interventions that increase uptake.

Source: Blom, Nyström and Jonsson, "Fecal Occult Blood Screening Outcomes Adjusted for Contamination Bias and Nonadherence," JAMA Network Open 2026;9(8):e2629856, published online August 20, 2026. Read the paper

4. Family history of colorectal cancer and colorectal cancer risk in inflammatory bowel disease (ESPRESSO nationwide cohort, Gastroenterology)

Authors include Åsa Everhov (Södersjukhuset and Karolinska Institutet) and Ola Olén (Sachs' Children and Youth Hospital and Karolinska Institutet), et al.; full author order not verified

Key points

  • Swedish nationwide registry-based cohort of 124,387 people with inflammatory bowel disease (IBD) diagnosed 1996-2023, compared with just over 1.2 million general-population individuals, linked through the Multigenerational Register and the ESPRESSO cohort.
  • Over a median follow-up of 11 years, 1,882 people with IBD developed colorectal cancer.
  • Two or more first-degree relatives with colorectal cancer conferred about 2.6 times the risk compared with IBD patients without a family history of cancer.
  • One first-degree relative diagnosed with colorectal cancer before age 50 was associated with a risk just under 50% higher.
  • The absolute colorectal cancer risk in people with an affected first-degree relative was roughly similar with or without IBD.

Key limitations

  • Observational registry design; associations do not establish causation.
  • Registry data may not capture all relevant risk factors, such as inflammatory activity, colonoscopy surveillance intensity or lifestyle.
  • Hazard ratios with confidence intervals and the exact publication date could not be verified from available sources.

Future directions

  • Incorporating family cancer history into risk-stratified colonoscopic surveillance schedules for IBD.
  • Evaluating whether intensified surveillance in IBD patients with a strong family history reduces cancer incidence and mortality.
  • Combining family history with disease-specific factors in multivariable risk prediction tools.

People with inflammatory bowel disease, particularly those with extensive or long-standing colitis, have an increased risk of colorectal cancer, and most guidelines recommend regular surveillance colonoscopy. Family history of colorectal cancer is an established risk factor in the general population and is already listed among risk modifiers in IBD surveillance guidance, but its magnitude within IBD, and how it interacts with the risk conferred by chronic inflammation, has been less precisely quantified in large population-based data.

Surveillance intervals in IBD are typically set according to disease extent, duration, inflammatory activity and comorbidities such as primary sclerosing cholangitis, with family history as an additional modifier. Prior estimates of the familial contribution have often come from smaller cohorts or case-control designs. Sweden's linked national registers, including the Multigenerational Register that connects individuals to their parents and siblings, and the ESPRESSO histopathology cohort, make it possible to measure family cancer burden objectively and to follow large numbers of people with IBD over long periods.

The investigators, from Karolinska Institutet and affiliated hospitals, identified 124,387 people with IBD in Sweden between 1996 and 2023 using the National Patient Register and the ESPRESSO cohort, and compared them with just over 1.2 million individuals from the general population. Cancer diagnoses and deaths were ascertained from the Cancer Register and Cause of Death Register, and first-degree relatives were identified through the Multigenerational Register. Risk of colorectal cancer was examined according to the number of affected first-degree relatives and the age at which relatives were diagnosed. Several authors reported collaborations or grants from pharmaceutical companies.

Over a median follow-up of 11 years, 1,882 people with IBD developed colorectal cancer. Compared with IBD patients with no family history of cancer, those with two or more first-degree relatives with colorectal cancer had about 2.6 times the risk of colorectal cancer. Having one first-degree relative diagnosed with colorectal cancer before age 50 was associated with a risk just under 50% higher. These findings indicate that family history contributes a substantial, graded increment of risk on top of IBD itself, with the strongest effect when several relatives are affected.

A notable additional observation was that the absolute risk of colorectal cancer among people with an affected first-degree relative was roughly the same whether or not they had IBD. This suggests that in individuals with a strong family history, the familial component may dominate, and that IBD patients with such a history may warrant attention comparable to that given to non-IBD relatives of patients with colorectal cancer. Detailed hazard ratios with confidence intervals, and results stratified by IBD subtype or disease extent, were not available in the summaries consulted for this roundup and should be checked in the full paper.

As a registry-based observational study, the analysis can establish associations but not causation. Registers may not capture inflammatory burden, endoscopic surveillance intensity, chemopreventive medication use, or lifestyle factors that may differ between families, and shared environmental exposures may contribute to familial clustering alongside inherited susceptibility. Family history recorded through registers is more objective than self-report, but cancers in relatives diagnosed before the registers' coverage may be missed. The exact online publication date of the paper could not be confirmed; it was publicized in early September 2026.

The findings support explicitly incorporating family cancer burden, including the number of affected relatives and their age at diagnosis, into risk-stratified surveillance for people with IBD. In practice, this means that gastroenterologists should routinely take and update a detailed family history and consider shorter surveillance intervals for patients with multiple affected relatives or a relative with early-onset disease. Future work should test whether such adjustments improve outcomes and integrate family history with disease-specific factors in validated risk prediction tools.

Source: Everhov, Olén et al., Gastroenterology, 2026 (exact online date not verified; publicized early September 2026). Read the paper

5. Early-onset versus later-onset colorectal cancer with liver-only metastases in Australian real-world practice, 2009-2024 (Medical Journal of Australia)

Savio G. Barreto (HPB and Liver Transplant Unit, Flinders Medical Centre, and Flinders University), Christos S. Karapetis, Shahid Ullah, Matthew Burge, Timothy J. Price, Jeanne Tie, et al.; senior author Peter Gibbs

Key points

  • Retrospective cohort study using prospectively collected clinical and molecular data from an Australian national database, 2009-2024: 1,691 patients with colorectal cancer metastatic only to the liver.
  • Patients diagnosed at age 50 or younger were compared with those diagnosed after 50.
  • Younger patients were more often women, more often had left-sided tumors, and more often carried certain genetic mutations.
  • Younger patients lived longer overall after liver-limited spread; BRAF and KRAS mutations were linked to poorer outcomes in both age groups.
  • Liver surgery followed by drug therapy was generally associated with better outcomes than other approaches (observational association).

Key limitations

  • Real-world, non-randomized data cannot show that any treatment caused better survival.
  • Survival estimates, hazard ratios and the exact publication date could not be verified from available sources.
  • Database studies are subject to selection effects in who is referred for liver surgery.

Future directions

  • Age-stratified analyses of molecular subgroups to refine prognosis in liver-limited disease.
  • Prospective evaluation of multimodal strategies in younger patients with liver-only metastases.
  • Integration of molecular profiling into multidisciplinary decisions about resection.

Colorectal cancer in adults younger than 50 has been rising in many high-income countries, and younger patients frequently present with advanced disease. The liver is the commonest site of distant spread, and a subset of patients with liver-only metastases can be cured or achieve long survival with resection combined with systemic therapy. Whether early-onset patients with liver-limited disease differ biologically or in outcome from older patients is relevant to how aggressively they are treated and how their prognosis is discussed.

Previous work has suggested that early-onset colorectal cancer is enriched for left-sided and rectal primaries and may differ in molecular features, but much of this evidence comes from heterogeneous populations mixing metastatic sites and treatment intents. Patients with liver-only metastases are a distinct group in whom surgery is often the pivotal intervention, and outcome comparisons by age in this setting, drawing on molecular data alongside treatment details, have been relatively scarce. Australia's national colorectal cancer databases, which collect clinical and molecular information prospectively in routine practice, offered an opportunity to address this question.

The study, led by Flinders University and Flinders Medical Centre with co-authors from oncology centers across Australia, used prospectively collected real-world clinical and molecular data from an Australian national database covering 2009 to 2024. It included 1,691 patients whose colorectal cancer had spread only to the liver and compared those diagnosed at age 50 or younger with those diagnosed after 50. Clinical characteristics, tumor sidedness, molecular alterations including BRAF and KRAS status, treatment approaches and survival were examined. This was a retrospective analysis of routine practice data rather than a clinical trial.

Younger patients differed from older patients in several respects: they were more likely to be women, their tumors were more likely to be left-sided, and their tumors were more likely to carry certain genetic mutations. Despite these differences, younger patients lived longer overall after their cancer had spread to the liver. BRAF and KRAS mutations were associated with poorer outcomes in both age groups, indicating that established molecular prognostic markers retain their significance regardless of age at diagnosis. Specific survival figures and hazard ratios were not available in the summaries consulted for this roundup.

Treatment patterns were also examined. Liver surgery followed by drug therapy was generally associated with better outcomes than other approaches, consistent with the established role of resection in liver-limited disease. Because younger patients are often fitter and more likely to be offered intensive multimodal treatment, part of their survival advantage may reflect treatment selection rather than intrinsically less aggressive disease. Lead author Savio Barreto stressed that every cancer is unique, a reminder that age alone should not drive treatment decisions without regard to molecular and clinical features.

The main limitation, acknowledged by the investigators, is that the data come from routine practice rather than a randomized trial, so the study cannot prove that any particular treatment caused better survival. Patients selected for liver surgery differ systematically from those who are not, and residual confounding by performance status, comorbidity and tumor burden is likely. The summaries available for this roundup did not report effect sizes, and the exact publication date of the paper could not be confirmed; it was publicized on September 1, 2026, at the boundary of this issue's window.

For clinicians, the study suggests that early-onset patients with liver-only metastases have a distinct clinical and molecular profile but, on average, a better prognosis than older patients, and that BRAF and KRAS status remain key prognostic factors at all ages. These findings support routine molecular profiling and multidisciplinary assessment for resectability in younger patients. Further research should examine whether the survival advantage persists after careful adjustment for treatment intensity and whether age-specific biology should alter surgical or systemic treatment strategies.

Source: Barreto et al., Medical Journal of Australia, 2026 (exact publication date not verified; publicized September 1, 2026). Read the paper

6. A tumor-to-liver FGF21-IGFBP1 relay drives muscle and bone loss in colorectal cancer cachexia (Nature Communications)

Joshua R. Huot (Indiana University School of Medicine), Urja R. Kamdar, Caleb J. Gammon, Patrick D. Livingston, Fabrizio Pin, et al.; co-corresponding author Andrea Bonetto (University of Colorado Anschutz)

Key points

  • Preclinical and translational study identifying a signaling relay in which tumor-derived FGF21 stimulates the liver to produce the hepatokine IGFBP1, which promotes osteoclast formation, muscle atrophy and bone loss.
  • IGFBP1 levels were about twice as high in people with colorectal cancer as in healthy individuals, and particularly high in patients with liver metastases.
  • Genetic or pharmacological inhibition of IGFBP1 preserved muscle and bone and improved muscle strength in models despite ongoing tumor growth.
  • Deleting tumor-derived FGF21 reduced hepatic IGFBP1 and lessened musculoskeletal wasting.
  • Blocking the pathway did not consistently reduce tumor burden; the benefit was on musculoskeletal health rather than tumor control.

Key limitations

  • Predominantly mouse-model data; human evidence is limited to circulating IGFBP1 measurements.
  • No clinical intervention has been tested; patient numbers for the human comparisons were not available in the sources consulted.
  • Blocking the axis did not consistently reduce tumor burden.

Future directions

  • Development of IGFBP1- or FGF21-directed therapies for clinical testing in cancer cachexia.
  • Validation of circulating IGFBP1 as a biomarker of cachexia risk in colorectal cancer cohorts.
  • Study of the axis alongside chemotherapy, which can itself worsen muscle and bone loss.

Cachexia, a syndrome of progressive loss of skeletal muscle and often bone, affects many patients with advanced colorectal cancer and is associated with reduced physical function, poorer tolerance of chemotherapy and shorter survival. It cannot be fully reversed by nutritional support, and no therapy reliably prevents it. Understanding the signals by which tumors drive wasting of distant tissues is therefore a priority for supportive oncology, particularly in metastatic colorectal cancer, where the liver is frequently involved.

Liver dysfunction has increasingly been linked to cachexia, and the liver secretes hormone-like proteins, or hepatokines, that can act on muscle and bone. Whether tumor-driven changes in liver signaling directly cause musculoskeletal decline, however, has been unclear. FGF21 is a stress-responsive hormone with metabolic effects, and IGFBP1 is a liver-derived binding protein for insulin-like growth factors. Huot, Bonetto and colleagues at Indiana University School of Medicine and the University of Colorado Anschutz set out to determine whether a tumor-to-liver relay could explain musculoskeletal wasting in colorectal cancer.

The investigators used several mouse models of colorectal cancer and compared findings with measurements in people with colorectal cancer and healthy individuals. They examined circulating and hepatic IGFBP1, its effects on osteoclast formation, muscle atrophy and bone, and the upstream role of tumor-derived FGF21. Interventions included genetic and pharmacological inhibition of IGFBP1 and deletion of FGF21 in tumor cells, with outcomes including muscle mass, muscle strength and bone measures. The paper was received in May 2025 and accepted in August 2026; the 23 authors span departments of anatomy, pathology, endocrinology, hepatology, informatics and orthopedics.

The central finding is that tumor-derived FGF21 stimulates the liver to produce IGFBP1, and that IGFBP1 is elevated in colorectal cancer patients and in several mouse models. According to the university's summary, IGFBP1 levels were about twice as high in people with colorectal cancer as in healthy individuals and particularly high in patients whose cancer had spread to the liver. In mouse models, IGFBP1 promoted osteoclast formation, muscle atrophy and bone loss, establishing it as a mediator linking the tumor, the liver and the musculoskeletal system.

Interrupting the relay protected muscle and bone. Genetic or pharmacological inhibition of IGFBP1 preserved muscle and bone mass and improved muscle strength despite ongoing tumor growth, and deleting FGF21 from tumor cells reduced hepatic IGFBP1 and lessened musculoskeletal wasting. Blocking the pathway did not consistently reduce tumor burden, indicating that its value would lie in preserving musculoskeletal health and function rather than in direct anticancer activity. The approach could therefore complement, rather than replace, anticancer therapy.

The work is largely preclinical. The human data in the available summaries are limited to circulating IGFBP1 levels, and the size of the patient comparison groups could not be verified. Mouse models of cachexia do not fully reproduce the slower, multifactorial wasting seen in patients, who are also exposed to chemotherapy, reduced intake and inflammation. Whether IGFBP1 inhibition is safe in humans, given the protein's normal roles in growth factor and glucose regulation, is unknown, and no clinical-grade inhibitor has yet been tested in patients.

The authors propose the FGF21-IGFBP1 axis as a therapeutic target for preserving musculoskeletal health in colorectal cancer cachexia. Next steps include developing inhibitors suitable for clinical testing, validating circulating IGFBP1 as a biomarker to identify patients at risk of wasting, and examining how the axis interacts with chemotherapy, which can itself aggravate muscle and bone loss. If confirmed in patients, the findings would add a mechanistically defined, liver-centered target to the limited options for cancer cachexia.

Source: Huot et al., "An FGF21-IGFBP1 tumor-liver relay drives musculoskeletal defects in colorectal cancer cachexia," Nature Communications, published August 27, 2026. Read the paper

7. Colorectal cancer causes peripheral nerve damage before chemotherapy in preclinical models (Nature Communications)

Senior author Andrew Shepherd (Department of Translational Neuroscience, The University of Texas MD Anderson Cancer Center), et al.; full author list not verified

Key points

  • Preclinical study in mouse and primate models of naturally developing colorectal cancer, led by MD Anderson Cancer Center.
  • Tumor-bearing animals developed peripheral neuropathy with subtle locomotor deficits before any chemotherapy.
  • Affected nerves showed inflammation, macrophage accumulation and myelin changes, with alterations in fat metabolism.
  • An anti-inflammatory drug reduced some early abnormalities but did not prevent all nerve injury; macrophage removal was also tested.
  • No human data were included; the authors call for nerve-function studies in patients before, during and after chemotherapy.

Key limitations

  • Preclinical models only, with no human samples or patient outcomes.
  • Quantitative results, sample sizes and the exact publication date were not available in the sources consulted.
  • Inflammation did not account for all nerve injury, so the mechanism is incomplete.

Future directions

  • Baseline nerve-function assessment in patients before oxaliplatin-based chemotherapy.
  • Testing whether pre-existing nerve damage increases vulnerability to chemotherapy-induced neuropathy.
  • Studies across colorectal cancer subtypes and of interventions targeting macrophages and inflammation.

Peripheral neuropathy is one of the most burdensome long-term effects of colorectal cancer treatment, largely attributed to oxaliplatin, a cornerstone of adjuvant and metastatic chemotherapy. Persistent numbness, pain and impaired balance can affect quality of life for years in survivors and frequently force dose reduction or early discontinuation. The prevailing assumption has been that neuropathy in these patients is a consequence of treatment, but whether the cancer itself damages peripheral nerves before therapy begins has received little attention.

Cancer-associated neuropathy independent of treatment is recognized in some settings, such as paraneoplastic syndromes, but has not been systematically examined in colorectal cancer. If tumors injure nerves before chemotherapy, some of the neuropathy attributed to oxaliplatin might reflect pre-existing damage, and patients with subclinical nerve injury could be more vulnerable to neurotoxic drugs. Andrew Shepherd's group at The University of Texas MD Anderson Cancer Center studies how cancer and its treatment affect the nervous system, which motivated a look at nerves in tumor-bearing animals before any treatment.

The investigators used preclinical models in which colorectal cancer develops naturally, including mouse and primate models according to the institutional summary. They assessed nerve structure and function, locomotor behavior, inflammation, macrophage infiltration, myelin and fat metabolism in the peripheral nerves of tumor-bearing animals. To probe mechanisms, they tested an anti-inflammatory drug and depletion of macrophages. The study did not include human samples or patient outcomes, and specific sample sizes and effect sizes were not reported in the summaries consulted for this roundup.

Tumor-bearing mice developed peripheral neuropathy accompanied by subtle locomotor deficits, before receiving any chemotherapy. The affected nerves showed inflammation, accumulation of macrophages and changes in myelin, the insulating sheath that supports nerve conduction, along with alterations in fat metabolism. Shepherd described the findings as advancing understanding of how colorectal cancer can damage the peripheral nervous system, noting that the damage is largely latent and could have major implications for quality of life in survivors.

Mechanistic experiments suggested that inflammation contributes but is not the whole story: an anti-inflammatory drug reduced some early abnormalities but did not prevent all nerve injury. This implies that other tumor-driven processes, possibly involving metabolic changes in the nerve, also play a role. The observation of similar changes in more than one species, as reported by the institution, raises the possibility that the phenomenon is conserved, though this has not been established in humans.

The study is entirely preclinical. Animal models of colorectal cancer may not reproduce the timing, tumor burden or systemic effects seen in patients, and the clinical relevance of subtle locomotor deficits in animals is uncertain. Quantitative results were not available in the sources consulted, so the magnitude of the effects cannot be judged here, and the paper itself could not be accessed directly; its publication date is inferred from news coverage dated August 20 and August 26, 2026. Whether pre-treatment nerve damage increases susceptibility to oxaliplatin neurotoxicity remains an open question.

If confirmed in patients, these findings would reframe neuropathy in colorectal cancer as partly a disease effect, with practical implications: baseline neurological assessment before oxaliplatin could identify patients at higher risk, and part of the neuropathy seen after treatment might be preventable by targeting tumor-driven inflammation or macrophage activity. The authors call for studies of nerve function in patients before, during and after chemotherapy and across colorectal cancer subtypes, which would be a feasible next step within existing adjuvant trials.

Source: Shepherd and colleagues, MD Anderson Cancer Center, Nature Communications, August 2026 (exact publication date not verified; reported August 20, 2026). Read the paper · Coverage (The ASCO Post)