Open questions — colorectal adenocarcinoma¶

Last curated: 2026-08-30. These are concrete questions exposed by the assembled evidence, not a list of fashionable topics. Stable identifiers are retained as questions evolve; a resolved question moves to Closed with the closing evidence.

How to read priority¶

Tier 1 questions could change practice, screening policy or the biological model and can be studied now. Tier 2 questions are important but narrower, dependent on infrastructure, or downstream of a Tier-1 answer. Priority is curator judgment rather than a formal evidence grade.

Dots not yet connected¶

Each row joins two mature evidence streams whose missing junction could produce a tractable study.

#	Dot A	Dot B	The missing junction	Powers
D1	Postoperative ctDNA strongly stratifies recurrence risk and reduced chemotherapy use in stage II disease (PMID 35657320)	Adjuvant benefit varies by stage and clinicopathologic risk (PMID 26527776)	As of a PubMed search updated through 2026-08-30, outcome evidence remains insufficient for one assay/timing/action algorithm to prove survival benefit across stages	OQ-1, OQ-2
D2	Complete clinical response permits organ preservation in selected rectal cancer (PMID 35483010)	Long-term organ preservation is feasible in a response-adapted program (PMID 37883738)	Response definition, surveillance intensity and community reproducibility have not been standardized against radical surgery	OQ-3
D3	MSI-high/dMMR tumors respond dramatically to checkpoint blockade (PMID 33264544)	Most colorectal cancers are mismatch-repair proficient with immune-excluded or stromal phenotypes (PMID 26457759)	PubMed searches updated through 2026-08-30 identify combination signals and randomized phase II studies, but reproducible phase III selection and benefit for a defined pMMR/MSS subgroup remain unestablished	OQ-4
D4	Consensus molecular subtypes integrate epithelial and stromal biology (PMID 26457759)	Retrospective analysis within a randomized trial reports CMS-treatment interactions (PMID 37018649)	No trial has yet assigned treatment prospectively using a locked CMS classifier and shown improved outcomes as of 2026-08-30	OQ-5
D5	Young-onset incidence is rising internationally (PMID 37105987)	Known hereditary syndromes explain only a minority of all colorectal cancers (PMID 35361330)	Prospective exposure, germline, somatic, microbiome and life-course data have not converged on preventable causes	OQ-6
D6	Colonoscopy can remove precursors, but invitation benefit is participation-sensitive (PMID 36214590)	FIT effectiveness requires repeated adherence and diagnostic follow-up (PMID 39028667)	Few programs optimize the entire screening cascade using randomized implementation designs and equity endpoints	OQ-7
D7	Serrated lesions follow distinct molecular and morphologic pathways (PMID 35361330)	Interval cancers cluster in settings compatible with missed or incompletely resected lesions	Detection-quality metrics are not consistently linked to molecularly characterized post-colonoscopy cancers	OQ-8
D8	Triplet/doublet cytotoxic and biologic combinations improve disease control in metastatic settings (PMID 32164906)	Financial toxicity and neuropathy persist beyond conventional efficacy endpoints (PMID 38182993, 29280005)	Treatment sequencing has not been optimized under patient-weighted net-benefit functions	OQ-9, OQ-22
D9	Liver metastasis resectability is dynamic and multidisciplinary (PMID 33591350)	ctDNA can detect molecular residual disease after curative-intent treatment	PubMed search updated through 2026-08-30 found prognostic and observational studies but no randomized post-metastasectomy ctDNA strategy selecting surveillance, systemic therapy or repeat local intervention	OQ-10
D10	Germline findings create actionable risk for relatives (PMID 33857637)	A Swedish randomized trial found no significant uptake advantage for offering direct letters over family-mediated disclosure (PMID 40745491)	The effective model in lower-uptake, geographically fragmented and legally diverse systems remains undefined	OQ-11
D11	Low anterior resection syndrome impairs quality of life (PMID 32530135)	Organ-preservation protocols can avoid rectal resection in responders (PMID 37883738)	Trials rarely compare long-term bowel, sexual and social function using a common patient-weighted framework	OQ-12
D12	Biomarker-defined therapies create small molecular subgroups	Trial participation and molecular testing are inequitably distributed	As of 2026-08-30, the evidence map contains disparity studies but no validated learning-system measure spanning tissue acquisition, testing, interpretation, treatment access and outcome by social group	OQ-13

When evidence closes a junction, update the row and sharpen or close the question it powers.

Tier 1 — field-changing and currently testable¶

OQ-1. Does ctDNA-guided intervention improve survival, rather than only refine prognosis or reduce chemotherapy use?¶

DYNAMIC showed that a ctDNA-guided approach in stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival within the trial's noninferiority design, but it did not establish that treating ctDNA positivity itself improves overall survival (Tie 2022, PMID 35657320). The decisive design randomizes intervention within a standardized postoperative molecular-residual-disease state, locks assay and sampling times, and follows disease-free and overall survival, toxicity and cost. → biomarkers and liquid biopsy, localized colon cancer

OQ-2. Which ctDNA assay, sampling schedule and threshold are portable across stages and treatments?¶

Tumor-informed and tumor-naïve assays differ in target selection, analytic sensitivity, false-positive mechanisms and dependence on tissue. Perioperative shedding, low-volume lung/peritoneal disease and clonal hematopoiesis complicate interpretation. Cross-platform prospective comparison on the same specimens, with blinded adjudication and prespecified clinical actions, is needed before “ctDNA-positive” can be treated as a universal state (PMID 35657320, 39675560). → biomarkers and liquid biopsy

OQ-3. Can watch-and-wait for rectal cancer be made reproducible outside expert organ-preservation programs?¶

OPRA supports response-adapted organ preservation and salvage, but the strategy depends on expert response assessment, repeated MRI/endoscopy/examination and reliable access to salvage surgery (Garcia-Aguilar 2022, PMID 35483010; Verheij 2024, PMID 37883738). A pragmatic comparison should measure local control, distant metastasis, stoma-free survival, bowel/sexual function, surveillance burden and failures caused by missed follow-up. → localized rectal cancer, survivorship

OQ-4. Can any biologically defined pMMR/MSS colorectal-cancer subgroup be made reliably checkpoint-responsive?¶

KEYNOTE-177 established first-line pembrolizumab benefit in MSI-high/dMMR metastatic disease, leaving the majority pMMR/MSS population without comparable immune sensitivity (André 2020, PMID 33264544). Radiation, antiangiogenic, targeted, bispecific, vaccine and cellular combinations generate signals but no general conversion rule. Trials need mechanistic entry criteria, paired tissue and explicit evidence that immune remodeling mediates clinical response. → molecular subtypes, precision oncology

OQ-5. Does any consensus molecular subtype predict treatment benefit prospectively beyond standard biomarkers?¶

The CMS framework reproducibly organizes colorectal cancers into four biological classes, but it is predominantly prognostic/descriptive and can be confounded by stromal content and sampling site (Guinney 2015, PMID 26457759). PanaMa reported treatment interactions in a retrospective CMS analysis nested within a randomized trial, which is hypothesis-generating rather than prospective classifier utility (Stahler 2023, PMID 37018649). A prospective trial must lock the classifier, return results fast enough to assign treatment, stratify by MSI/RAS/BRAF/HER2 and test whether CMS-guided assignment improves outcomes. → molecular subtypes

OQ-6. What is causing the rise in young-onset colorectal cancer, and which causes are preventable?¶

The trend is established, but proposed explanations—adiposity, diet, antibiotics, metabolic disease, birth-cohort exposures and microbiome change—remain incompletely separated from diagnostic intensity and each other (Spaander 2023, PMID 37105987; Islami 2024, PMID 37962495). The needed platform begins before diagnosis and links longitudinal exposure records, biospecimens, germline and tumor features across countries and ancestry groups. → epidemiology, hereditary syndromes

OQ-7. Which screening program maximizes completed diagnostic pathways and mortality reduction under real-world participation?¶

NordICC showed that invitation to colonoscopy produced a modest intention-to-screen effect amid limited participation, while FIT depends on repeated completion and timely colonoscopy after an abnormal result (Bretthauer 2022, PMID 36214590; Doubeni 2024, PMID 39028667). Head-to-head program trials should randomize invitation, navigation and follow-up—not merely test technology—and report cancer mortality, stage, complications, completion and disparities. → screening and early detection

OQ-8. Can detection and complete resection of serrated lesions be improved enough to reduce post-colonoscopy cancers?¶

Sessile serrated lesions are subtle, proximal and variably recognized; their biology differs from conventional adenomas (Sullivan 2022, PMID 35361330). The missing proof chain links operator-level detection and resection quality to molecularly characterized interval cancers and then tests whether targeted training, imaging or surveillance reduces them without disproportionate procedural burden. → adenoma and serrated pathways, screening

OQ-9. What first-line metastatic sequence maximizes lifetime benefit rather than first progression-free survival?¶

TRIBE2 supports an intensive triplet strategy in selected patients, but real care includes molecularly targeted options, maintenance, local therapy, cumulative neuropathy and attrition before later lines (Cremolini 2020, PMID 32164906; Biller 2021, PMID 33591350). Strategy trials need treatment-sequence estimands, quality-adjusted survival, molecular resistance sampling and the proportion who actually reach each planned line. → metastatic systemic therapy, precision oncology

OQ-10. Can molecular residual disease guide therapy after resection or ablation of colorectal metastases?¶

Curative-intent liver or lung treatment is followed by frequent recurrence, yet anatomic risk scores incompletely capture residual disease (Biller 2021, PMID 33591350). Prospective trials should test whether postoperative ctDNA can select systemic therapy, intensified surveillance or repeat local treatment, while accounting for low-shedding sites and intervention-triggered lead-time bias. → liver and lung metastasis, biomarkers

OQ-11. Which cascade-testing model actually reaches relatives while preserving autonomy and privacy?¶

Universal tumor/germline pathways identify inherited risk only if results move through families. Cascade testing loses eligible relatives through communication, cost, geography and fragmented responsibility (Uson 2022, PMID 33857637). A Swedish randomized trial found 71% counselling uptake with an offer of direct letters versus 67% with family-mediated disclosure alone (adjusted OR 1.24, 95% CI 0.79–1.95), so the remaining question is which model improves outcomes where baseline uptake is lower and systems are more fragmented (Ehrencrona 2025, PMID 40745491). Future comparisons should measure verified testing, distress, privacy harms and downstream prevention. → hereditary syndromes and genetics

OQ-12. Can rectal-cancer treatment be selected using a common patient-weighted functional endpoint?¶

TNT, surgery, radiotherapy and watch-and-wait trade disease control against low anterior resection syndrome, stoma, sexual/urinary dysfunction and surveillance (Bahadoer 2021, PMID 33301740; Pieniowski 2020, PMID 32530135; Verheij 2024, PMID 37883738). A core endpoint integrating organ preservation, oncologic failure and long-term function would make regimens comparable in the dimensions patients actually live with. → localized rectal cancer, patient experience

OQ-13. Where in the precision-oncology cascade do inequities arise, and which intervention closes them?¶

Having an actionable alteration is not equivalent to receiving matched treatment. Tissue adequacy, ordering, turnaround, interpretation, insurance, specialist referral and trial geography can each fail, against a background of documented colorectal-cancer disparities (Islami 2024, PMID 37962495; Tobin 2023, PMID 36890731). A prospective cascade registry with randomized navigation interventions should report each transition by race, rurality, disability, language and socioeconomic position. → precision oncology, patient experience

Tier 2 — important, narrower or infrastructure-dependent¶

Prevention and early detection¶

OQ-14. What is the least burdensome safe surveillance strategy after adenoma or serrated-polyp removal? Interval recommendations extrapolate from heterogeneous observational risk, while procedural burden and capacity are real. Comparative interval studies should use cancer incidence, advanced neoplasia, complications and colonoscopy demand (PMID 32044092, 35361330). → screening, guideline registry
OQ-15. Can multi-cancer or blood-based screening reduce colorectal-cancer mortality without weakening precursor prevention? Blood tests may improve acceptance but generally do not remove adenomas, and stage-shift surrogates can mislead. Randomized mortality endpoints and downstream-colonoscopy accounting are essential (PMID 39028667, 38477985). → screening, biomarkers
OQ-16. How should screening be individualized after age 75 or with serious comorbidity? Average-risk age cutoffs do not resolve competing mortality, prior screening, procedural risk and individual preferences. Decision trials should test benefit-harm communication and actual outcomes, not only model predictions (PMID 33657038, 37105987). → screening
OQ-17. Which intervention most improves diagnostic colonoscopy after an abnormal stool test? The cascade fails after a positive result through communication, access, preparation and transport. Navigation strategies need randomized comparison with completion time, stage and equity outcomes (PMID 27197277, 35705780). → screening, patient experience

Localized disease¶

OQ-18. Which stage II colon cancers benefit enough from chemotherapy to justify toxicity? Clinicopathologic risk, MMR and emerging ctDNA signals overlap but are not interchangeable. A prospective decision model must test predictive interaction, not merely recurrence association (PMID 26527776, 35657320). → localized colon cancer
OQ-19. Can adjuvant duration be individualized using residual-risk dynamics? IDEA established duration tradeoffs at group level, but neuropathy, regimen, stage and molecular residual disease could support adaptive stopping or escalation (PMID 33271092, 29280005). → localized colon cancer, survivorship
OQ-20. Which total-neoadjuvant strategy is best for which rectal tumor? RAPIDO, PRODIGE 23 and STELLAR differ in radiation, chemotherapy, sequencing, eligibility and endpoints; indirect comparison is fragile (PMID 33301740, 33862000, 35263150). A biomarker- and MRI-stratified platform trial could separate systemic-risk control from organ-preservation goals. → localized rectal cancer
OQ-21. Can local excision plus response-adapted therapy safely preserve the rectum in earlier-stage disease? The target population differs from locally advanced watch-and-wait, and undertreated nodal disease remains the central risk. Trials need meticulous MRI/pathology, completion-surgery rules and long-term function. (PMID 35483010, 37883738). → localized rectal cancer

Metastatic and precision treatment¶

OQ-22. Can cumulative neuropathy be prevented without sacrificing cure or control? Oxaliplatin exposure is modifiable, but prevention interventions remain limited and symptom/function endpoints are inconsistent (Kuriyama 2018, PMID 29280005). Pragmatic dose-adaptation studies should integrate recurrence risk and patient-valued function. → survivorship
OQ-23. What is the optimal therapy after acquired resistance to targeted treatment? Anti-EGFR rechallenge, HER2, BRAF and KRAS-directed strategies depend on evolving subclones; archival tissue can be misleading. Serial ctDNA-guided trials should test whether resistance decay or emergence predicts benefit (PMID 33591350, 39675560). → precision oncology
OQ-24. Who benefits from aggressive conversion therapy followed by metastasis-directed treatment? Response alone can select favorable biology and exaggerate apparent benefit. Prospective multidisciplinary criteria and randomized strategy comparisons are needed (PMID 32164906, 33591350). → liver and lung metastasis
OQ-25. When does local therapy add value in oligometastatic colorectal cancer? Surgery, ablation and stereotactic radiation are used across anatomically and biologically different states. Trials must distinguish genuinely limited disease from temporarily visible disease and report systemic-therapy-free time, complications and survival (PMID 33591350). → liver and lung metastasis

Survivorship, experience and systems¶

OQ-26. Which intervention prevents or treats low anterior resection syndrome most effectively? High prevalence and quality-of-life impact are established, but comparative effectiveness across diet, medication, irrigation, rehabilitation, neuromodulation and stoma is uncertain (Pieniowski 2020, PMID 32530135; Wiltink 2020, PMID 32025805). → survivorship
OQ-27. Can proactive sexual-health care improve outcomes rather than only document dysfunction? Dysfunction and counseling gaps are clear, while intervention evidence remains small and heterogeneous (Wallington 2021, PMID 32777386; Arthur 2018, PMID 29947348). → survivorship, patient experience
OQ-28. Which financial-navigation interventions reduce hardship and treatment disruption? Financial toxicity is documented, especially during prolonged metastatic treatment, but service availability is not outcome evidence (Azzani 2024, PMID 38182993; Bhimani 2022, PMID 36063775). Trials should measure debt, work loss, adherence, quality of life and survival. → patient experience
OQ-29. How can surveillance reduce recurrence anxiety while preserving detection benefit? Follow-up can reassure and repeatedly reactivate threat; watch-and-wait intensifies this dual role. Comparative models should integrate oncologic outcomes with distress and function (PMID 36988922, 37883738). → survivorship
OQ-30. What adaptations make screening and treatment genuinely accessible to people with disabilities? Structural barriers in equipment, communication, transport and assumptions about quality of life are documented but colorectal-specific intervention evidence is thin (Iezzoni 2022, PMID 35358465; Honein-AbouHaidar 2016, PMID 27197277). → patient experience, screening

Closed¶

(None at this build. Move a question here only when outcome-level evidence resolves it; record the closing date and citation.)