ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by providers and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more . PURPOSE: To provide evidence-based guidance for clinicians who treat patients with locally advanced rectal cancer. METHODS: A systematic review of the literature published from 2013 to 2023 was conducted to identify relevant systematic reviews, phase II and III randomized controlled trials (RCTs), and observational studies where applicable. RESULTS: Twelve RCTs, two systematic reviews, and one nonrandomized study met the inclusion criteria for this systematic review. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RECOMMENDATIONS: Following assessment with magnetic resonance imaging, for patients with microsatellite stable or proficient mismatch repair locally advanced rectal cancer, total neoadjuvant therapy (TNT; ie chemoradiation [CRT] and chemotherapy) should be offered as initial treatment for patients with tumors located in the lower rectum and/or patients who are at higher risk for local and/or distant metastases. Patients without higher-risk factors may discuss chemotherapy with selective CRT depending on extent of response, TNT, or neoadjuvant long-course CRT or short-course radiation. For patients who are candidates for TNT, the preferred timing for chemotherapy is after radiation, and neoadjuvant long-course CRT is preferred over short-course radiation therapy (RT), however short-course RT may also be a viable treatment option depending on circumstances. Nonoperative management may be discussed as an alternative to total mesorectal excision for patients who have a clinical complete response to neoadjuvant therapy. For patients whose tumors are microsatellite instability-high or mismatch repair deficient, immunotherapy is recommended. Additional information is available at http://www.asco.org/gastrointestinal-cancer-guidelines .

PURPOSE: Anti–epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance. METHODS: Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre–anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment. RESULTS: ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including EGFR ( P = .0007), KRAS ( P = .0017), LRP1B ( P = .0046), ZNF217 ( P = .0086), MAP2K1 ( P = .018), PIK3CG ( P = .018), BRAF ( P = .048), and NRAS ( P = .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including EGFR ( P < .0001), SMO ( P < .0001), BRAF ( P < .0001), MET ( P = .0002), FLT3 ( P = .0002), NOTCH4 ( P = .0006), ERBB2 ( P = .004), and FGFR1 ( P = .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without ( P = .010). Although tumor mutation burden (TMB) did not differ pretreatment ( P = .63), anti-EGFR exposure increased TMB ( P = .028), whereas lack of anti-EGFR exposure resulted in declining TMB ( P = .014). CONCLUSION: Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.

PURPOSE: Organ-sparing therapy for early-stage I/IIA rectal cancer is intended to avoid functional disturbances or a permanent ostomy associated with total mesorectal excision (TME). The objective of this phase II trial was to determine the outcomes and organ-sparing rate of patients with early-stage rectal cancer treated with neoadjuvant chemotherapy followed by transanal excision surgery (TES). METHODS: This phase II trial included patients with clinical T1-T3abN0 low- or mid-rectal adenocarcinoma eligible for endoscopic resection who were treated with 3 months of chemotherapy (modified folinic acid–fluorouracil-oxaliplatin 6 or capecitabine-oxaliplatin). Those with evidence of response proceeded to transanal endoscopic surgery 2-6 weeks later. The primary end point was protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1N0/X and who avoided radical surgery. RESULTS: Of 58 patients enrolled, all commenced chemotherapy and 56 proceeded to surgery. A total of 33/58 patients had tumor downstaging to ypT0/1N0/X on the surgery specimen, resulting in an intention-to-treat protocol-specified organ preservation rate of 57% (90% CI, 45 to 68). Of 23 remaining patients recommended for TME surgery on the basis of protocol requirements, 13 declined and elected to proceed directly to observation resulting in 79% (90% CI, 69 to 88) achieving organ preservation. The remaining 10/23 patients proceeded to recommended TME of whom seven had no histopathologic residual disease. The 1-year and 2-year locoregional relapse-free survival was, respectively, 98% (95% CI, 86 to 100) and 90% (95% CI, 58 to 98), and there were no distant recurrences or deaths. Minimal change in quality of life and rectal function scores was observed. CONCLUSION: Three months of induction chemotherapy may successfully downstage a significant proportion of patients with early-stage rectal cancer, allowing well-tolerated organ-preserving surgery.

Purpose: Tissue-derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology-agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset in which this was validated lacked colorectal cancers (CRC), and there is limited evidence for immunotherapy benefits in CRC using this threshold. Patients and Methods: CO.26 was a randomized phase II study of 180 patients, comparing durvalumab and tremelimumab (D + T, n = 119 patients) versus best supportive care (BSC; n = 61 patients). ctDNA sequencing was available for 168 patients (n = 118 D + T; n = 50), of whom 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on OS were determined using a minimal P value approach. This report includes the final OS analysis. Results: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D + T compared with BSC in microsatellite stable (MSS) metastatic CRC [HR, 0.71 (95% CI, 0.28–1.80); P = 0.47]. No tissue TMB threshold could identify a high TMB group that benefited from ICI. By contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D + T [HR, 0.34 (95% CI, 0.13–0.85); P = 0.022], as was clonal pTMB ≥10.6 mutations/Mb [HR, 0.10 (95% CI, 0.014–0.79); P = 0.029] and subclonal pTMB ≥25.9/Mb [HR, 0.20 (95% CI, 0.061–0.69); P = 0.010]. Higher pTMB was associated with length of time on cytotoxic agents (P = 0.021) and prior anti-EGFR exposure (P = 2.44 × 10−06). Conclusions: pTMB derived from either clonal or subclonal mutations may identify a group likely to benefit from immunotherapy, although validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial.