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Metastatic colorectal cancer (mCRC) patients respond differently to chemotherapy, and early identification of patients with limited or no clinical benefit could prompt treatment switching with improved outcomes. We examined CEA and circulating tumor DNA (ctDNA) dynamics during first-line oxaliplatin-based chemotherapy, and their association with radiological response/survival ( N = 40). ctDNA dynamics hold prognostic value, supporting the idea of prospectively validating a ctDNA-response framework early in the care pathway. Introduction: Patients with metastatic colorectal cancer (mCRC) respond differently to first-line chemotherapy. Early identification of patients with limited or no clinical benefit could prompt a timelier introduction of second-line therapy and potentially lead to improved overall outcomes. Carcinoembryonic antigen (CEA) is currently the only blood-based marker in clinical use for disease control monitoring in mCRC. Circulating cell-free DNA (cfDNA), including circulating tumor DNA (ctDNA) could become a useful surrogate for oncological outcomes. Materials and methods: Forty patients with RAS-/BRAF-mutated mCRC from the prospective NORDIC-VII trial (NCT00145314) were included. An exploratory model system was made to describe the early on-treatment kinetics of CEA, cfDNA and ctDNA during first-line oxaliplatin-based chemotherapy, and investigate the associations with radiological response, progression-free survival (PFS) and overall survival (OS). Results: Summary metrics were made, representing percentage change from treatment start to time-grid day 7 (P-7), day 14 (P-14), and day 49 (P-49); slope from time-grid day 0 to 7 (S-7), day 8 to 14 (S-14), and day 15 to 49 (S-49); and area under the curve from time-grid day 0 to 49 (AUC). Notably P-49 and S-49 for ctDNA and CEA were associated with radiological response and/or PFS. The early dynamics of the two markers differed substantially, with faster and more marked changes in ctDNA compared with CEA. Nine patients did not reach complete/near complete molecular ctDNA response close to first evaluation (similar to week 8), a state associated with a short PFS (HR 2.72; 95% CI, 1.22-6.06; P = .01) and OS (HR 3.12; 95% CI, 1.35-7.23; P < .01). Contrary, twenty-two patients did not reach radiological response (i.e., complete or partial response) at first evaluation, but this was not associated with PFS (HR 1.21; 95% CI, 0.64-2.30; P = .55) nor OS (HR 1.37; 95% CI, 0.70-2.68; P = .37). Conclusion: Early dynamics of ctDNA during first-line oxaliplatin-based chemotherapy hold prognostic value, supporting the idea of prospectively validating a ctDNA-RECIST framework in the early care pathway of mCRC patients. Trial registration: ClinicalTrials.gov, NCT00145314.

Background

The FOxTROT trial has reported advantages of neoadjuvant chemotherapy (NAC) in locally advanced colon cancer (LACC). In this article, we present results of the embedded randomised phase II trial testing the addition of panitumumab to neoadjuvant FOLFOX compared with FOLFOX alone in RAS and BRAF-wild-type (wt) patients and with biomarker hyperselection.

Patients and methods

Patients had operable, computed tomography-predicted stage T3-4, N0-2, M0 colon adenocarcinoma. KRAS-wt patients allocated to NAC could optionally be sub-randomised 1 : 1 to FOLFOX ± panitumumab during the preoperative phase. RAS/BRAF were tested by next-generation sequencing; and epiregulin (EREG)/amphiregulin (AREG) by RNAseq. The primary endpoint was time to recurrence (TTR) in RAS/BRAF-wt patients; secondary endpoints included safety, histological down-staging, disease-free survival (DFS), colon cancer-specific survival (CCSS), overall survival (OS) and impact of primary tumour location and EREG/AREG.

Results

In total 269 KRAS-wt patients were enrolled into the embedded phase II trial. Extended RAS/BRAF data were available for 232 (83%) patients; 22/232 (9.5%) were RAS-mutant; 41/210 (20%) were BRAF-mutant. Median follow-up was 42 months. In 169 RAS/BRAF-wt patients, there was a trend towards reduced recurrences with FOLFOX plus panitumumab compared with FOLFOX (12% versus 21%, hazard ratio = 0.51, P = 0.09); significant improvements were seen for DFS, CCSS and OS. Within the hyperselected EREG/AREG-high group, there was significant reduction in recurrences with panitumumab. Panitumumab was not associated with increased pathological regression of the primary tumour (tumour regression grade 1-3 16% versus 22%, P = 0.27). FOLFOX plus panitumumab was associated with higher rates of grade 3 diarrhoea (8% versus 3%) and rash (22% versus 2%).

Conclusion

This exploratory analysis from a randomised phase II study shows a non-significant improvement in TTR from the addition of neoadjuvant panitumumab to perioperative FOLFOX in RAS/BRAF-wt LACC. Hyperselection with EREG/AREG status was associated with increased efficacy. A dedicated prospective trial within a biomarker-selected population is under development.

PURPOSE

The ESPAC4 trial showed that adjuvant chemotherapy with gemcitabine plus capecitabine (GemCap) produced longer overall survival (OS) than gemcitabine monotherapy. Subsequently, the PRODIGE24-CCTG PA.6 trial showed even longer survival for modified fluorouracil, folinic acid, irinotecan, and oxaliplatin (mFOLFIRINOX) than gemcitabine but had more restrictive eligibility criteria. Our aim was to analyze the ESPAC4 survival on long-term follow-up.

METHODS

The OS of 732 ESPAC4 patients comparing 367 randomly assigned to gemcitabine and 365 to GemCap was previously reported after a median follow-up time of 43.2 months (95% CI, 39.7 to 45.5) and 458 deaths. Analysis was now carried out after a median follow-up of 104 months (101-108) and 566 deaths.

RESULTS

The median OS was 29.5 months (27.5-32.1) for all patients, 28.4 months (25.2-32.0) in the gemcitabine group and 31.6 months (26.5-38.0) in the GemCap group (hazard ratio [HR], 0.83 [0.71 to 0.98]; P = .031). R0 patients given gemcitabine had a median survival of 32.2 months (27.9-41.6) compared with 49.9 months (39.0-82.3) for those given GemCap (HR, 0.63 [0.47 to 0.84]; P = .002). Lymph node-negative patients had significantly higher 5 year OS rates on GemCap (59% [49%-71%]) than gemcitabine (53% [42%-66%]; HR, 0.63 [0.41 to 0.98]; P = .04) but not those with positive lymph nodes (P = .225). The OS advantage for GemCap was retained in the PRODIGE24 subgroup of 193 (26.4%) ESPAC4 patients not eligible for PRODIGE24 with a median survival of 20.7 (16.2-27.3) months in patients allocated to gemcitabine compared with 25.9 (22.3-30.2) months for ineligible patients allocated to GemCap (HR, 0.71 [95% CI, 0.52 to 0.98]; chi 2log-rank-1df = 4.31; P = .038).

CONCLUSION

GemCap is a standard option for patients not eligible for mFOLFIRINOX. Exploratory evidence suggests that GemCap may be particularly efficacious in R0 patients and also in lymph node-negative patients.

Background

Perineal wound complications (PWCs) occur in 15–30% of patients after abdominoperineal excision (APE) and are associated with adverse events, such as delayed wound healing, prolonged hospitalization, a delay in initiating postoperative chemotherapy, and decreased quality of life. Preoperative radiotherapy and chemotherapy are risk factors for wound complications. It is unknown whether total neoadjuvant treatment (TNT) affects the risk of PWCs compared with chemoradiotherapy (CRT).

Methods

This study compared patients from the experimental (EXP; short-course radiotherapy, chemotherapy, and surgery as TNT) and standard-of-care (STD; CRT, surgery, and postoperative chemotherapy depending on hospital policy) treatment arms of the RAPIDO trial who underwent APE within 6 months after preoperative treatment. The primary outcome was the incidence of PWCs (infection, abscess, dehiscence, wound discharge, presacral abscess affecting the perineum) of any grade ≤ 30 days after APE. Secondary outcomes were the incidence of PWCs >30 days after APE, length of hospital stay, characteristics associated with PWCs, and oncological outcomes in patients with versus without PWC.

Results

Of the 901 patients who started treatment (460 in EXP arm, 441 in STD arm), 153 (33%) and 160 (36%) underwent APE after TNT and CRT, respectively. After TNT and CRT, the incidence of PWCs ≤30 days after APE, readmission, and reoperation was 54 of 153 (35%) versus 53 of 160 (33%) (P = 0.69), 9% versus 12% (P = 0.54), and 7% versus 8% (P = 0.75), respectively. The median length of hospital stay was 2–3 days longer for patients with PWC. Univariable analysis revealed that pretreatment albumin <35 g/l, hypertension, and haemoglobin ≤ 8.0 mmol/l were associated with PWC. Oncological outcomes were similar between patients with and without PWCs.

Conclusion

In the RAPIDO trial, TNT and CRT resulted in a similar incidence of PWCs among patients with high-risk locally advanced rectal cancer who underwent APE.

Background

Patients with inflammatory bowel disease have an increased risk of colorectal cancer. There is a scarcity of large studies with a focus on rectal cancer in patients with inflammatory bowel disease. This study aimed to compare survival in resected patients with rectal cancer with and without inflammatory bowel disease.

Methods

This national population-based study used the Colorectal Cancer Data Base. All Swedish patients ≥18 years of age with a diagnosis of stage I–III rectal cancer between 1997 and 2021, surgically treated with curative intent, were included and followed up until 2022. The outcome of interest was recurrence-free survival. Flexible parametric survival models adjusted for time since surgery, year of diagnosis, sex, age at diagnosis, and Charlson Co-morbidity Index were used to estimate proportional and time-dependent hazard ratios of recurrence-free survival with 95% confidence intervals.

Results

Overall, 22 082 patients with rectal cancer were included, among whom 323 (1.5%) had inflammatory bowel disease. Neoadjuvant radiotherapy/chemoradiotherapy was given to 55% and 63% of patients with and without inflammatory bowel disease respectively. The median follow-up time was 5.2 years (interquartile range (i.q.r.) 2.3–10) in patients with inflammatory bowel disease and 5.9 years (i.q.r. 2.9–10) in patients without inflammatory bowel disease. Based on the adjusted proportional hazards model, no overall difference in recurrence-free survival was found (HR 1.05, 95% c.i. 0.87 to 1.26). In the time-dependent adjusted model, patients with rectal cancer with inflammatory bowel disease experienced a lower recurrence-free survival during the first year after surgery (1 year HR 1.36, 95% c.i. 1.06 to 1.73), after which there was no difference in comparison with patients without inflammatory bowel disease (5 years HR 0.77, 95% c.i. 0.56 to 1.06).

Conclusion

Despite lower recurrence-free survival during the first year among those with inflammatory bowel disease, there were no long-term differences between patients with or without inflammatory bowel disease.

BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.

Rectal cancer poses challenges in preoperative treatment response, with up to 30% achieving a complete response (CR). Personalized treatment relies on accurate identification of responders at diagnosis. This study aimed to unravel CR determinants, overall survival (OS), and time to recurrence (TTR) using clinical and targeted sequencing data. Analyzing 402 patients undergoing preoperative treatment, tumor stage, size, and treatment emerged as robust response predictors. CR rates were higher in smaller, early-stage, and intensively treated tumors. Targeted sequencing analyzed 216 cases, while 120 patients provided hotspot mutation data. KRAS mutation dramatically reduced CR odds by over 50% (odds ratio [OR] = 0.3 in the targeted sequencing and OR = 0.4 hotspot cohorts, respectively). In contrast, SMAD4 and SYNE1 mutations were associated with higher CR rates (OR = 6.0 and 6.8, respectively). Favorable OS was linked to younger age, CR, and low baseline carcinoembryonic antigen levels. Notably, CR and an APC mutation increased TTR, while a BRAF mutation negatively affected TTR. Beyond tumor burden, SMAD4 and SYNE1 mutations significantly influenced CR. KRAS mutations independently correlated with radiotherapy resistance, and BRAF mutations heightened recurrence risk. Intriguingly, non-responding tumors with initially small sizes carried a higher risk of recurrence. The findings, even if limited in addition to the imperfect clinical factors, offer insights into rectal cancer treatment response, guiding personalized therapeutic strategies. By uncovering factors impacting CR, OS, and TTR, this study underscores the importance of tailored approaches for rectal cancer patients. These findings, based on extensive analysis and mutation data, pave the way for personalized interventions, optimizing outcomes in the challenges of rectal cancer preoperative treatment.

Background

Co-occurring mutations in pairs of genes can pinpoint clinically relevant subgroups of cancer. Most colorectal cancers (CRCs) are microsatellite stable (MSS) and have few frequent mutations. Large patient cohorts and broad genomic coverage are needed for comprehensive co-mutation profiling.

Methods

Co-mutations were identified in a population-based Swedish cohort analyzed by whole-genome sequencing (n=819 stage I-IV MSS CRCs). Prognostic value was further evaluated in a publicly available dataset of clinically sequenced metastatic CRCs (MSK-IMPACT; n=934 MSS). Multivariable Cox proportional hazards analyses with clinicopathological parameters were performed for locoregional (stage I-III) and metastatic (stage IV and recurrent) cancers separately.

Results

Prevalent co-mutations were detected in 23 unique gene pairs, 20 of which included APC, TP53, KRAS and/or PIK3CA. Several co-mutations involving APC were associated with good overall survival in locoregional CRC, including APC-TCF7L2 (multivariable HR: 0.49, 95% CI 0.27-0.89). This co-mutation was prognostic also in metastatic cancers (multivariable HR: 0.49 and 0.37, 95% CI: 0.24-0.98 and 0.17-0.82 in the Swedish and MSK cohorts, respectively). APC-SOX9 co-mutations were mutually exclusive with APC-TCF7L2, and the co-mutations combined had stronger prognostic associations than APC alone in both metastatic cohorts. BRAF p.V600E-RNF43 co-mutations were associated with poor overall and recurrence-free survival in locoregional CRC (multivariable HR: 4.13 and 3.2, 95% CI: 1.78-9.54 and 1.53-8.04, respectively).

Conclusions

We report a genome-wide evaluation of co-occurring mutations in MSS CRCs, and suggest that co-mutations can improve the prognostic stratification compared to single mutations alone.