Impact of Primary Tumor Location on Demographics, Resectability, Outcomes, and Quality of Life in Finnish Metastatic Colorectal Cancer Patients (Subgroup Analysis of the RAXO Study).

The primary tumor location (PTL) is associated with the phenotype, metastatic sites, mutations, and outcomes of metastatic colorectal cancer (mCRC) patients, but this has mostly been studied according to sidedness (right vs. left sided). We studied right colon vs. left colon vs. rectal PTL in a real-life study population (n = 1080). Health-related quality of life (HRQoL) was assessed multi-cross-sectionally with QLQ-C30, QLQ-CR29, EQ-5D, and 15D. A chi-square, Kaplan-Meier, and Cox regression were used to compare the groups. The PTL was in the right colon in 310 patients (29%), the left colon in 396 patients (37%), and the rectum in 375 patients (35%). The PTL was associated with distinct differences in metastatic sites during the disease trajectory. The resectability, conversion, and resection rates were lowest in the right colon, followed by the rectum, and were highest in the left colon. Overall survival was shortest for right colon compared with left colon or rectal PTL (median 21 vs. 35 vs. 36 months), with the same trends after metastasectomy or systemic therapy only. PTL also remained statistically significant in a multivariable model. The distribution of symptoms varied according to PTL, especially between the right colon (with general symptoms of metastases) and rectal PTL (with sexual- and bowel-related symptoms). mCRC, according to PTL, behaves differently regarding metastatic sites, resectability of the metastases, outcomes of treatment, and HRQoL.

Clinical and genetic factors associated with tumor response to neoadjuvant (chemo)radiotherapy, survival and recurrence risk in rectal cancer.

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.

Atypical (non-V600E) BRAF mutations in metastatic colorectal cancer in population and real-world cohorts.

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.

Resectability, Resections, Survival Outcomes, and Quality of Life in Older Adult Patients with Metastatic Colorectal Cancer (the RAXO-Study).

Older adults are underrepresented in metastatic colorectal cancer (mCRC) studies and thus may not receive optimal treatment, especially not metastasectomies. The prospective Finnish real-life RAXO-study included 1086 any organ mCRC patients. We assessed repeated centralized resectability, overall survival (OS), and quality of life (QoL) using 15D and EORTC QLQ-C30/CR29. Older adults (>75 years; n = 181, 17%) had worse ECOG performance status than adults (<75 years, n = 905, 83%), and their metastases were less likely upfront resectable. The local hospitals underestimated resectability in 48% of older adults and in 34% of adults compared with the centralized multidisciplinary team (MDT) evaluation (p < 0.001). The older adults compared with adults were less likely to undergo curative-intent R0/1-resection (19% vs. 32%), but when resection was achieved, OS was not significantly different (HR 1.54 [CI 95% 0.9-2.6]; 5-year OS-rate 58% vs. 67%). 'Systemic therapy only' patients had no age-related survival differences. QoL was similar in older adults and adults during curative treatment phase (15D 0.882-0.959/0.872-0.907 [scale 0-1]; GHS 62-94/68-79 [scale 0-100], respectively). Complete curative-intent resection of mCRC leads to excellent survival and QoL even in older adults. Older adults with mCRC should be actively evaluated by a specialized MDT and offered surgical or local ablative treatment whenever possible.

Sex differences in metastatic surgery following diagnosis of synchronous metastatic colorectal cancer.

The aim was to investigate gender differences in the likelihood to receive metastatic surgery, and to compare overall survival between men and women, among patients with synchronous metastatic colorectal cancer (mCRC) in a population-based setting. All Swedish adult patients diagnosed with synchronous mCRC in 2007-2016 were identified using the nationwide colorectal cancer database (CRCBaSe). Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression, comparing the odds of receiving treatment. The Kaplan-Meier method was used to calculate survival proportions and Cox regression models to estimate hazard ratios (HRs) and 95% CIs of all-cause mortality rates. All multivariable models were adjusted for age, ASA score, Charlson comorbidity index, year of diagnosis, location of primary tumor and single or multiple metastatic locations. A total of 12 201 patients met the study criteria. Women received 23% less metastatic surgery for mCRC (adjusted OR = 0.77, CI:0.69-0.86) and experienced a slightly higher mortality following diagnosis (adjusted HR = 1.09, CI:1.05-1.14). In analyses restricted to patients who received metastatic surgery, no significant differences in mortality were found. In conclusion, this population-based study showed that women less often received metastatic surgery of mCRC and experienced slightly higher all-cause mortality compared with men. The differences persisted despite adjustments of patient and cancer characteristics. Gender differences in receiving treatment are unacceptable if the underlying explanation cannot be motivated. Further studies are needed to understand if the differences are based on sex (i.e., biology) or gender (including clinically unmotivated differences in treatment approach).

Temporal development in survival, and gender and regional differences in the Swedish population of patients with synchronous and metachronous metastatic colorectal cancer.

BACKGROUND: Survival in patients with metastatic colorectal cancer (mCRC) has markedly improved in patients included in clinical trials. In population-based materials, improvements were seen until about a decade ago, but it is unclear if survival has continued to improve. It is also unclear if regional or gender differences exist. MATERIAL AND METHODS: All patients with mCRC (N = 19,566) in Sweden between 2007 and 2016 were identified from the national quality register, SCRCR, with almost complete coverage. Overall survival (OS) from diagnosis of metastatic disease was calculated in two calendar periods, 2007-2011 and 2012-2016. Differences between groups were compared using Cox regression. RESULTS: Median age was 72 years, 55% were males, synchronous presentation was seen in 13,630 patients and metachronous in 5936. In synchronous disease, the primary tumour was removed more often during the first than the second period (51% vs 41%, p < 0.001). Median OS (mOS) was 14.0 months. It was longer in those with metachronous than synchronous disease (17.6 vs 13.1 months, p < 0.001) and in males (15.0 vs 12.8 months, p < 0.001), and markedly influenced by age and primary location. It was longer in patients diagnosed during the second period than during the first (14.9 vs 13.1 months, HR 0.89 (95% CI 0.86-0.92), p < 0.001). This difference was seen in all subgroups according to sex, age, presentation, and sidedness. mOS was about one month shorter in 1/6 healthcare regions, most pronounced during the first period. Differences in median of up to 5 months were seen between the region with the shortest and longest mOS. CONCLUSIONS: Overall survival in Swedish patients with mCRC has improved during the past decade but is still substantially worse than reported from clinical trials/hospital-based series, reflecting the selection of patients to trials. Regional differences were seen, but they decreased with time. Women did not have a poorer prognosis in multivariable analyses.

Resectability, conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study.

BACKGROUND: Outcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively studied. METHODS: This substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status. RESULTS: Patients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups. CONCLUSIONS: There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status. CLINICAL TRIAL REGISTRATION: NCT01531621/EudraCT2011-003158-24.

Health-Related Quality of Life in Metastatic Colorectal Cancer Patients Treated with Curative Resection and/or Local Ablative Therapy or Systemic Therapy in the Finnish RAXO-Study.

Metastasectomy and/or local ablative therapy in metastatic colorectal cancer (mCRC) patients often provide long-term survival. Health-related quality of life (HRQoL) data in curatively treated mCRC are limited. In the RAXO-study that evaluated repeated resectability, a multi-cross-sectional HRQoL substudy with 15D, EQ-5D-3L, QLQ-C30, and QLQ-CR29 questionnaires was conducted. Mean values of patients in different treatment groups were compared with age- and gender-standardized general Finnish populations. The questionnaire completion rate was 444/477 patients (93%, 1751 questionnaires). Mean HRQoL was 0.89−0.91 with the 15D, 0.85−0.87 with the EQ-5D, 68−80 with the EQ-5D-VAS, and 68−79 for global health status during curative treatment phases, with improvements in the remission phase (disease-free >18 months). In the remission phase, mean EQ-5D and 15D scores were similar to the general population. HRQoL remained stable during first- to later-line treatments, when the aim was no longer cure, and declined notably when tumour-controlling therapy was no longer meaningful. The symptom burden affecting mCRC survivors' well-being included insomnia, impotence, urinary frequency, and fatigue. Symptom burden was lower after treatment and slightly higher, though stable, through all phases of systemic therapy. HRQoL was high in curative treatment phases, further emphasizing the strategy of metastasectomy in mCRC when clinically meaningful.

KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer.

BACKGROUND: KRAS mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in KRAS-G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting. METHODS: Patients from three Nordic population-based cohorts and the real-life RAXO-study were combined. RAS and BRAF tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as KRAS, NRAS, and BRAF-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan-Meier, and differences were compared using Cox regression, adjusted for baseline factors. RESULTS: The KRAS-G12C frequency was 2%-4% of all tested in the seven cohorts (mean 3%) and 4%-8% of KRAS mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with KRAS-G12C- vs. other KRAS-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to KRAS mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74-1.42, reference KRAS-G12C) nor within treatment groups defined as "systemic chemotherapy, alone or with biologics", "metastasectomy and/or ablations", or "best supportive care", RAS and BRAF wild-type tumors (n = 548) differed similarly to KRAS-G12C, as to other KRAS- or NRAS-mutated (n = 66) tumors. CONCLUSIONS: In these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with KRAS-G12C tumors and those with other KRAS mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a KRAS-G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.

Repeated centralized multidisciplinary team assessment of resectability, clinical behavior, and outcomes in 1086 Finnish metastatic colorectal cancer patients (RAXO): A nationwide prospective intervention study.

BACKGROUND: Resection of colorectal cancer (CRC) metastases provides good survival but is probably underused in real-world practice. METHODS: A prospective Finnish nationwide study enrolled treatable metastatic CRC patients. The intervention was the assessment of resectability upfront and twice during first-line therapy by the multidisciplinary team (MDT) at Helsinki tertiary referral centre. The primary outcome was resection rates and survival. FINDINGS: In 2012-2018, 1086 patients were included. Median follow-up was 58 months. Multiple metastatic sites were present in 500 (46%) patients at baseline and in 820 (76%) during disease trajectory. In MDT assessments, 447 (41%) were classified as resectable, 310 (29%) upfront and 137 (18%) after conversion therapy. Six-hundred and ninety curative intent resections or local ablative therapies (LAT) were performed in 399 patients (89% of 447 resectable). Multiple metastasectomies for multisite or later developing metastases were performed in 148 (37%) patients. Overall, 414 liver, 112 lung, 57 peritoneal, and 107 other metastasectomies were performed. Median OS was 80·4 months in R0/1-resected (HR 0·15; CI95% 0·12-0·19), 39·1 months in R2-resected/LAT (0·39; 0·29-0·53) patients, and 20·8 months in patients treated with "systemic therapy alone" (reference), with 5-year OS rates of 66%, 40%, and 6%, respectively. INTERPRETATION: Repeated centralized MDT assessment in real-world metastatic CRC patients generates high resectability (41%) and resection rates (37%) with impressive survival, even when multisite metastases are present or develop later. FUNDING: The funders had no role in the study design, analysis, and interpretation of the data or writing of this report.

Completeness and accuracy of the registration of recurrences in the Swedish Colorectal Cancer Registry (SCRCR) and an update of recurrence risk in colon cancer.

BACKGROUND: The completeness and accuracy of the registration of synchronous metastases and recurrences in the Swedish Colorectal Cancer Registry has not been investigated. Knowing how accurate these parameters are in the registry is a prerequisite to adequately measure the current recurrence risk. METHODS: All charts for patients diagnosed with stage I-III colorectal cancer (CRC) in two regions were reviewed. In one of the regions, all registrations of synchronous metastases were similarly investigated. After the database had been corrected, recurrence risk in colon cancer was calculated stratified by risk group as suggested by ESMO in 2020. RESULTS: In patients operated upon more than five years ago (N = 1235), there were 20 (1.6%) recurrences not reported. In more recent patients, more recurrences were unreported (4.0%). Few synchronous metastases were wrongly registered (3.6%) and, likewise, few synchronous metastases were not registered (about 1%). The five-year recurrence risk in stage II was 6% for low-risk, 11% for intermediate risk, and 23% for high-risk colon cancer patients. In stage III, it was 25% in low- and 45% in high-risk patients. Incorporation of risk factors in stage III modified the risks substantially even if this is not considered by ESMO. Adjuvant chemotherapy lowered the risk in stage III but not to any relevant extent in stage II. CONCLUSION: The registration of recurrences in the registry after 5 years is accurate to between 1 and 2% but less accurate earlier. A small number of unreported recurrences and falsely reported recurrences were discovered in the chart review. The recurrence risk in this validated and updated patient series matches what has been recently reported, except for the risk of recurrence in stage II low risk colon cancers which seem to be even a few percentage points lower (6 vs. 9%).

Recurrence Risk after Radical Colorectal Cancer Surgery-Less Than before, But How High Is It?

Adjuvant chemotherapy aims at eradicating tumour cells sometimes present after radical surgery for a colorectal cancer (CRC) and thereby diminish the recurrence rate and prolong time to recurrence (TTR). Remaining tumour cells will lead to recurrent disease that is usually fatal. Adjuvant therapy is administered based upon the estimated recurrence risk, which in turn defines the need for this treatment. This systematic overview aims at describing whether the need has decreased since trials showing that adjuvant chemotherapy provides benefits in colon cancer were performed decades ago. Thanks to other improvements than the administration of adjuvant chemotherapy, such as better staging, improved surgery, the use of radiotherapy and more careful pathology, recurrence risks have decreased. Methodological difficulties including intertrial comparisons decades apart and the present selective use of adjuvant therapy prevent an accurate estimate of the magnitude of the decreased need. Furthermore, most trials do not report recurrence rates or TTR, only disease-free and overall survival (DFS/OS). Fewer colon cancer patients, particularly in stage II but also in stage III, today display a sufficient need for adjuvant treatment considering the burden of treatment, especially when oxaliplatin is added. In rectal cancer, neo-adjuvant treatment will be increasingly used, diminishing the need for adjuvant treatment.

Detection of KRAS mutations in liquid biopsies from metastatic colorectal cancer patients using droplet digital PCR, Idylla, and next generation sequencing.

Circulating tumor DNA (ctDNA) is released from cancer cells and oncogenic mutations in ctDNA can be measured from plasma samples. Droplet digital PCR (ddPCR) is a sensitive and specific method for the detection of mutations in ctDNA. We analyzed serial plasma samples (n = 80) from ten metastatic colorectal cancer (mCRC) patients with a known KRAS mutation in their primary tumor. The patients were undergoing oncological treatment with bevacizumab in combination with alternating capecitabine and oxaliplatin or irinotecan. Baseline ddPCR KRAS mutation allele frequency (MAF) values ranged from 0% to 63%. The first radiologic response evaluation criteria in solid tumors (RECIST) evaluation was performed 45-63 days after the initiation of treatment, and by this time three patients had an undetectable level of KRAS mutation, one had a MAF value of 0.5%, and one had a MAF value of 3% that had been reduced by 95% from the baseline value. In three of these patients the RECIST assessment was stable disease and in two partial response. In seven patients, ddPCR MAF values increased before radiological disease progression or death, while one patient remained disease-free with an undetectable KRAS mutation level. Next, we analyzed all available plasma samples with the Idylla ctKRAS system (n = 60), and found that the overall degree of agreement between ddPCR and Idylla was almost perfect (kappa value = 0.860). We used next-generation sequencing (NGS) to detect treatment-induced mutations in the last serial plasma sample of each patient, but were unable to find any new mutations when compared to the primary tumor. This study shows that ddPCR and Idylla are equally efficient for the detection of KRAS mutations in the liquid biopsies from mCRC patients and that ctDNA may indicate the disappearance of treatment responsive KRAS positive mCRC clones and serve as an early sign of disease progression.