ABSTRACT BACKGROUND Metastatic colorectal cancer patients with deficient mismatch repair (dMMR mCRC) benefit from immunotherapy. Interpretation of the single-arm immunotherapy trials is

complicated by insignificant survival data during systemic non-immunotherapy. We present survival data on a large, comprehensive cohort of dMMR mCRC patients, treated with or without

systemic non-immunotherapy. METHODS Two hundred and eighty-one dMMR mCRC patients (_n_ = 54 from three prospective Phase 3 CAIRO trials; _n_ = 227 from the Netherlands Cancer Registry).

Overall survival was analysed from diagnosis of mCRC (OS), from initiation of first-line (OS1) and second-line (OS2) systemic treatment. Cox regression analysis examined prognostic factors.

patients had a 7.6-month shorter median OS than pMMR patients. CONCLUSION Available data from immunotherapy trials lack a control arm with standard systemic treatment. Given the poor outcome

compared to the immunotherapy results, our data strongly suggest a survival benefit of immunotherapy in dMMR mCRC patients. SIMILAR CONTENT BEING VIEWED BY OTHERS MISMATCH REPAIR SYSTEM

PROTEIN DEFICIENCY AS A RESISTANCE FACTOR FOR LOCALLY ADVANCED RECTAL ADENOCARCINOMA PATIENTS RECEIVING NEOADJUVANT CHEMO-RADIOTHERAPY Article 25 September 2023 NEOADJUVANT IMMUNOTHERAPY FOR

DMMR AND PMMR COLORECTAL CANCERS: THERAPEUTIC STRATEGIES AND PUTATIVE BIOMARKERS OF RESPONSE Article 24 September 2024 LONG-TERM EFFICACY OF PEMBROLIZUMAB AND THE CLINICAL UTILITY OF CTDNA

IN LOCALLY ADVANCED DMMR/MSI-H SOLID TUMORS Article Open access 15 May 2025 BACKGROUND Approximately 5% of metastatic colorectal cancer (mCRC) patients have a tumour with deficient DNA

mismatch repair (dMMR), also referred to as microsatellite instability.1 dMMR arises through germline mutations or epigenetic methylation and inactivation of the MMR pathway, resulting in

insertions or deletions in tandem repetitive sequences in DNA, a hypermutated genome, and a strong immune infiltrate.2 Sporadic dMMR tumours frequently harbour a _BRAFV600E_ mutation and

sporadic dMMR patients have a worse prognosis compared to Lynch syndrome patients.2,3 A dMMR tumour status has prognostic and therapeutic implications for patients, with dMMR having a

favourable impact on prognosis in early-stage CRC, but resulting in a worse prognosis in mCRC compared to proficient mismatch repair (pMMR) tumours.1,4,5 Immune checkpoint inhibitor (ICI)

trials have shown a durable response in pretreated dMMR mCRC patients.6,7,8 dMMR tumours are highly sensitive to ICI due to the high mutational load, immune infiltrate and immune checkpoint

signalling.6 Overman demonstrated a 1-year OS rate of 85% in dMMR mCRC patients, who were refractory to at least one systemic treatment line, upon treatment with nivolumab/ipilimumab.8 ICI

have been approved by the Food and Drug Administration (FDA) in dMMR mCRC patients beyond first-line treatment. However, the European Medicines Agency (EMA) has not approved ICI based on the

lack of a standard control arm without immunotherapy in the ICI trials. For a better interpretation of published immunotherapy results, survival data beyond first-line in dMMR mCRC patients

who did not receive immunotherapy are needed. Due to the low incidence of dMMR among mCRC patients, data on survival in dMMR mCRC patients receiving standard systemic treatments are

scarce.1,3,9,10,11,12 Published data of survival beyond first-line treatment in a cohort of dMMR mCRC patients not receiving immunotherapy are highly needed. We report on the survival and

factors affecting survival of a large cohort of dMMR mCRC patients. METHODS STUDY POPULATION We analysed dMMR mCRC patients in two populations: population-based patients registered in the

Netherlands Cancer Registry (NCR) managed by the Netherlands Comprehensive Cancer Organisation (IKNL), and trial-based patients from three prospective Phase 3 first-line clinical trials

(CAIRO,13 CAIRO214 and CAIRO315). For trial-based patients, patient inclusion criteria, informed consent and study protocols for the trials were published previously.13,14,15 The privacy

rights for patients were maintained. Inclusion criteria for the current analysis were histologically proven mCRC with a dMMR tumour. Patients who received immunotherapy during the course of

their disease were excluded. Clinical data of all newly diagnosed cancer patients in the Netherlands are registered in the NCR. dMMR mCRC patients with an incidence date between January 1,

2015 and December 31, 2017 were included, since mismatch repair status is registered in the NCR for patients with an incidence date only after 2015. Figure 1 is a flow diagram of the

patients identified in the NCR cohort. dMMR status was known when determined in routine clinical practice during the period of data registration. NCR-derived patients include all synchronous

and some metachronous mCRC patients with known dMMR status due to the data collection procedure of the NCR. For the same registration period, the overall survival and treatment status for

pMMR mCRC NCR-derived patients was collected. DATA COLLECTION For population-based patients, pseudonymised clinical data on demographic characteristics, tumour characteristics and treatment

information (type, response) were obtained from the NCR. Vital status for NCR patients was obtained using a yearly coupling with the municipal population registry to the cancer registry on

February 1st, 2019. For NCR pMMR patients, clinical variables were obtained from the first registration period. For patients in the CAIRO trials, clinical data were available and follow-up

information was updated up to October 2019. Data registration was completed for all dMMR patients, population-based and trial-based, by ensuring that no more than 30 days of clinical data

was lacking prior to the vital status coupling. If data registration could not be completed, vital status was censored to the last known date of clinical data (_n_ = 13). Any _BRAF_ mutation

detected was included in the definition of _BRAF-_mutant status. Sidedness of the primary tumour was defined as right-sided (coecum-transverse colon), left-sided (splenic flexure-sigmoid)

and rectosigmoid/rectal. Antitumour therapy was defined as systemic treatment (excluding adjuvant therapy) or local treatment (surgical resection of metastases, radiofrequency ablation

(RFA), microwave ablation (MWA), HIPEC (Hyperthermic Intraperitoneal Chemotherapy) or PIPAC (Pressurized Intra Peritoneal Aerosol Chemotherapy)). Antitumour therapy was categorised as

follows: no antitumour therapy, local treatment only, local and systemic treatment and systemic treatment only. DEFICIENT MISMATCH REPAIR In the CAIRO trials dMMR status was determined

according to the study protocol.1,16,17 In the NCR cohort, dMMR was determined according to Dutch guidelines in accredited laboratories, using immunohistochemistry and/or polymerase chain

reaction. STUDY PARAMETERS Overall survival was defined as the interval from diagnosis of metastatic disease until death of any cause or date of last follow-up if alive (OS). In patients

receiving systemic treatment, OS was measured from each treatment line initiation, resulting in OS1 in patients receiving first-line systemic treatment, and similarly OS2 and OS3 in patients

receiving second-line or third-line systemic treatment starting from second-line or third-line initiation, respectively. Survival rates and patient characteristics were obtained from

published ICI trials.7,8 In order to bring our results in perspective with ICI trials without a control arm, our results were reported alongside the most comparable ICI trials, which

analysed survival from second-line. STATISTICAL ANALYSIS Baseline characteristics of the patients were analysed for the whole cohort and relevant differences between population-based and

trial-based groups were described. Kaplan–Meier curves and 9-month and 12-month survival rate estimates were obtained for OS, OS1, OS2 and OS3. Subgroup analyses between population-based and

trial-based patients were performed using the log-rank test. Cox regression univariate and multivariable analysis was performed in patients receiving first-line treatment for OS. Ten

preselected prognostic factors were selected: age at diagnosis of metastatic disease, gender, trial participation, _BRAF_ mutation, primary tumour sidedness, metastatic sites location, stage

at diagnosis, number of treatment lines given, primary tumour resection and metastasectomy.3,10,18 An unadjusted median overall survival (from diagnosis metastatic disease) for each level

of the covariates was obtained by performing a log-rank test in patients receiving first-line systemic therapy. Multiple imputation by chained equations was used for covariates with missing

data.19 From the complete dataset of variables, predictor variables with a correlation >0.20 with the missing variables and <15% missing values were selected to use alongside the ten

covariates and Cox regression outcome variables in multiple imputation. Patients with missing data were compared to patients with complete-cases (Supplementary Table S1). Univariate hazard

ratios for each covariate were obtained using Cox regression. A stratified Cox proportional hazards multivariable model was obtained using the preselected ten covariates for OS; stratified

for the number of treatment lines received since this covariate violated the proportional hazards assumption. Regression analysis was performed on each imputed dataset and combined using

Rubin’s rules. All analyses were performed in R (version 3.5.1, “survival”, “survminer”, “mice” and “lattice” packages20). RESULTS PATIENT CHARACTERISTICS The cohort comprises 281 patients:

227 population-based (NCR) and 54 trial-based patients. The characteristics of the cohort are described in Table 1. Of the 281 patients, 57% were female, 73% had a right-sided tumour. Age

had a bimodal distribution around 50 and 70 years. Of patients with a known _BRAF_ mutation status, 55% (_n_ = 82/150) had a _BRAF_ mutation. A primary tumour resection and metastasectomy

was performed in 78% and 23% of patients, respectively. Of patients with a known WHO performance score at start of first-line treatment, 93% (_n_ = 102/109) had a WHO performance score of

0–1, with an unknown performance score in 64 patients. In our cohort, 26% (_n_ = 72) of patients received no antitumour treatment, 13% (_n_ = _36_) received local treatment, 14% (_n_ = 38)

received local and systemic treatment and 48% (_n_ = 135) received only systemic treatment (Table 1). Sixty-two percent of patients received first-line, 26% second-line and 8% third-line

systemic non-immunotherapy. The type of treatment regimens and agents used per treatment line are described in Supplementary Table S2. Comparing patient characteristics between

population-based (2015–2018) and trial-based patients (2002–2011): population-based patients were older at diagnosis of metastatic disease (age above 75 years in 24% versus 10%), had less

primary tumour resections (74% versus 96%) and more often resection of metastases (26% versus 9%), as shown in Supplementary Table S3. All trial-based patients were recruited from

intervention trials with first-line systemic therapy, which is reflected in the proportion of patients receiving systemic therapy (100% trial-based versus 52% population-based). FOLLOW-UP

For the population-based and trial-based cohort, the median follow-up period from diagnosis of metastatic disease was 8.3 months (interquartile range [IQR] 3.1–17.6) and 16.8 months

(9.5–22.8), respectively. At the end of the follow-up period, 70.1% of patients were deceased, which was an indication that follow-up was adequate. Follow-up was completed for 264 patients

(94%). OS DURING TREATMENT The Kaplan–Meier survival curves from diagnosis of metastatic disease and from start of each therapy line are demonstrated in Fig. 2. We describe survival for

patients who received antitumour therapy (systemic treatment, excluding adjuvant therapy, surgical resection of metastases and/or local treatment of metastases (including HIPEC or PIPAC))

versus patients who did not receive antitumour therapy. For patients who received antitumour therapy, median OS was 16.0 months (95% Confidence Interval [C.I.] 13.8–19.6; _n_ = 207), whereas

OS was 2.5 months (95% C.I. 1.8–3.5; _n_ = 72) in patients without antitumour therapy. Furthermore, examining survival per type of treatment received, median OS was longer in patients

receiving local and systemic therapy (median OS 29.9 months, 95% C.I. 17.9-not reached; _n_ = _38_) compared to patients receiving only systemic therapy (13.9 months, 95% C.I. 11.4–16.5; _n_

 = _133_), as shown in Supplementary Table S4. Compared to the other treatment categories, patients receiving local and systemic treatment more often had primary rectal tumours (19% compared

to <7% in other categories), _BRAF_ wildtype tumours (65% compared to <49% in other categories) and were younger (≤55 years in 42% versus <23% in other categories), as shown in

Supplementary Table S5. Median OS increased in patients who received more systemic treatment lines (Supplementary Table S4). In order to examine the OS from initiation of each treatment

line, comprising only patients receiving the given treatment line, we examined the OS1, OS2 and OS3. The median overall survival from first-line systemic therapy initiation (OS1) was 12.8

months (95% C.I. 10.7–15.2; _n_ = 170), from second-line systemic therapy initiation (OS2) 6.2 months (95% C.I. 5.4–8.9; _n_ = 70) and from third-line systemic therapy initiation (OS3) 3.6

months (95% C.I. 2.7–not reached; _n_ = 19). From first-line systemic therapy initiation (OS1), estimated 9-month and 12-month survival rates were 63.6% (95% C.I. 56.6–71.5) and 53.8% (95%

C.I. 46.5–62.1). Similarly, from second-line initiation (OS2), 9-month and 12-month survival rates were 35.9% (95% C.I. 25.9–49.9) and 17.2% (95% C.I. 9.7–30.7). In patients who received

second-line systemic treatment with a known WHO performance score ≤1, similar to the inclusion criteria of the CheckMate 142 trials (_n_ = 24),7,8 predicted 9-month and 12-month survival

rates from start of second-line systemic therapy were 43.6% (95% C.I. 27.4–69.4) and 17.4% (95% C.I. 7.2–42.4), respectively. Supplementary Table S6 demonstrates the characteristics of our

second-line patients alongside the nivolumab and nivolumab/ipilimumab CheckMate 142 trial cohorts. We compared the survival between population-based and trial-based dMMR patients, examining

differences in OS among treated patients, OS1 and OS2. There was no significant difference in log-rank comparison of population-based versus trial-based patients in OS, OS1 or OS2. The

median OS was 16.0 months (95%C.I. 13.0–22.1; _n_ = 155) and 16.8 months (95% C.I. 13.5–21.0; _n_ = 52; _p_ = 0.27) in population-based and trial-based patients, respectively. Similarly, the

median OS1 was 12.6 months (95% C.I. 10.1–15.0; _n_ = 118 population-based) and 13.5 months (95% C.I. 9.1–19.6; _n_ = 52 trial-based; _p_ = 0.59). The median OS2 was 6.1 months (95% C.I.

4.4–8.9) in 43 population-based patients and 6.7 months (95% C.I. 5.0–10.2; _p_ = 0.58) in 27 trial-based patients. For population-based patients, we compared the median OS between patients

with dMMR tumours versus pMMR tumours. For trial-based patients this was previously published, showing that the median OS was shorter in dMMR versus pMMR trial-based patients.1,17 For

population-based patients, the median OS was significantly shorter in patients with dMMR tumours upon receiving antitumour therapy than pMMR tumours (Table 2). The median OS was 7.6 months

shorter, with a median OS of 16.0 months (95% C.I. 13.0–22.1; _n_ = 155) for dMMR tumours compared to 23.6 months (95%C.I. 22.6–24.6; _n_ = 2746; _p_ < 0.005) for pMMR tumours in patients

receiving treatment. In untreated patients, median OS was 2.5 months (95% C.I. 1.8–3.5; _n_ = 72) for dMMR tumours versus 3.9 months (95% C.I. 3.4–4.8; _n_ = 610_; p_ = 0.005) for pMMR

tumours. PROGNOSTIC VARIABLES ASSOCIATED WITH OVERALL SURVIVAL IN PATIENTS RECEIVING FIRST-LINE SYSTEMIC TREATMENT In univariate analysis, metastasectomy and sidedness were significantly

associated with OS from diagnosis of metastatic disease in patients receiving first-line systemic treatment (Table 3). _BRAF_ mutational status had a higher risk for shorter OS, albeit

nonsignificant, in univariate analysis (unadjusted hazard ratio [HR] 1.51 (95% C.I. 1.00–2.28); _p_ = 0.052) as shown in Table 3. The final multivariable model was a stratified Cox

regression model for the number of treatment lines received (≤2 and >2) since the variable violated the proportional hazards assumption. In the stratified Cox regression model for number

of treatment lines received, metastasectomy is significantly associated with a longer survival (hazard ratio [HR] 0.49 (95% C.I. 0.26–0.90); _p_ < 0.05) and right-sided tumour location is

significantly associated with a shorter survival (HR1.71 (95% C.I. 1.04–2.79); _p_ < 0.05) as shown in Table 3. In patients receiving first-line systemic treatment, the unadjusted median

OS was 29.5 months (95% C.I. 17.9– not reached; _n_ = 35) and 14.1 months (95% C.I. 11.5–17.2; _n_ = 136) for patients with and without a metastasectomy, respectively (Table 3). Similarly,

the unadjusted median OS was 13.8 months (95% C.I. 10.9–17.2; _n_ = 114) versus 21.6 months (95% C.I. 16.5–72.1; _n_ = 53) in patients receiving first-line systemic treatment with a

right-sided versus left-sided primary tumour location. _BRAF_ mutational status had a higher risk for shorter OS, albeit nonsignificant, in multivariable analysis (HR1.61 (95% C.I.

0.94–2.77); _p_ = 0.086), with an unadjusted median OS of 11.5 months (95% C.I. 8.7–17.9; _n_ = 59) in patients receiving first-line systemic treatment with a _BRAF_-mutant tumour versus

19.6 months (95% C.I. 14.6–22.7; _n_ = 63) in patients with a _BRAF_-wildtype tumour. The other covariates were not significantly associated with survival in the final multivariable model.

DISCUSSION We present survival data of a large, comprehensive cohort of dMMR mCRC patients, not treated with immunotherapy. Our cohort offers a unique insight into the survival of dMMR mCRC

patients while receiving systemic non-immunotherapy in first-, second- and third-line treatment. The OS in our dMMR mCRC cohort for all patients and patients receiving first-line treatment

is comparable to previously reported survival data in dMMR mCRC patients without immunotherapy, including two population-based dMMR mCRC cohorts with a similar percentage of patients

receiving systemic therapy.5,9,10,12,21 However, the OS in our dMMR mCRC patients is shorter than the median OS in three other publications, which ranged from 26–39 months.3,11,22 The

difference may be due to the patient characteristics in the cohorts, with cohorts including patients receiving immunotherapy,22 a high proportion (44–63%) of Lynch syndrome (_BRAF_ wildtype)

patients,3,22 and a high proportion (57%) of patients who underwent a metastasectomy.11 The median OS from initiation of second-line treatment (6.2 months) in our cohort is drastically

shorter than the recently reported median OS in second-line patients (21.6 months) in a cohort of dMMR mCRC patients receiving systemic non-immunotherapy and immunotherapy.22 The difference

may be due to our cohort comprising only patients receiving systemic non-immunotherapy, while the Tougeron et al. dMMR mCRC patient cohort included patients receiving immunotherapy and a

high proportion (44%) of Lynch syndrome patients.22 In our population-based patients, the median OS during treatment was significantly shorter in dMMR compared to pMMR mCRC patients. This

supports previous studies reporting a worse survival in mCRC patients with dMMR1,5,12 and is in contrast to studies showing a nonsignificant, null or opposite effect on survival.9,11,21,23

The conflicting results may lie in heterogeneity of the population cohort being studied, with studies finding a null or opposite effect on survival having included patients with a low

percentage of _BRAF_ mutations,9 only metachronous disease23 or younger patients.11 Our population reflects a clinically relevant cross-sectional population of Dutch patients who received

MMR testing, indicating that patients with mCRC and known dMMR have a worse prognosis compared to pMMR patients. In patients treated with at least one line of systemic treatment, we observed

a significant association between metastasectomy with better survival and right-sided primary tumour location at diagnosis (‘sidedness’) with worse survival. In unselected mCRC patients and

dMMR mCRC patients, metastasectomy is a known prognostic factor for OS.3,10,24 Sidedness is an important prognostic factor in mCRC patients. However, sidedness has not yet been shown to be

associated with OS in patients with dMMR tumours.3,24 Our results indicate that in dMMR mCRC patients, right-sidedness is associated with worse survival. Patients receiving first-line

systemic treatment with a _BRAF_ mutation had a higher risk for shorter survival in multivariable analysis, although nonsignificant, which is reflected with an 8-month difference in the

unadjusted median OS in patients with a _BRAF_ mutant versus _BRAF_-wildtype tumour. Studies have demonstrated that _BRAF_ mutational status was prognostic within dMMR mCRC patients;10,23

however, this is not consistently shown.5,22 Although we did not identify a significant association for _BRAF_ mutation with survival in patients receiving first-line systemic treatment, our

results suggest that patients with a _BRAF_ mutation do have a higher risk for shorter survival. In addition to the prognostic factors which we examined in dMMR mCRC patients receiving

first-line systemic treatment, other factors may contribute to the worse prognosis seen in dMMR mCRC patients. Population-based dMMR mCRC patients have a lower response rate to first-line

systemic non-immunotherapy compared to pMMR mCRC patients (5% versus 44%, respectively) and are also less likely to receive systemic therapy compared to pMMR mCRC patients (47% versus 73%,

_p_ < 0.001).5,21 Thus, the worse prognosis in dMMR mCRC patients is likely driven by several factors, potentially including primary tumour sidedness, _BRAF_ mutational status, the

response rate to systemic therapy, the ability to receive a metastatic resection, and other less well known factors, such as the PD-L1 gene expression level, reflecting immune evasion.25

Additionally, although dMMR mCRC patients are often analysed as one entity, different subgroups with different prognosis should be identified to compare survival results between studies

including Lynch syndrome (often _BRAF_-wildtype), sporadic _BRAF_ mutated dMMR tumours and sporadic _BRAF-_wildtype dMMR tumours.3,9,10 Although _BRAF_ status and MMR status was known, due

to unavailable data regarding MLH1 methylation and Lynch syndrome status we were unable to distinguish between sporadic versus Lynch origin. We are aware of several limitations. Although we

were able to include a broad range of relevant variables, we cannot exclude confounding from unmeasured variables. Secondly, our retrospective study design may have resulted in a selection

of the population, since MMR status was not determined in all patients in daily practice. Lastly, comparison of our data with other studies may be confounded by differences in patient

characteristics. Our study is unique in providing survival data on a large cohort of population-based and trial-based dMMR mCRC patients in the pre-immunotherapy era. Our survival data of

dMMR mCRC patients beyond first-line treatment may be compared with for instance the CheckMate 142 trial results, which examined nivolumab and nivolumab/ipilimumab treatment in dMMR mCRC

patients beyond first-line treatment.7,8 The 9-month and 12-month survival rates of patients receiving second-line treatment in our cohort of 35.9% and 17.2%, respectively, are lower than

the published 9-month survival rate in the nivolumab/ipilimumab arm of 87%, the 12-month survival rates in the nivolumab arm of 73% and the nivolumab/ipilimumab arm of 85%.7,8 The cohorts

are comparable in key patient and tumour characteristics, although the immunotherapy cohorts were more heavily pretreated (40–54% receiving ≥3 treatment lines in the CheckMate 142 trials

compared to 29% in our cohort) and patients more often having _BRAF_-wildtype status. Both characteristics may reflect a patient selection in the CheckMate 142 trials with a less aggressive

clinical course compared to our cohort. Still, even the heavily treated patients in our cohort (who had received ≥3 treatment lines) had a median OS of only 18 months. However, as we had no

access to individual patient data of the other cohorts, a direct comparison between the cohorts was not possible. A comparison with the Phase 2 pembrolizumab trial was not possible due to

the low number of patients in our cohort who received third-line treatment.6 The CheckMate 142 results for patients receiving nivolumab/ipilimumab in first-line setting suggest a benefit of

immunotherapy compared to our systemic non-immunotherapy first-line cohort, with a median 12-month OS rate of 83% versus 54%, respectively.26 This is supported by the Keynote-177 Phase 3

randomised controlled trial results, which show that dMMR mCRC patients have a PFS benefit when receiving first-line pembrolizumab versus first-line systemic therapy (mFOLFOX6 or FOLFIRI

combined with bevacizumab or cetuximab), with a median PFS of 16.5 months versus 8.2 months, respectively (HR0.60, 95% C.I. 0.45–0.80, _p_ = 0.0002).27 In conclusion, we present survival

data on a large, comprehensive cohort of dMMR mCRC patients, treated with or without systemic non-immunotherapy. Currently, available data from immunotherapy trials lack a control arm with

standard systemic treatment. We demonstrate a poor prognostic value for dMMR in mCRC patients. Given the poor outcome in our dataset compared to the results of immunotherapy in dMMR mCRC

patients, our data strongly support a survival benefit of immunotherapy in dMMR mCRC patients. REFERENCES * Venderbosch, S., Nagtegaal, I. D., Maughan, T. S., Smith, C. G., Cheadle, J. P.,

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accepted for an oral presentation at the 2019 AACR Annual Meeting.28 The following oncologists and research nurses were involved in the study: M. Bax (Maxima Medical Center), M. Beusink

(Amsterdam University Medical Center), C. Bresser-de Ruyter (Rode Kruis Hospital Beverwijk), S. Brouwer (Hospital Rijnstate), A. Cats (MD, Stichting Antoni van Leeuwenhoek Hospital), M. de

Buck (Zorgsaam), H. de Graaf (MD, Medical Center Leeuwarden, Leeuwarden), M. Deelen (Diakonessenhuis Hospital Utrecht), M. Fellinger (Ziekenhuisgroep Twente), N. Golsteijn (Hospital

Rivierenland), S.M. Hiddema (Groene Hart Hospital), D.F.S. Kehrer (MD, IJsselland Hospital), M. Laven (Catharina Hospital), H. Polderdijk (Haga Hospital), F. Ramakers (Zuyderland Medical

Center), C.J. Rienks-Bosma (Medical Center Leeuwarden), R. Roukema (Antonius Hospital Sneek), S. Ruijgrok (IJsselland Hospital), J. Schellekens-van Bronswijk (Bravis Hospital), T. Simon

(LangeLand Hospital), S. Sloof (Gelre Hospital), D.J. Storm (Spaarne Hospital), E. Valenteijn (Zaans Medical Center), S. van Broekhoven (Franciscus Gasthuis & Vlietland), A.J. van de

Vendel (Hospital Gelderse Vallei), E.J.E. van Gestel-Wink (Meander Medical Center), M.-L. van Groesen (OLVG), I. van Rooij-Tieleman (VieCuri Medical Center), M. Vercoulen (Elkerliek

Hospital), M.J. Weterman (Amsterdam University Medical Center, University of Amsterdam). We thank the registration team of the Netherlands Comprehensive Cancer Organisation (IKNL) for the

collection of data for the Netherlands Cancer Registry as well as IKNL staff for scientific advice. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medical Oncology, University

Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584CG, Utrecht, The Netherlands G. Emerens Wensink, Patricia A. H. Hamers, Geraldine R. Vink, Jeanine M. L. Roodhart & 

Miriam Koopman * Department of Research, Netherlands Comprehensive Cancer Organisation, Postbus 19079, 3501DB, Utrecht, The Netherlands Marloes A. G. Elferink, Linda Mol & Geraldine R.

Vink * Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, P.O. Box 85500, 3508GA, Utrecht, The Netherlands Anne M. May * Department of

Medical Oncology, Zaans Medical Center, Postbus 210, 1500EE, Zaandam, The Netherlands Sandra D. Bakker * Department of Medical Oncology, Catharina Hospital, Postbus 1350, 5602ZA, Eindhoven,

The Netherlands Geert-Jan Creemers * Department of Medical Oncology, Isala Hospital, Dokter van Heesweg 2, 8025AB, Zwolle, The Netherlands Jan Willem B. de Groot * Department of Medical

Oncology, Spaarne Gasthuis, Spaarnepoort 1, 2134TM, Hoofddorp, The Netherlands Gerty J. de Klerk * Department of Medical Oncology, Maasstad Hospital, Postbus 9100, 3007AC, Rotterdam, The

Netherlands Brigitte C. M. Haberkorn * Department of Medical Oncology, Hospital Gelderse Vallei, Willy Brandtlaan 10, 6716RP, Ede, The Netherlands Annebeth W. Haringhuizen * Department of

Medical Oncology, Ziekenhuisgroep Twente, Postbus 7600, 7600SZ, Almelo, The Netherlands Ronald Hoekstra * Department of Medical Oncology, St. Antonius Hospital, Postbus 2500, 3430EM,

Nieuwegein, The Netherlands J. Cornelis B. Hunting * Department of Medical Oncology, OLVG, Oosterpark 9, 1091AC, Amsterdam, The Netherlands Emile D. Kerver * Department of Medical Oncology,

Franciscus Gasthuis & Vlietland, Vlietlandplein, 3118JH, Schiedam, The Netherlands Danielle Mathijssen-van Stein * Department of Medical Oncology, Medical Center Leeuwarden, Postbus 888,

8901BR, Leeuwarden, The Netherlands Marco B. Polée * Department of Medical Oncology, Jeroen Bosch Hospital, Postbus 90153, 5200ME, ‘s-Hertogenbosch, The Netherlands Johannes F. M. Pruijt *

Department of Medical Oncology, HagaZiekenhuis, Els Borst-Eilersplein 275, 2545AA, den Haag, The Netherlands Patricia Quarles van Ufford-Mannesse * Department of Medical Oncology, Radboud

University Medical Center, Postbus 9101, 6500HB, Nijmegen, the Netherlands Sandra Radema * Department of Medical Oncology, Rode Kruis Hospital, Postbus 1074, 1940EB, Beverwijk, The

Netherlands Ronald C. Rietbroek * Department of Medical Oncology, Maxima Medical Center, Postbus 90052, 5600PD, Eindhoven, The Netherlands Lieke H. J. Simkens * Department of Medical

Oncology, Groene Hart Hospital, Bleulandweg 10, 2803HH, Gouda, The Netherlands Bea C. Tanis * Department of Medical Oncology, Diakonessenhuis Utrecht, Postbus 80250, 3508TG, Utrecht, The

Netherlands Daan ten Bokkel Huinink * Department of Medical Oncology, Hospital Rivierenland, President Kennedylaan 1, 4002WP, Tiel, The Netherlands Manuel L. R. Tjin-A-Ton * Department of

Medical Oncology, Gelre Hospital, Postbus 9014, 7300DS, Apeldoorn, The Netherlands Cathrien S. Tromp-van Driel * Department of Medical Oncology, Bravis Hospital Bergen op Zoom, Postbus 999,

4700AZ, Roosendaal, The Netherlands Monique M. Troost * Department of Medical Oncology, VieCuri Medical Center, Postbus 1926, 5900BX, Venlo, The Netherlands Agnes J. van de Wouw & 

Hanneke J. H. M. J. Vestjens * Department of Medical Oncology, Zuyderland Medical Center Heerlen, Postbus 5500, 6130MB, Sittard-Geleen, The Netherlands Franchette W. P. J. van den Berkmortel

* Department of Medical Oncology, LangeLand Hospital, Postbus 3015, 2700KJ, Zoetermeer, The Netherlands Anke J. M. van der Pas * Department of Medical Oncology, Tergooi, Van Riebeeckweg

212, 1213XZ, Hilversum, The Netherlands Ankie M. T. van der Velden * Department of Medical Oncology, ZorgSaam Hospital, Wielingenlaan 2, 4535PA, Terneuzen, The Netherlands Marjan A. van Dijk

* Department of Medical Oncology, Meander Medical Center, Postbus 1502, 3800BM, Amersfoort, The Netherlands Joyce M. van Dodewaard-de Jong * Department of Medical Oncology, Reinier de Graaf

Gasthuis, Postbus 5011, 2600GA, Delft, The Netherlands Edith B. van Druten * Department of Medical Oncology, Hospital Rijnstate, Wagnerlaan 55, 6815AD, Arnhem, The Netherlands Theo van

Voorthuizen * Department of Medical Oncology, Antonius Hospital Sneek, Postbus 20000, 8600BA, Sneek, The Netherlands Gerrit Jan Veldhuis * Department of Medical Oncology, Amsterdam

University Medical Center, VU Medical Center, P.O. Box 7057, 1007MB, Amsterdam, The Netherlands Henk M. W. Verheul * Department of Medical Oncology, Elkerliek Hospital, Postbus 98, 5700AB,

Helmond, The Netherlands Jeroen Vincent * Department of Surgical Oncology, University Medical Center Utrecht, Utrecht University, Postbus 98, 5700AB, Utrecht, The Netherlands Onno W.

Kranenburg * Utrecht Platform for Organoid Technology, University Medical Center Utrecht, Utrecht University, Postbus 98, 5700AB, Utrecht, The Netherlands Onno W. Kranenburg * Department of

Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Postbus 22660, Amsterdam, The Netherlands Cornelis J. A. Punt Authors * G. Emerens Wensink View author

publications You can also search for this author inPubMed Google Scholar * Marloes A. G. Elferink View author publications You can also search for this author inPubMed Google Scholar * Anne

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inPubMed Google Scholar * Miriam Koopman View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Study concepts and design were completed by

G.E.W., M.A.G.E., A.M.M., P.A.H.H., C.J.A.P., G.R.V., J.M.L.R. and M.K. Data acquisition: all authors with the exception of A.M.M. and P.A.H.H. Quality control of data and algorithms, data

analysis and interpretation, statistical analysis, manuscript preparation and editing were completed by G.E.W., M.A.G.E., A.M.M., C.J.A.P., G.R.V., J.M.L.R. and M.K. The manuscript was

reviewed and approved by all authors. CORRESPONDING AUTHOR Correspondence to Miriam Koopman. ETHICS DECLARATIONS ETHICS APPROVAL AND CONSENT TO PARTICIPATE For trial-based patients, patient

inclusion criteria, informed consent and study protocols for the trials were published previously.13,14,15 For population-based patients, pseudonymised clinical data on demographic

characteristics, tumour characteristics and treatment information (type, response) were obtained from the Netherlands Cancer Registry. The privacy rights for patients were maintained. The

study was performed in accordance with the Declaration of Helsinki. CONSENT TO PUBLISH not applicable. DATA AVAILABILITY The datasets generated during and analyzed during the current study

are not publicly available due to the regulations of the Netherlands Cancer Registry but are available from the corresponding author or Netherlands Cancer Registry on reasonable request.

COMPETING INTERESTS The authors declare no conflict of interest. J.W.B.G. Institutional financial instructs (IFI): BMS, Pierre Fabre, Roche, MSD, Shire, Amgen; M.K. IFI: Amgen, Bayer, BMS,

Merck-Serono, Nordic Farma, Roche, Servier, Sirtex, Sanofi-Aventis; Non-financial interests (NFI): advisory role ZON-MW, daily board member DCCG, P.I. PLCRC; CJAP IFI: Amgen, Roche; J.M.L.R.

IFI: Servier, Merck, Bayer; T.v.V. NFI: Pfizer, Ipsen, Astellas, Roche, Bayer; H.V. IFI: Immunovo, Glycostem, Roche; G.R.V. IFI: Servier, Bayer, Merck, BMS, Lilly. All grants were unrelated

to the study and paid to the individual’s institution. FUNDING INFORMATION None. ADDITIONAL INFORMATION NOTE This work is published under the standard license to publish agreement. After 12

months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0). PUBLISHER’S NOTE Springer Nature remains

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this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wensink, G.E., Elferink, M.A.G., May, A.M. _et al._ Survival of

patients with deficient mismatch repair metastatic colorectal cancer in the pre-immunotherapy era. _Br J Cancer_ 124, 399–406 (2021). https://doi.org/10.1038/s41416-020-01076-0 Download

citation * Received: 12 March 2020 * Revised: 24 August 2020 * Accepted: 02 September 2020 * Published: 13 October 2020 * Issue Date: 19 January 2021 * DOI:

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