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BackgroundImmune checkpoint inhibitors (ICIs) are the gold standard therapy in patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A significant proportion of patients show resistance, making the identification of determinants of response crucial. Growing evidence supports the role of sex in determining susceptibility to anticancer therapies, but data is lacking for patients with MSI-H CRC.MethodsIn this real-world cohort comprising 624 patients with MSI-H mCRC receiving ICIs, we investigated the impact of sex on patients’ outcomes, overall and according to RAS-BRAF mutational status or type of treatment (anti-PD-(L)1 with or without anti-CTLA-4 agents). We then investigated these associations also in two independent cohorts of patients with early-stage or advanced MSI-H CRC unexposed to ICIs. Finally, we explored two public microarray and RNA-seq datasets from patients with non-metastatic or metastatic MSI-H CRC to gain translational insights on the association between sex, BRAF status and immune contextures/ICI efficacy.ResultsAlthough no differences were observed between females and males either overall or in the BRAF wild-type cohort, male sex was associated with inferior progression-free survival (PFS) and overall survival (OS) in the BRAF mutated cohort (in multivariable models, HR for PFS: 1.79, 95% CI: 1.13 to 2.83, p=0.014, and for OS: 2.33, 95% CI: 1.36 to 3.98, p=0.002). Males receiving anti-PD-(L)1 monotherapy had the worst outcomes, with a 3-year PFS and 3-year OS of 23.9% and 41.8%, respectively, while the addition of anti-CTLA-4 agents rescued such a worse outcome. We also observed that females experienced a higher frequency of any-grade immune-related adverse events. Conversely, sex was not prognostic in the independent cohorts of patients with MSI-H CRCs not treated with ICIs. Exploratory transcriptomic analyses suggest that tumors of males with BRAF mutated MSI-H metastatic CRC are characterized by an enrichment of androgen receptor signature and an immune-depleted microenvironment, with a reduction in memory B cells, activated natural killer cells, and activated myeloid dendritic cells.ConclusionsOverall, our findings suggest a complex interplay between sex and BRAF mutational status that may modulate the activity of ICIs in patients with MSI-H mCRC and pave the way to novel tailored strategies.

Background Current knowledge on prognostic biomarkers (especially BRAFV600E/RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors. Methods This observational cohort study combined a population‐based Dutch cohort (2014–2019) and a large French multicenter cohort (2007–2017). All mCRC patients with a histologically proven dMMR tumor were included. Results In our real‐world data cohort of 707 dMMR mCRC patients, 438 patients were treated with first‐line palliative systemic chemotherapy. Mean age of first‐line treated patients was 61.9 years, 49% were male, and 40% had Lynch syndrome. BRAFV600E mutation was present in 47% of tumors and 30% harbored a RAS mutation. Multivariable regression analysis on OS showed significant hazard rates (HR) for known prognostic factors as age and performance status, however showed no significance for Lynch syndrome (HR: 1.07, 95% CI: 0.66–1.72), BRAFV600E mutational status (HR: 1.02, 95% CI: 0.67–1.54), and RAS mutational status (HR: 1.01, 95% CI: 0.64–1.59), with similar results for PFS. Conclusion BRAFV600E and RAS mutational status are not associated with prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Lynch syndrome is also not an independent prognostic factor for survival. These findings underline that prognostic factors of patients with dMMR mCRC are different of those with pMMR, which could be taken into consideration when prognosis is used for clinical decision‐making in dMMR mCRC patients and underline the complex heterogeneity of mCRC. An original research article to provide insight in the prognostic value of Lynch syndrome, BRAFV600E and RAS mutation status on survival outcomes with pooled individual patient data from the large Dutch and French deficient mismatch repair (dMMR) / microsatellite instability‐high (MSI‐H) metastatic colorectal cancer (mCRC) cohort. Lynch syndrome, BRAFV600E and RAS mutational status are not independently associated with overall survival in dMMR/MSI‐H mCRC patients treated with palliative first‐line chemotherapy, in contrast to proficient MMR mCRC patients. This could be taken into consideration when prognosis is used for clinical decision‐making in dMMR mCRC patients and underline the complex heterogeneity of mCRC.

Background. Cancer has become an important cause of death in solid organ transplant patients. The cause of malignancies in patients with solid organ transplants is multifactorial, but the use of intensive immunosuppression is regarded as an important factor. We describe the spontaneous, complete regression of colon cancer liver metastases, without initiation of antitumor therapy, in a solid organ transplant patient after modulation of immunosuppressants. Case Presentation. A 59-year-old female was admitted with fever, general discomfort, and elevated liver enzymes. She had received a single lung transplant, five years prior, for end-stage chronic obstructive pulmonary disease. Abdominal ultrasound and a computed tomography scan showed extensive liver lesions, and liver biopsy determined that the lesions were liver metastases originating from a colonic adenocarcinoma. Histopathologic analysis revealed that the primary tumor and liver metastases were mismatch repair-deficient (BRAFV600E mutant and MLH1/PMS2-deficient), also known as a microsatellite instable tumor. The patient’s clinical condition deteriorated rapidly, and she was discharged home with palliative care. No antitumor treatment was initiated. Additionally, there was a short period without any immunosuppressants. Unexpectedly, her clinical condition improved, and complete regression of liver metastases was observed on imaging two months later. Unfortunately, the patient developed rejection of her lung transplant and succumbed to pulmonary disease six months following her cancer diagnosis. The autopsy confirmed the primary colon tumor location and complete regression of >40 liver metastases. Conclusions. Disinhibition and reset of the host immune response could have led to immune destruction of the liver metastases of this patient’s immunogenic dMMR colon carcinoma. This case underscores the huge impact that temporary relief from immunosuppressive therapy could have on tumor homeostasis. Balanced management of care for organ transplant recipients with malignancies requires a multidisciplinary approach involving medical oncologists and transplant physicians to reach the best quality of care in these complex cases.

Background Encorafenib-cetuximab has been approved for pretreated BRAF V600E -mutated metastatic colorectal cancer (mCRC) patients based on efficacy demonstrated in the randomized phase III BEACON trial. The aim of this real-world effectiveness study is to improve knowledge on the generalizability of trial results. Methods This population-based real-world study includes all mCRC patients in the Netherlands treated with encorafenib-cetuximab since approval. Individual patient data and pathology reports were collected. Overall survival (OS) was compared to BEACON and subgroup analyses were conducted for patients who would have been eligible and ineligible for BEACON. Results 166 patients were included with a median follow-up time of 14.5 months. Median OS was 6.7 months (95% CI:6.0–8.3) and differed from BEACON (9.3 months; 95% CI:8.0–11.3, p -value 0.002). Thirty-six percent of real-world patients would have been ineligible for the BEACON trial. Trial ineligible subgroups with symptomatic brain metastases and WHO performance status ≥2 had the poorest median OS of 5.0 months (95% CI:4.0-NR) and 3.9 months (95% CI:2.4-NR). Conclusion This real-world cohort of mCRC patients treated with encorafenib-cetuximab showed a clinically relevant efficacy-effectiveness gap for OS. The chance of survival benefit from encorafenib-cetuximab in patients with brain metastases and/or WHO performance status ≥2 is negligible as neither efficacy nor effectiveness has been demonstrated.

Abstract Background Patients with deficient mismatch repair (dMMR) and/or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) show marked sensitivity to immune checkpoint inhibitors (ICIs). Dual PD-1/CTLA-4 blockade with nivolumab and ipilimumab showed superior progression-free survival (PFS) over chemotherapy and anti-PD-1 monotherapy, but data on treatment-naïve patients is not available yet. Methods This international multicenter study included patients with dMMR/MSI-H mCRC receiving either chemotherapy with or without biologics, or anti-PD-1 monotherapy, or dual PD-1/CTLA-4 blockade as a first-line treatment. Data were adjusted using inverse probability of treatment weighting (IPTW) to account for baseline imbalances. IPTW-adjusted survival and subgroup analyses were conducted. Results Among 711 patients, 51.2% received chemotherapy with or without biologics, 37.1% anti-PD-1 monotherapy, and 11.7% dual checkpoint blockade. Anti-CTLA-4 combination therapy significantly improved PFS (HR: 0.14; P < .001) and OS (HR: 0.13; P < .001) vs chemotherapy. In first-line IPTW-adjusted analyses (median follow-up: 29.2 months), dual blockade showed superior PFS over PD-1 monotherapy (HR: 0.58, 95% CI, 0.35-0.97, P = .037), with a favorable OS trend (HR: 0.61, 95% CI, 0.33-1.14, P = .12), and higher objective response rate (ORR) (71.5% vs 55.5%; OR: 1.15; 95% CI, 1.03-1.29; P = .016) and disease control rate (DCR) (93.7% vs 75.8%; OR, 1.18; 95% CI, 1.08-1.28; P < .001). Subgroup analyses suggested greater benefit in patients with left-sided and BRAF mutated tumors, while those with right-sided BRAF wild-type status showed no incremental benefit from dual ICI. Toxicity profile was manageable for both ICI regimen, with grade 3 or 4 immune-related adverse events registered in 11.9% and 15.7% cases in anti-PD-1 monotherapy and anti-CTLA-4 combination groups, respectively. Conclusions First-line dual PD-1/CTLA-4 blockade demonstrated superior efficacy over anti-PD-1 monotherapy in dMMR/MSI-H mCRC regardless of clinical variables. Compared to previous published data across treatment lines, the prognostic impact of several clinical features does not seem to be retained in patients treated upfront with ICIs combination.

Background It is unclear whether curative-intent local therapy of metastases is of similar benefit for the biological distinct subgroup of patients with deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC) compared with proficient mismatch repair (pMMR) mCRC. Patients and Methods In this nationwide study, recurrence-free (RFS) and overall survival (OS) were analyzed in patients with dMMR versus pMMR mCRC who underwent curative-intent local treatment of metastases between 2015 and 2018. Subgroup analyses were performed for resection of colorectal liver metastases (CRLM) and cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy (CRS ± HIPEC). Multivariable regression was conducted. Results Median RFS was 11.1 months [95% confidence interval (CI) 8.5–41.1 months] for patients with dMMR tumors compared with 8.9 months (95% CI 8.1–9.8 months) for pMMR tumors. Two-year RFS was higher in patients with dMMR versus pMMR (43% vs. 21%). Results were similar within subgroups of local treatment (CRLM and CRS ± HIPEC). Characteristics differed significantly between patients with dMMR and pMMR mCRC; however, multivariable analysis continued to demonstrate dMMR as independent factor for improved RFS [hazard ratio (HR): 0.57, 95% CI 0.38–0.87]. Median OS was 33.3 months for dMMR mCRC compared with 43.5 months for pMMR mCRC, mainly due to poor survival of patients with dMMR in cases of recurrence in the preimmunotherapy era. Conclusion Patients with dMMR eligible for curative-intent local treatment of metastases showed a comparable to more favorable RFS compared with patients with pMMR, with a clinically relevant proportion of patients remaining free of recurrence. This supports local treatment as a valuable treatment option in patients with dMMR mCRC and can aid in shared decision-making regarding upfront local therapy versus immunotherapy.

Background Immune checkpoint inhibitors (ICIs) are the gold standard therapy in patients with deficient mismatch repair (dMMR)/microsatellite instabilityhigh (MSI-H) metastatic colorectal cancer (mCRC). A significant proportion of patients show resistance, making the identification of determinants of response crucial. Growing evidence supports the role of sex in determining susceptibility to anticancer therapies, but data is lacking for patients with MSI-H CRC. Methods In this real-world cohort comprising 624 patients with MSI-H mCRC receiving ICIs, we investigated the impact of sex on patients' outcomes, overall and according to RAS-BRAF mutational status or type of treatment (anti-PD-(L)1 with or without anti-CTLA-4 agents). We then investigated these associations also in two independent cohorts of patients with early-stage or advanced MSI-H CRC unexposed to ICIs. Finally, we explored two public microarray and RNA-seq datasets from patients with non-metastatic or metastatic MSI-H CRC to gain translational insights on the association between sex, BRAF status and immune contextures/ICI efficacy. Results Although no differences were observed between females and males either overall or in the BRAF wild-type cohort, male sex was associated with inferior progressionfree survival (PFS) and overall survival (OS) in the BRAF mutated cohort (in multivariable models, HR for PFS: 1.79, 95% CI: 1.13 to 2.83, p=0.014, and for OS: 2.33, 95% CI: 1.36 to 3.98, p=0.002). Males receiving anti-PD-(L)1 monotherapy had the worst outcomes, with a 3-year PFS and 3-year OS of 23.9% and 41.8%, respectively, while the addition of anti-CTLA-4 agents rescued such a worse outcome. We also observed that females experienced a higher frequency of any-grade immune-related adverse events. Conversely, sex was not prognostic in the independent cohorts of patients with MSI-H CRCs not treated with ICIs. Exploratory transcriptomic analyses suggest that tumors of males with BRAF mutated MSI-H metastatic CRC are characterized by an enrichment of androgen receptor signature and an immune-depleted WHAT IS ALREADY KNOWN ON THIS TOPIC⇒ Deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) is sensitive to immune checkpoint inhibitors (ICIs), but a portion of patients display primary or acquired resistance. Sex has been found to determine susceptibility to ICIs in other disease settings, but data is scarce for dMMR/MSI-H CRC. WHAT THIS STUDY ADDS⇒ Male sex was associated with worse outcomes in patients with BRAF mutated dMMR/MSI-H mCRC treated with ICIs, especially when receiving anti-PD1 monotherapy. Contrarily, it was not found to be prognostic in independent cohorts of early-stage and advanced dMMR/MSI-H CRC unexposed to ICIs. An enrichment of androgen receptor signature and an immune-depleted microenvironment observed in males with BRAF mutated MSI-H mCRC may be responsible for the poorer sensitivity to ICIs.

Current knowledge on prognostic biomarkers (especially BRAF /RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors. This observational cohort study combined a population-based Dutch cohort (2014-2019) and a large French multicenter cohort (2007-2017). All mCRC patients with a histologically proven dMMR tumor were included. In our real-world data cohort of 707 dMMR mCRC patients, 438 patients were treated with first-line palliative systemic chemotherapy. Mean age of first-line treated patients was 61.9 years, 49% were male, and 40% had Lynch syndrome. BRAF mutation was present in 47% of tumors and 30% harbored a RAS mutation. Multivariable regression analysis on OS showed significant hazard rates (HR) for known prognostic factors as age and performance status, however showed no significance for Lynch syndrome (HR: 1.07, 95% CI: 0.66-1.72), BRAF mutational status (HR: 1.02, 95% CI: 0.67-1.54), and RAS mutational status (HR: 1.01, 95% CI: 0.64-1.59), with similar results for PFS. BRAF and RAS mutational status are not associated with prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Lynch syndrome is also not an independent prognostic factor for survival. These findings underline that prognostic factors of patients with dMMR mCRC are different of those with pMMR, which could be taken into consideration when prognosis is used for clinical decision-making in dMMR mCRC patients and underline the complex heterogeneity of mCRC.