dMMR Colon Cancer Research Articles

Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair–Deficient Colon Cancer

BackgroundMismatch repair–deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited.MethodsWe conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses.ResultsOf 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease.ConclusionsIn patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.)

Clinical outcomes and impact of mismatch repair deficiency (dMMR) in patients with pT4N0 colon cancer (CC): Data from a large, consecutive, multicenter, real-world cohort.

3619 Background: T4 is widely recognized as one of the most important and independent prognostic factors in adjuvant setting for CC patients. However, the optimal management in terms of adjuvant treatment in stage II (pT4N0) as well as the impact of DNA mismatch repair deficiency (dMMR) in this subset of patients remain unclear. Here, we present a large, multicenter, real-world analysis of pT4N0 CC patients. Methods: A real-world database including pts treated at 9 Italian institutions from April 2010 to November 2023 was queried. Clinico-pathological characteristics of pts diagnosed with a stage II pT4N0 CC were analyzed. Pts were stratified according to duration of treatment, DNA mismatch repair (MMR) status, type of adjuvant chemotherapy (ACT). The primary endpoints were median relapse-free survival (RFS) and overall survival (OS). Results: A total of 380 pts was included, and outcomes data were available for 288 pts.Median age was 73 years and 49% of pts were male. 47 pts (16%) had dMMR CC, among which Lynch Syndrome was diagnosed in 19%. 10% of pts had BRAF mutant tumor, and 38% KRAS mutant tumor. After a median follow-up of 40.6 months (37.9-49.3), 3-yr RFS and 5-yr RFS were 70% and 55%, respectively, regardless treatment; 3-yr OS was 88% and 5-yr OS 73%. 154 pts (53%) received ACT: oxaliplatin (oxa)-based CT was given to 103 pts (67%), compared to 51 pts who received monotherapy (33%). Six-month ACT was given to 38 pts (74.5%) and 75 pts (72.8%) in the monotherapy and oxa-based group, respectively. Pts receiving 6-month ACT had a significant longer OS compared to those who did not receive ACT (HR 0.17; 0.08-0.34; p <.001). A trend towards improved OS was observed in pts receiving 6-month ACT versus pts receiving 3-month ACT (HR 0.46; 0.16-1.29; p 0.129). Similar results were observed in terms of RFS: 6-month ACT showed a longer RFS compared to 3-month ACT (HR 0.58; 0.32-1.05; p .068), and a significantly longer RFS compared to no-ACT (HR 0.50; 0.32-0.77; p .001). Oxa-based ACT was associated with a significant improvement in OS compared to monotherapy (HR 0.30; 0.11-0.85; p .016). Overall, pts with dMMR CC did not show a statistically significant difference in terms of OS and RFS (p .66 and .19 respectively) compared to proficient MMR pts. Conclusions: In this large real-world dataset, T4 was confirmed being a key poor prognostic factor, independently to MMR status. We observed that ACT provides large benefit in this population, and oxa-based ACT may be better than monotherapy. In addition, 6-month oxa-based ACT showed a trend towards a better outcome in comparison to 3-month ACT, even if not statistically significant. Given the retrospective nature of the study, these data should be validated in larger and prospective cohorts; however, this work may help oncologists in shared decision making in this specific subgroup of patients.

The effects of oxaliplatin-based adjuvant chemotherapy in high-risk stage II colon cancer with mismatch repair-deficient: a retrospective study

BackgroundFor high-risk stageIImismatch repair deficient (dMMR) colon cancers, the benefit of adjuvant chemotherapy remains debatable. The principal aim of this study was to evaluate the prognostic value of high-risk factors and the effect of oxaliplatin-based adjuvant chemotherapy among dMMR stageIIcolon cancers.MethodsPatients with stage II dMMR colon cancers diagnosed between June 2011 and May 2018 were enrolled in the study. Clinicopathological characteristics, treatment, and follow-up data were retrospectively collected. The high-risk group was defined as having one of the following factors: pT4 disease, fewer than twelve lymph nodes harvested (< 12 LNs), poorly differentiated histology, perineural invasion (PNI), lymphatic vascular invasion (LVI), or elevated preoperative carcinoembryonic antigen (CEA). The low-risk group did not have any risk factors above. Factors associated with disease-free survival (DFS) were included in univariate and multivariate Cox analyses.ResultsWe collected a total of 262 consecutive patients with stage II dMMR colon cancer. 179 patients (68.3%) have at least one high-risk factor. With a median follow-up of 50.1 months, the low-risk group was associated with a tended to have a better 3-year DFS than the high-risk group (96.4% vs 89.4%; P = 0.056). Both elevated preoperative CEA (HR 2.93; 95% CI 1.26–6.82; P = 0.013) and pT4 disease (HR 2.58; 95% CI 1.06–6.25; P = 0.037) were independent risk factors of recurrence. Then, the 3-year DFS was 92.6% for the surgery alone group and 88.1% for the adjuvant chemotherapy group (HR 1.64; 95% CI 0.67–4.02; P = 0.280). Furthermore, no survival benefit from oxaliplatin-based adjuvant chemotherapy was observed in the high-risk group and in the subgroups with pT4 disease or < 12 LNs.ConclusionsThese data suggests that not all high-risk factors have a similar impact on stage II dMMR colon cancers. Elevated preoperative CEA and pT4 tumor stage are associated with increased recurrence risk. However, oxaliplatin-based adjuvant chemotherapy shows no survival benefits in stage II dMMR colon cancers, either with or without high-risk factors.

The impact of mismatch repair status and systemic inflammatory markers on radiological staging in colon cancer.

Mismatch repair (MMR) deficient (dMMR) colon cancer (CC) is distinct from MMR proficient (pMMR) CC, yet the impact of MMR status on radiological staging is unclear. The purpose of this study was to investigate how MMR status impacts CC CT staging. We retrospectively compared CT staging accuracy between dMMR and pMMR CC patients undergoing curative resection. Accuracy was assessed as individual tumour (T)/nodal (N) stages and as dichotomous "statuses" (T1/2 vs T3/4; N0 vs N1/2). Patient characteristics were analysed for factors to support staging. There was no significant difference in overall staging accuracy between the dMMR (44 patients) and pMMR (57 patients) groups. dMMR tumours with incorrect N stage/"status" were more likely to be overstaged than pMMR tumours (90% vs 59%; p = 0.023 for "N status"). Platelet count, CRP and neutrophil count (AUC 0.76 (p = 0.0078), 0.75 (p = 0.034) and 0.70 (p = 0.044), respectively) were associated with "N status" in dMMR tumours. Whilst overall staging accuracy was similar between groups, incorrectly N staged dMMR tumours were more likely to be overstaged than pMMR tumours, risking inappropriate surgical or neoadjuvant treatment. We describe novel relationships between several inflammatory markers and pathological "N status" in dMMR CC, which if integrated into routine practice may improve CT staging accuracy. Compared to pMMR CC, dMMR CC is at significant risk of N overstaging. Platelet count, CRP and neutrophil count are higher in dMMR CC patients with nodal metastases than those without, and their role in refining clinical staging requires further investigation.

Stage III deficient mismatch repair colon patients get greater benefit from earlier starting oxaliplatin-based chemotherapy regimen

We evaluate the prognostic value of chemotherapy and other prognostic factors on overall survival among colon patients with deficient mismatch repair (dMMR), and determine the optimum time to start chemotherapy after surgery. Data of 306 colon cancer patients with dMMR who received radical surgery were collected from three Chinese centers between August 2012 and January 2018. Overall survival (OS) was assessed with the Kaplan–Meier method and log-rank. Cox regression analysis were used to assess influencing prognosis factors. The median follow-up time for all patients was 45.0 months (range, 1.0–100). There was a nonsignificant OS benefit from chemotherapy for patients with stage I and stage II disease, including high-risk stage II disease (log-rank p: 0.386, 0.779, 0.921), and a significant OS benefit for patients with stage III and stage IV disease for receiving post-operation chemotherapy (log-rank p = 0.002, 0.019). Stage III patients benefitted from chemotherapy regimens that contained oxaliplatin (log-rank p = 0.004), and Starting chemotherapy with oxaliplatin treatment earlier resulted in better outcomes (95% CI 0.013–0.857; p = 0.035). Chemotherapy regimens containing oxaliplatin can prolong the survival time of stage III and IV dMMR colon cancer patients. This beneficial manifestation was more pronounced after starting chemotherapy treatment early post operation. High risk stage II dMMR colon patients including T4N0M0 cannot benefit from chemotherapy.

Exploring the radiological differences of lymph nodes between mismatch repair deficient and mismatch repair proficient colon cancer.

e15643 Background: Mismatch repair (MMR) deficient (dMMR) colon cancer (CC) accounts for 15-20% of CC diagnoses and is characterised by clinicopathological features distinct from MMR proficient (pMMR) CC. Regardless of MMR status, CT staging is a critical part of the workup for newly diagnosed CC. Whilst CT can accurately predict T stage, it is less effective for N stage. Incorrect N staging may risk poor prognostication, more invasive surgery and may have implications for emerging neoadjuvant therapies. We recently illustrated the impact of MMR status on CT staging, with N staging accuracy significantly worse in dMMR than pMMR CC. Furthermore, we highlighted the clinical utility of using serum inflammatory markers to predict N stage more accurately in dMMR CC. It is increasingly apparent that MMR status has implications for CT staging and should be considered when developing strategies to improve performance. It is therefore crucial to understand how lymph node appearances differ according to MMR status. Here, we investigated whether radiological features of lymph nodes differ between dMMR and pMMR CC. Methods: CT scans were retrospectively assessed for patients who underwent curative resection from March 2019 to July 2020. Axial images were used to identify nodes &gt; 5mm in longest diameter within the tumour drainage territory. The following were collected for each node: location (pericolic, intermediate, main; according to Japanese Society for Cancer of the Colon and Rectum criteria), long axis diameter and short axis diameter. The following were collected for the largest node: short to long axis ratio (SLAr), attenuation and heterogeneity. Characteristics were compared between the dMMR and pMMR groups. Results: This cohort comprised 92 patients, with 53 and 39 in the pMMR and dMMR groups, respectively. As expected, there were greater proportions of females and right-sided tumours in the dMMR group. Median SLAr and median attenuation of the largest node were significantly greater in the dMMR than the pMMR group (0.7 v 0.57, p = 0.0012 and 53.1HU v 40.4HU, p = 0.013, respectively). Number and distribution of enlarged nodes, and location, long axis and heterogeneity of the largest node did not differ between the groups. Conclusions: dMMR and pMMR CC are increasingly recognised as distinct entities, with implications for prognosis and treatment. There is growing evidence illustrating the impact of MMR status on CT staging, and in particular N staging. Here, we illustrated the similarities and differences of lymph nodes on CT between dMMR and pMMR CC. To the best of our knowledge, this is the first analysis to explore the relevance of the largest node and to illustrate the SLAr and attenuation of the largest node being significantly greater in dMMR CC. Recognising these differences will be crucial as we develop strategies for selecting patients to receive neoadjuvant immunotherapy in dMMR CC.

Evaluating the efficacy and safety of neoadjuvant pembrolizumab in patients with stage I–III MMR-deficient colon cancer: a national, multicentre, prospective, single-arm, phase II study protocol

IntroductionWithin the last two decades, major advances have been made in the surgical approach for patients with colorectal cancer. However, to this day we face considerable challenges in reducing surgery-related...

The impact of time to surgery on oncological outcomes in stage I-III dMMR colon cancer – A nationwide cohort study

IntroductionOne of the considerations when investigating neoadjuvant interventions is the prolonging of time from diagnosis to curative surgery (i.e. the treatment interval [TI]). The aim of this study was to investigate the association between the length of TI and overall survival and disease-free survival in patients with deficient mismatch repair (dMMR) colon cancer. Materials and methodsThis retrospective propensity score-adjusted study included all patients of ≥18 years of age undergoing elective curative surgery for stage I-III, dMMR colon cancer. Data were extracted from four Danish patient databases. Outcomes were investigated in groups with TIs of ≤14 days versus >14 days. Propensity scores were computed using all demographics, diagnoses and measurements. Matching was done in a 1:1 ratio. ResultsA total of 4130 patients were included in the study with a mean age of 73.8 years and a median follow-up time of 43.9 months. After matching, 2794 patients were included in the analysis of overall survival. No significant difference in overall survival was seen between patients with TIs of ≤14 days versus >14 days (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.81–1.17; p = 0.78). In the analysis of disease-free survival, 1798 patients were included after matching. This showed no significant difference between patients with TIs of ≤14 days versus >14 days (HR, 0.85; 95% CI, 0.69–1.06; p = 0.14). ConclusionNo associations were found between TI and overall survival and disease-free survival in patients with stage I-III, dMMR colon cancer undergoing elective curative surgery.

Therapy with pembrolizumab in treatment-naïve patients with nonmetastatic, mismatch repair deficient colorectal cancer.

Therapy with immune checkpoint inhibitors (ICI) is effective in patients with metastatic mismatch-repair deficient (dMMR) colorectal cancer (CRC); however, data on treatment with neoadjuvant ICI in patients with locally advanced CRC are limited. From March 2019 to June 2020, five Danish oncological centers treated 10 patients with a treatment-naïve dMMR CRC with preoperative pembrolizumab, 9 with a nonmetastatic, unresectable colon cancer and 1 with a locally advanced rectum cancer. All 10 patients were evaluated regularly at a multidisciplinary team (MDT) meeting, and they all had a radical resection after a median of 8cycles (range 2-13) of pembrolizumab. A microscopic evaluation of the resected tumors revealed no remaining tumor cells in five patients, while five still had tumor cells present. The patients were given no additional therapy. No recurrences were reported after a median follow-up of 26 months (range 23-38.5months). Biopsies from Danish patients with CRC are routinely screened for dMMR proteins. In 2017, data from the Danish Colorectal Cancer Group showed that 19% (565/3000) of the patients with colon cancer and 1.5% (19/1279) of those with rectum cancer had an dMMR tumor. Among the patients with MMR determination, 26% (99/384) patients had a T4 dMMR colon cancer; thus, the 10 patients treated with neoadjuvant pembrolizumab comprised about 9% of the patients with a T4 dMMR colon cancer (9/99) and 5% of patients with dMMR rectal cancer (1/19). Therapy with pembrolizumab was feasible and effective. Larger prospective trials are needed to confirm our findings.

Energy balance-related factors in childhood and adolescence and risk of colorectal cancer based on KRAS, PIK3CA, and BRAF mutations and MMR status.

KRAS mutations (KRASmut ), PIK3CAmut , BRAFmut ,and deficient DNA mismatch repair (dMMR) have been associated with the Warburg effect. We previously reported differential associations between early-life energy balance-related factors (height, energy restriction, body mass index[BMI]) and colorectal cancer (CRC) subtypes based on the Warburg effect. We now investigated associations of early-life energy balance-related factors and the risk of CRC subgroups based on mutation and MMR status. Data from the Netherlands Cohort Study was used. KRASmut , PIK3CAmut, BRAFmut, and MMR status were available for 2349 CRC cases, and complete covariate data for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox regression was used to estimate associations of height, energy restriction proxies (exposure to Dutch Hunger Winter, Second World War, Economic Depression), and early adult BMI (age 20 years) with risk of CRC based on individual molecular features and combinations thereof (all-wild-type+MMR-proficient [pMMR]; any-mutation/dMMR).Height was positively associated with any-mutation/dMMR CRC but not all-wild-type+pMMR CRC, with the exception of rectal cancer in men, and with heterogeneity in associations observed for colon cancer in men (p-heterogeneity = 0.049) and rectal cancer in women (p-heterogeneity = 0.014). Results on early-life energy restriction proxies in relation to the risk of CRC subgroups did not show clear patterns. Early adult BMI was positively, but not significantly, associated with KRASmut colon cancer in men and with BRAFmut and dMMR colon cancer in women. Our results suggest a role of KRASmut , PIK3CAmut , BRAFmut , and dMMR in the etiological pathway between height and CRC risk. KRASmut might potentially play a role in associations of early adult BMI with colon cancer risk in men, and BRAFmut and dMMR in women.

LBA7 Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study

Neoadjuvant immunotherapy has shown promising responses in several cancer types. For colon cancer (CC), NICHE was the first neoadjuvant immunotherapy study to show pathologic responses in 100% of dMMR tumors. Importantly, disease-free survival (DFS) in patients (pts) with stage III dMMR CC is similar to that of pMMR pts, with 3-year recurrence risks of over 40% in high-risk (T4 and/or N2) stage III tumors despite adjuvant chemotherapy. Improving outcome for this patient population is urgently needed. In the NICHE-2 study, pts with non-metastatic dMMR CC were treated with one dose of ipilimumab (1mg/kg) and two doses of nivolumab (3mg/kg) and underwent surgery ≤6 weeks of registration. The co-primary endpoints were safety (ITT) and 3-year DFS (PP). Secondary endpoints included major pathologic response (MPR) and complete response (pCR) rates. Pathologic response was defined as ≤50% residual viable tumor (RVT), and MPR as ≤10% RVT. Here we present safety and pathologic response data. A total of 112 pts were treated. Grade 3-4 immune-related adverse events were observed in 3 (3%) patients and only 3 pts experienced delay in surgery, meeting the safety primary endpoint. In the PP population (n=107), baseline radiologic assessment revealed 89% stage III, 77% high-risk stage III (Table), and 64% T4 tumors. With a median time from first dose to surgery of 5 weeks, pathologic response was observed in 106/107 (99%) pts, consisting of 102/107 (95%) MPR and 4 (4%) PR. PCR was observed in 72/107 (67%) pts. At a median follow-up of 13 months (range 1-57), none of the pts had disease recurrence.Table: LBA7Pathologic responseMPRpCRClinical stageI/II (n = 12)11 (92%)9 (75%)Low risk IIIa/b (n = 13)13 (100%)10 (77%)High risk IIIa/b (n = 17)16 (94%)10 (59%)High risk IIIc (n = 65)62 (95%)43 (66%)Total (n = 107)102 (95%)72 (67%) Open table in a new tab In NICHE-2 we confirm the previously reported pathologic responses to short-term neoadjuvant nivolumab plus ipilimumab in a large cohort of dMMR CC pts, with an MPR rate of 95%, including 67% pCR. The first survival data suggest a strong potential for neoadjuvant immunotherapy to become standard of care and allow further exploration of organ-sparing approaches.

Abstract 1382: Comparison of intratumoral T-cell repertoires in DNA mismatch repair proficient and deficient colon adenocarcinoma

Abstract Colon tumors with deficient DNA mismatch repair (dMMR) are infiltrated more densely by T cells than tumors with proficient mismatch repair (pMMR). However, high tumor-infiltrating lymphocytes (TIL) are found in a subset of pMMR tumors and low TIL are seen in a subset of dMMR colon cancer. In this study, we compared T-cell repertoires in 20 pMMR and 27 dMMR colon tumors with high and low TIL counts. CDR3 regions of the TCR beta chain were sequenced by ImmunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA). The fraction T cells was calculated by normalizing TCR beta template counts to the total DNA. Sample richness was calculated as the number of unique productive rearrangements in a sample after computationally down-sampling to a common number of T cells to control for variation in sample depth. Simpson clonality was computed as a measure of how evenly productive rearrangements are distributed amongst the total number of T cells. Statistical analyses were performed using Prism 8.0 (GraphPad, La Jolla, CA). The mean TIL counts per high power field (HPF) for TIL-high and TIL-low dMMR tumors were 17.4 (range, 5-37) and 1.8 (range, 0-4). In pMMR tumors, they were 12.8 (range, 6-37) for TIL-high and 0.3 (range, 0-1) for TIL-low groups. The number of T cells measured by TCR sequencing correlated positively with the TIL count (Spearman rho = 0.391; P = 0.007). When comparing by MMR status, we found that dMMR tumors exhibited a trend towards higher Simpson clonality index (P = 0.09), with significantly lower repertoire richness compared to pMMR tumors (P = 0.030). Within dMMR tumors, TIL-high dMMR tumors had higher density (P = 0.017), higher clonality (P = 0.003), and a less rich repertoire (P = 0.003) compared to TIL-low dMMR tumors. Within pMMR tumors, while the T cell density was higher in the TIL-high tumors, we did not observe differences in T cell clonality or repertoire richness between TIL-high vs TIL-low pMMR tumors. Our study found that T cells in dMMR tumors are more clonal and their repertoire is less rich compared with T cells in pMMR tumors. In the dMMR group, T cells in TIL-high tumors were more clonal and their repertoire was less rich compared with T cells in TIL-low tumors, but in the pMMR group, T-cell diversity in TIL-high tumors was comparable to T-cell diversity in TIL-low tumors. These findings suggest that T cells clonally expand in dMMR tumors, possibly in response to MMR deficiency-induced tumor neoantigens. Citation Format: Jin K. Kim, Chin-Tung Chen, Asama Khan, Neil Segal, Zsofia Stadler, Jinru Shia, Vinod P. Balachandran. Comparison of intratumoral T-cell repertoires in DNA mismatch repair proficient and deficient colon adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1382.

Neoadjuvant nivolumab, ipilimumab, and celecoxib in MMR-proficient and MMR-deficient colon cancers: Final clinical analysis of the NICHE study.

3511 Background: The combination of PD-1 and CTLA4 blockade has changed the treatment landscape for several cancer types. Although this treatment is highly effective in metastatic mismatch-repair deficient (dMMR) colorectal cancers, metastatic MMR-proficient (pMMR) tumors do not respond. The NICHE study was the first neoadjuvant immunotherapy study in colon cancer (CC) to show impressive responses in 100% of dMMR ( n= 20) and 27% of pMMR ( n= 15) CC. In contrast, pathologic response to neoadjuvant chemotherapy using standard of care folfox is approximately 5% in dMMR tumors. Here we present the final efficacy data for the original NICHE study cohorts. Methods: Patients with non-metastatic, resectable dMMR or pMMR CC were treated with a single dose of ipilimumab 1mg/kg and two doses of nivolumab 3mg/kg and underwent surgery within 6 weeks. In addition, patients with pMMR tumors were randomized to receive celecoxib. The primary endpoints were safety and feasibility, and secondary endpoints included pathologic response rate and disease-free survival in 30 patients with dMMR and 30 with pMMR tumors. Pathologic response was defined as 50% or less viable tumor rest (VTR), and major pathologic response (MPR) as &lt;10% VTR. Results: Thirty patients with pMMR and 32 with dMMR tumors were evaluable for the efficacy analyses. In the pMMR cohort, pathologic response was observed in 9/30 (30%, 95% CI 14-46%) patients, consisting of 7 MPR (including 3 pathologic complete responses {pCR}) and 2 partial responses. Four out of 9 pMMR responders had received celecoxib. Five patients received adjuvant chemotherapy. At a median follow-up of 25 months (IQR 12-35 months), 3 patients (all non-responders) in the pMMR group had disease recurrence. In the 32 patients with dMMR tumors, pathologic response was observed in 100% of patients, with 31/32 MPR (97%, 95% CI 91-100%) and one partial response. Pathologic complete response was observed in 22/32 (69%, 95% CI 53-85%) patients. None of the patients in the dMMR cohort had disease recurrence. Surgery was delayed in one patient with a pMMR tumor due to myositis. Grade 3 immune-related adverse events were observed in 12% of patients, consistent with our previous report on the primary endpoint. There were no grade 4 immune-related AEs nor unexpected surgical complications. Conclusions: These data confirm our previously published results of the NICHE study, with responses to neoadjuvant nivolumab plus ipilimumab in 30% of pMMR and 100% of dMMR CC in the completed original cohorts. Validation of the dMMR responses in a large group of dMMR patients is ongoing and has the potential to change current practice. Clinical trial information: NCT03026140.

Prognostic impact of high-risk factors and KRAS mutation in patients with stage II deficient mismatch repair colon cancer: a retrospective cohort study.

BackgroundDeficient mismatch repair (dMMR) is associated with a good prognosis in patients with stage II colon cancer and observation is recommended after surgery in these patients. In contrast, patients with high-risk factors and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is associated with a poor prognosis in colon cancer. However, the prognosis and treatment of patients with dMMR colon cancer combined with high-risk factors or KRAS mutation remains unclear. This study aimed to evaluate whether patients with dMMR colon cancer combined with high-risk factors or KRAS mutation require further treatment.MethodsThis single-center retrospective study included patients who received radical surgical resection and mismatch repair (MMR) immunohistochemical detection at The Sixth Affiliated Hospital of Sun Yat-sen University between May 2011 and March 2021. The high-risk factors and KRAS mutation were assessed by clinicopathological data and targeted sequencing. Associations with disease-free survival (DFS) were evaluated using multivariable Cox models.ResultsAmong the 1,357 patients with stage II colorectal cancer included, 226 of these patients had dMMR. Patients in the dMMR group were more likely to be younger [<50 years: odds ratio (OR) =0.401, 95% CI: 0.288–0.558, P<0.001], with poor differentiation (OR =5.800, 95% CI: 3.437–9.787, P<0.001), no perineural invasion (OR =0.132, 95% CI: 0.047–0.368, P<0.001), and more than 12 excised lymph nodes (OR =0.427, 95% CI: 0.188–0.968, P=0.042). The disease-free survival (DFS) of patients with stage II dMMR colon cancer with high-risk factors was similar to that of patients without high-risk factors (hazard ratio (HR) =1.285, 95% CI: 0.273–6.051, P=0.607). A total of 836 patients had complete data regarding KRAS status. Compared with KRAS wild-type patients, patients with KRAS gene mutation had a trend of poor prognosis in patients with stage II colon cancer (HR=1.483, 95% CI: 0.983–2.239, P=0.061). In addition, dMMR appeared to be a protective factor in patients with KRAS mutation (HR =0.138, 95% CI: 0.019–1.002, P=0.0501).ConclusionsThe survival of patients with stage II dMMR colon cancer with high-risk factors was similar to that of patients without high-risk factors, regardless of the presence of KRAS mutation.

Distinct Hypoxia-Related Gene Profiling Characterizes Clinicopathological Features and Immune Status of Mismatch Repair-Deficient Colon Cancer.

Despite dramatic responses to immune checkpoint inhibitors (ICIs) in patients with colon cancer (CC) harboring deficient mismatch repair (dMMR), more than half of these patients ultimately progress and experience primary or secondary drug resistance. There is no useful biomarker that is currently validated to accurately predict this resistance or stratify patients who may benefit from ICI-based immunotherapy. As hypoxic and acidic tumor microenvironment would greatly impair tumor-suppressing functions of tumor-infiltrating lymphocytes (TILs), we sought to explore distinct immunological phenotypes by analysis of the intratumoral hypoxia state using a well-established gene signature. Based on the Gene Expression Omnibus (GEO) (n = 88) and The Cancer Genome Atlas (TCGA) (n = 49) databases of patients with CC, we found that dMMR CC patients could be separated into normoxia subgroup (NS) and hypoxia subgroup (HS) with different levels of expression of hypoxia-related genes (lower in NS group and higher in HS group) using NMF package. Tumoral parenchyma in the HS group had a relatively lower level of immune cell infiltration, particularly CD8+ T cells and M1 macrophages than the NS group, and coincided with higher expression of immune checkpoint molecules and C-X-C motif chemokines, which might be associated with ICI resistance and prognosis. Furthermore, three genes, namely, MT1E, MT2A, and MAFF, were identified to be differentially expressed between NS and HS groups in both GEO and TCGA cohorts. Based on these genes, a prognostic model with stable and valuable predicting ability has been built for clinical application. In conclusion, the varying tumor-immune microenvironment (TIME) classified by hypoxia-related genes might be closely associated with different therapeutic responses of ICIs and prognosis of dMMR CC patients.

Duration of FOLFOX Adjuvant Chemotherapy in High-Risk Stage II and Stage III Colon Cancer With Deficient Mismatch Repair.

BackgroundWe evaluated the impact of 3 months of mFOLFOX6 adjuvant chemotherapy or surgery alone in comparison with 6 months of mFOLFOX6 on disease-free survival (DFS) in deficient mismatch repair (dMMR) colon cancer (CC) patients.MethodsThis retrospective study identified a cohort of patients with high-risk stage II and III dMMR CC who underwent curative surgery between May 2011 and July 2019. DFS was compared using the Kaplan-Meier survival methods and Cox proportional hazards models. Propensity-score matching was performed to reduce imbalance in baseline characteristics.ResultsA total of 242 dMMR CC patients were identified; 66 patients received 6 months of mFOLFOX6, 87 patients received 3 months of mFOLFOX6, and 89 patients were treated with surgery alone. The 3-year DFS rate was 72.8% in 3-month therapy group and 86.1% in 6-month therapy group, with a hazard ratio (HR) of 2.78 (95CI%, 1.18 to 6.47; P= 0.019). The difference in DFS between surgery alone group and 6-month therapy group was also observed but was nonsignificant (HR= 2.30, 95%CI, 0.99 to 5.38; P=0.054). The benefit of 6-month therapy in DFS compared with 3-month therapy group was pronounced for patients with stage III (HR=2.81, 95%CI, 1.03 to 7.67; P=0.044) but not for high-risk stage II patients. Propensity score matched analysis confirmed a DFS benefit in the 6-month therapy group.ConclusionThis study suggested that a 6-month duration of mFOLFOX6 adjuvant chemotherapy in dMMR CC patients may be associated with improved DFS compared with 3-month therapy, particularly in patients with stage III. The observational nature of the study implies caution should be taken in the interpretation of these results.

Prognostic and predictive roles of DNA mismatch repair status in colon cancer patients treated with oxaliplatin-based chemotherapy: a retrospective study.

This study aims to evaluated the prognostic and predictive roles of DNA mismatch repair status in colon cancer patients treated with oxaliplatin-based chemotherapy. From 2005 to 2008, patients who underwent curative surgical resection for high-risk stage II or stage III colon cancer were recruited in this study. These patients had been received oxaliplatin-based chemotherapy. A total 324 patients were included (41.7% at stage II and 58.3% at stage III), and 59 patients (18.2%) exhibited mismatch repair-deficient (dMMR). The prognostic analysis revealed an increase in disease-free survival (DFS) for dMMR patients versus proficient MMR (pMMR) patients (81.4% versus 64.2%, P = 0.009), and overall survival (OS) (86.4% versus 69.1%, P = 0.004). Among the 82 patients who did not receive adjuvant therapy, the 5-year DFS was significantly higher in patients with dMMR (81.3%) than in patients with pMMR (49.7%, P = 0.040). In the multivariate models, dMMR was independently associated with improved DFS (HR = 2.171, 95% CI: 1.108 - 4.253, P = 0.024) and OS (HR = 2.521, 95% CI: 1.190 - 5.339, P = 0.016). In the predictive analysis, it was observed that the benefit of treatment significantly differed according to the DNA MMR status (P = 0.020). Compared with surgery alone, oxaliplatin-based adjuvant chemotherapy improved the 5-year DFS (69.9% versus 56.2%, P = 0.024) among patients with pMMR in the multivariable analysis (HR = 0.794, 95% CI = 0.646 - 0.976, P = 0.029). In contrast, the oxaliplatin-based chemotherapy in the group with dMMR had no benefit in DFS (83.1% versus 81.8%, HR 1.040, 95% CI: 0.276 - 3.922, P = 0.954). Patients with dMMR colon cancer are associated with improved survival rates, compared with pMMR colon cancer. MMR status is an independent prognostic biomarker for DFS in patients with high-risk stage II and stage III colon cancer. Oxaliplatin-based adjuvant chemotherapy mainly benefits patients with pMMR, but may not benefit patients with tumors exhibiting dMMR.

Duration of FOLFOX adjuvant chemotherapy in high-risk stage II and stage III colon cancer with deficient DNA mismatch repair.

4075 Background: In the IDEA collaboration, noninferiority was not confirmed for 3 months versus 6 months of FOLFOX adjuvant chemotherapy among patients with high-risk stage II and stage III colon cancer (CC). Patients with deficient DNA mismatch repair (dMMR) have a good prognosis, but for whom, whether limiting the duration of adjuvant therapy will compromise oncologic outcomes remains undefined. We evaluated the impact of 3 months of FOLFOX adjuvant chemotherapy or surgery alone in comparison with 6 months of FOLFOX on disease-free survival (DFS) in dMMR CC patients. Methods: This retrospective study included all consecutive patients who underwent curative surgical resection for high-risk stage II or III dMMR CC between May, 2011 and July, 2019. Prognostic factors were analyzed using Cox models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Results: A total of 242 dMMR CC patients were included (43.4% high-risk stage II, 56.6% stage III). The patients received 6 months of FOLFOX adjuvant chemotherapy (n = 66; median cycles [rang] = 12 [10-12]), 3 months of FOLFOX (n = 87; median cycles [rang] = 6 [4-8]), or surgery alone (n = 89). Three groups were generally well balanced, although more patients with stage III were in the 6-month therapy group (74.2%), compared with the 3-month therapy group (57.5%) and the surgery alone group (42.7%). As compared with 6 months of FOLFOX adjuvant chemotherapy in the overall population, 3 months therapy reduced DFS in multivariable analysis (HR, 2.78; 95CI, 1.18 to 6.47; P = 0.02), similar to surgery alone (HR, 2.30; 95CI, 0.99 to 5.38; P = 0.05). In the subgroup analysis, a therapy duration of 6 months was statistically superior to a duration of 3 months only in the patients with stage III, with a 3-year rate of DFS of 86.2% versus 70.8% (HR, 3.06; 95% CI, 1.14 to 8.19; P = 0.026). Conclusions: This study supports the 6-month duration of FOLFOX adjuvant chemotherapy in stage III dMMR CC.

Clinical Outcomes in Patients With Colon Cancer With Microsatellite Instability of Sporadic or Familial Origin Treated With Adjuvant FOLFOX With or Without Cetuximab: A Pooled Analysis of the PETACC8 and N0147 Trials.

The microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually regarded as a single biologic entity, given the absence of comparative analyses regarding prognosis and response to chemotherapy between sporadic and familial dMMR cancers. Patients with stage III colon cancers were randomly assigned to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without cetuximab in 2 large adjuvant phase III trials (N = 5,577). Among patients with MSI and KRAS exon 2 wild-type (WT) tumors, the prognostic and predictive impacts of sporadic versus familial dMMR cancers and BRAF V600E mutational status were determined. Multivariable Cox proportional hazards models were used to assess disease-free survival (DFS) by treatment arm, adjusting for age, sex, tumor grade, Eastern Cooperative Oncology Group performance status, pT/pN stage, and primary tumor location. Among patients with MSI status with complete data for dMMR mechanism analysis (n = 354), 255 (72%) had sporadic (BRAF mutation and/or MLH1 methylation) and 99 (28%) had familial tumors (BRAF WT and unmethylated MLH1 or loss of MSH2/MSH6/PMS2 protein expression). A large proportion of dMMR sporadic tumors were mutated for BRAF (n = 200). In patients treated with FOLFOX, DFS did not differ statistically by dMMR mechanism, whereas in patients treated with FOLFOX plus cetuximab, those with sporadic tumors had worse DFS than those with familial cancers (multivariable hazard ratio, 2.69; 95% CI, 1.02 to 7.08; P = .04). Considering the predictive utility, the interaction between treatment and dMMR mechanism was significant (P = .03). Furthermore, a nonsignificant trend toward a deleterious effect of adding cetuximab to FOLFOX was observed in patients with BRAF-mutant but not BRAF WT tumors. The addition of cetuximab to adjuvant FOLFOX was associated with shorter DFS in patients with sporadic dMMR colon cancer. Additional studies are needed to validate these results in metastatic disease.

Expression of secreted frizzled-related protein 4 in DNA mismatch repair-deficient and mismatch repair-proficient colorectal cancers

To investigate the expressions of secreted frizzled-related protein 4 (SFRP4) in stage Ⅱ DNA mismatch repair-deficient (dMMR) and mismatch repair- proficient (pMMR) colorectal cancers and explore their clinical significance. We collected fresh stage Ⅱ colon cancer tissues with different MMR status detected by immunohistochemistry (IHC). The differentially expressed mRNAs between dMMR and pMMR tumors were identified by Affymetrix Human oeLncRNA gene chip, and the expression of SFRP4 in these cancer tissues and in colorectal cancer cell lines were detected using Western blotting and real- time quantitative PCR. The apoptosis rates of HCT116 cells with and without siRNA- mediated transient SFRP4 knockdown were determined using flow cytometry. We further investigated the expression pattern of Ki-67 and its correlation with SFRP4 expression. Compared with pMMR colon cancer tissues or cells, both dMMR colon cancer tissues (P=0.014) and cells (P=0.0079) showed significantly increased expression of SFRP4, which was in negative correlation with Ki-67 (P=0.041). In HCT116 cells, transient SFRP4 knockdown resulted in decreased cell apoptosis, including both early apoptosis (P=0.003) and late apoptosis (P=0.024). Up-regulation of SFRP4 in dMMR stage Ⅱ colon cancer promotes apoptosis and inhibits proliferation of the cancer cells, and may improve the prognosis of dMMR colon cancer.