Early evaluation of the effectiveness and cost-effectiveness of ctDNA-guided selection for adjuvant chemotherapy in stage II colon cancer.

Background: Current patient selection for adjuvant chemotherapy (ACT) after curative surgery for stage II colon cancer (CC) is suboptimal, causing overtreatment of high-risk patients and undertreatment of low-risk patients. Postoperative circulating tumor DNA (ctDNA) could improve patient selection for ACT. Objectives: We conducted an early model-based evaluation of the (cost-)effectiveness of ctDNA-guided selection for ACT in stage II CC in the Netherlands to assess the conditions for cost-effective implementation. Methods: A validated Markov model, simulating 1000 stage II CC patients from diagnosis to death, was supplemented with ctDNA data. Five ACT selection strategies were evaluated: the current guideline (pT4, pMMR), ctDNA-only, and three strategies that combined ctDNA status with pT4 and pMMR status in different ways. For each strategy, the costs, life years, quality-adjusted life years (QALYs), recurrences, and CC deaths were estimated. Sensitivity analyses were performed to assess the impact of the costs of ctDNA testing, strategy adherence, ctDNA as a predictive biomarker, and ctDNA test performance. Results: Model predictions showed that compared to current guidelines, the ctDNA-only strategy was less effective (+2.2% recurrences, -0.016 QALYs), while the combination strategies were more effective (-3.6% recurrences, +0.038 QALYs). The combination strategies were not cost-effective, since the incremental cost-effectiveness ratio was €67,413 per QALY, exceeding the willingness-to-pay threshold of €50,000 per QALY. Sensitivity analyses showed that the combination strategies would be cost-effective if the ctDNA test costs were lower than €1500, or if ctDNA status was predictive of treatment response, or if the ctDNA test performance improved substantially. Conclusion: Adding ctDNA to current high-risk clinicopathological features (pT4 and pMMR) can improve patient selection for ACT and can also potentially be cost-effective. Future studies should investigate the predictive value of post-surgery ctDNA status to accurately evaluate the cost-effectiveness of ctDNA testing for ACT decisions in stage II CC.

Effectiveness and cost-effectiveness of circulating tumour DNA-guided selection for adjuvant chemotherapy in patients with stage II colon cancer Most patients with stage II colon cancer (CC) are cured by surgery. Therefore, guidelines recommend to only offer adjuvant chemotherapy to patients who have a tumor with high-risk features. However, current selection is suboptimal, leading to recurrence of cancer in 13% of low-risk patients and unnecessary administration of chemotherapy in some high-risk patients. Previous studies indicate that a biomarker, so-called circulating tumour DNA (ctDNA), could improve the selection of high-risk patients for adjuvant chemotherapy, as patients who have detectable ctDNA in their blood after surgery are likely to develop a recurrence. Despite its potential, implementation is still pending. Our study assessed the long-term effectiveness and costs associated with various ctDNA-guided strategies for selecting high-risk patients for adjuvant chemotherapy in stage II CC. We used an health-economic model to simulate a cohort of 1000 Dutch patients with stage II CC from diagnosis to death. Next, we compared the health outcomes and costs of the ctDNA-guided strategies to those when selection is based on the Dutch guideline. We found that a combination of the Dutch guideline and ctDNA was the most effective strategy, but not cost-effective. Additional analyses showed that ctDNA-guided selection were cost-effective if the costs of the ctDNA test were below 1500 euros, if the ctDNA test performed significantly better, or if patients with detectable ctDNA responded better to chemotherapy. Thus, while post-surgery ctDNA status is a good indicator for recurrence risk, specific criteria related to ctDNA test performance and costs, in addition to combining ctDNA with current high-risk features, should be met to achieve cost-effective implementation. Looking ahead, future studies should explore how patients with detectable ctDNA respond to chemotherapy for next assessments of the cost-effectiveness of ctDNA-guided strategies in selecting patients with stage II CC for adjuvant chemotherapy.

Stromal localization of inactive CD8+ T cells in metastatic mismatch repair deficient colorectal cancer.

BACKGROUND: The determinants of metastasis in mismatch repair deficiency with high levels of microsatellite instability (MSI-H) in colorectal cancer (CRC) are poorly understood. Here, we hypothesized that distinct immune and stromal microenvironments in primary tumors may discriminate between non-metastatic MSI-H CRC and metastatic MSI-H CRC. METHODS: We profiled 46,727 single cells using high-plex imaging mass cytometry and analyzed both differential cell type abundance, and spatial distribution of fibroblasts and immune cells in primary CRC tumors with or without metastatic capacity. We validated our findings in a second independent cohort using immunohistochemistry. RESULTS: High-plex imaging mass cytometry and hierarchical clustering based on microenvironmental markers separated primary MSI-H CRC tumors with and without metastatic capacity. Primary tumors with metastatic capacity displayed a high stromal content and low influx of CD8+ T cells, which expressed significantly lower levels of markers reflecting proliferation (Ki67) and antigen-experience (CD45RO) compared to CD8+ T cells in non-metastatic tumors. CD8+ T cells showed intra-epithelial localization in non-metastatic tumors, but stromal localization in metastatic tumors, which was validated in a second cohort. CONCLUSION: We conclude that localization of phenotypically distinct CD8+ T cells within stroma may predict metastasis formation in MSI-H CRC.

Comparison of NTRK fusion detection methods in microsatellite-instability-high metastatic colorectal cancer.

Tropomyosin receptor kinase (TRK) inhibitors have been approved for metastatic solid tumors harboring NTRK fusions, but the detection of NTRK fusions is challenging. International guidelines recommend pan-TRK immunohistochemistry (IHC) screening followed by next generation sequencing (NGS) in tumor types with low prevalence of NTRK fusions, including metastatic colorectal cancer (mCRC). RNA-based NGS is preferred, but is expensive, time-consuming, and extracting good-quality RNA from FFPE tissue is challenging. Alternatives in daily clinical practice are warranted. We assessed the diagnostic performance of RNA-NGS, FFPE-targeted locus capture (FFPE-TLC), fluorescence in situ hybridization (FISH), and the 5'/3' imbalance quantitative RT-PCR (qRT-PCR) after IHC screening in 268 patients with microsatellite-instability-high mCRC, the subgroup in which NTRK fusions are most prevalent (1-5%). A consensus result was determined after review of all assay results. In 16 IHC positive tumors, 10 NTRK fusions were detected. In 33 IHC negative samples, no additional transcribed NTRK fusions were found, underscoring the high sensitivity of IHC. Sensitivity of RNA-NGS, FFPE-TLC, FISH, and qRT-PCR was 90%, 90%, 78%, and 100%, respectively. Specificity was 100% for all assays. Robustness, defined as the percentage of samples that provided an interpretable result in the first run, was 100% for FFPE-TLC, yet more limited for RNA-NGS (85%), FISH (70%), and qRT-PCR (70%). Overall, we do not recommend FISH for the detection of NTRK fusions in mCRC due to its low sensitivity and limited robustness. We conclude that RNA-NGS, FFPE-TLC, and qRT-PCR are appropriate assays for NTRK fusion detection, after enrichment with pan-TRK IHC, in routine clinical practice.

Cell-Free Circulating (Tumor) DNA before Surgery as a Prognostic Factor in Non-Metastatic Colorectal Cancer: A Systematic Review.

Identification of non-metastatic colorectal cancer (CRC) patients with a high risk of recurrence after tumor resection is important to select patients who might benefit from adjuvant treatment. Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) analyses after surgery are promising biomarkers to predict recurrence in these patients. However, these analyses face several challenges and do not allow guidance of neoadjuvant treatment, which might become a novel standard option in colon cancer treatment. The prognostic value of cfDNA/ctDNA before surgery is unclear. This systematic review aims to provide an overview of publications in which the prognostic value of presurgery cfDNA/ctDNA in non-metastatic CRC patients was studied and is performed according to PRISMA guidelines. A total of 29 out of 1233 articles were included and categorized into three groups that reflect the type of approach: measurement of cfDNA, ctDNA somatic alterations, and ctDNA methylation. Overall, a clear association between presurgery cfDNA/ctDNA and the outcome was not observed, but large studies that primarily focus on the prognostic value of presurgery cfDNA/ctDNA are lacking. Designing and performing studies that focus on the value of presurgery cfDNA/ctDNA is needed, in addition to standardization in the reporting of cfDNA/ctDNA results according to existing guidelines to improve comparability and interpretation among studies.