Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti–PD-1–Based Immunotherapy as Curative-Intent Treatment

Authors:
Jie-Hai Yu State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

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Le-En Liao State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

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Bin-Yi Xiao State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

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Xuan Zhang Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China

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Ai-Wen Wu Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China

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Yong Cheng Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

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Jing-Hua Tang State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

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Wu Jiang State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

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Ling-Heng Kong State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

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Kai Han State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

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Wei-Jian Mei State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

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Zhi-Gang Hong State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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Wan-Jun Yang State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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Dan-Dan Li State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou, China

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Zhi-Zhong Pan State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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Yun-Feng Li Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China

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Xiao-Shi Zhang State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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Pei-Rong Ding State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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Background: Neoadjuvant anti–PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti–PD-1 therapy. Methods: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti–PD-1–based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. Results: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0–77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0–12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0–36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6–48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. Conclusions: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti–PD-1–based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.

Background

Although standard treatment options for rectal cancer include surgery, chemotherapy, and radiation therapy,1,2 treatment of deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC) presents a totally different landscape.36 Evidence has emerged that immune checkpoint inhibitors (ICIs) as neoadjuvant therapy or curative-intent therapy in the management of dMMR/MSI-H CRC are very promising. It has been consistently reported that PD-1 blockades are highly effective in dMMR/MSI-H CRCs in the neoadjuvant setting, with a major pathologic response rate of 94% to 100% and pathologic complete response (pCR) rate of 60% to 88%.7,8

The remarkable pCR rate led to testing the hypothesis of using nonoperative management in patients with dMMR/MSI-H low-lying rectal cancer who experience complete clinical response (cCR) following neoadjuvant ICI therapy. In 2019, Zhang et al9 reported on a patient with dMMR locally advanced rectal cancer (LARC) who experienced cCR after neoadjuvant treatment with PD-1 blockades and was successfully managed using a watch-and-wait (WW) approach, and similar cases were reported by Demisse et al10 and our team.11,12

The milestone study was reported by Cercek et al,13 demonstrating that all 12 patients with dMMR/MSI-H LARC experienced cCR after 6 months of anti–PD-1 therapy. With a median follow-up time (from study enrollment) of 12 months, no progression or recurrence was observed, suggesting the potential of PD-1 antibody as a curative-intent therapy. Subsequently, a larger cohort (n=19) from our team reinforced the exceptional short-term outcome of the WW strategy in patients with dMMR/MSI-H rectal cancer who experienced cCR after neoadjuvant anti–PD-1 treatment—with a median follow-up time of 17.1 months, no recurrence was observed.11 In addition, Chen et al14 also reported a similar result in a cohort of 9 patients who achieved cCR and were then managed with the WW strategy. Collectively, this evidence suggests the potential of anti–PD-1 treatment as a curative-intent therapy and a treatment alternative for organ and function preservation in patients with dMMR/MSI-H LARC. However, the long-term outcomes of the WW approach in this population remain largely unknown, primarily due to the relatively short follow-up time in previous studies.

In this study, we aimed to investigate the long-term outcomes of patients with dMMR/MSI-H rectal cancer who experienced cCR following anti–PD-1 therapy and received nonoperative management.

Methods

Study Design and Patient Selection

This was a multicenter retrospective cohort study. Patients with dMMR/MSI-H nonmetastatic rectal cancer who received at least 1 dose of PD-1 blockade at 1 of 4 medical centers in China between March 2018 and May 2022 were screened. Those who met the following criteria were included: (1) pathologically confirmed rectal adenocarcinoma, (2) dMMR and/or MSI-H status, (3) stage II/III or stage I with tumor located in the distal rectum, (4) received at least 1 cycle of PD-1 inhibitors, (5) experienced cCR and decided to be managed with a nonoperative approach, and (6) followed up for at least 1 year after cCR. Patients treated with chemotherapy or chemoradiotherapy after experiencing cCR were excluded. Informed consent from patients was waived due to the retrospective nature of this study, and the study protocol was approved by the ethics committee of each study center.

Study Procedures

Data were collected from each center using a standardized electronic form, and the data mainly included information on demographics, clinical and genomic characteristics, treatments, and follow-ups.

Tumor response was evaluated according to RECIST (version 1.1)15 after every 2 to 3 cycles of anti–PD-1 immunotherapy. cCR was defined as the absence of residual tumor on digital rectal examination, colonoscopy, and pelvic MRI, accompanied by a normal serum CEA level and negative findings on chest and abdominal CT scans. PET/CT was not mandatory. Adverse events were evaluated according to CTCAE, version 5.0. After completing treatment, patients were followed up every 3 months. The last day of follow-up was May 10, 2023.

Statistical Analysis

Continuous variables were described as medians with ranges, and categorical variables were shown as frequency. Survival analysis was calculated using the Kaplan-Meier method.

The starting timepoint in this study was the day cCR was achieved. The primary endpoint was disease-free survival, which was defined as the absence of any recurrence, including at the local site and distant recurrence, and death as a result of any cause. Overall survival was defined as the absence of death from any cause. Analyses were performed using SPSS Statistics, version 22.0 (IBM Corp.).

Results

Baseline Characteristics

From March 2018 to May 2022, a total of 61 patients with dMMR/MSI-H nonmetastatic rectal cancer received at least 2 doses of PD-1 blockades at 1 of 4 medical centers. A cCR was experienced by 44 (72.1%) patients. Among them, 41 patients decided to pursue organ preservation and were consequently managed with a WW strategy. Among these patients, 24 were followed up ≥1 year after experiencing cCR and were finally included in the analysis (Figure 1). Median age at diagnosis was 51.0 years (range, 19.0–77.0 years), and 58.3% of the patients were male. Baseline characteristics are provided in Table 1, and details regarding individual patients are provided in Table 2.

Figure 1.
Figure 1.

Study profile.

Abbreviations: cCR, clinical complete response; dMMR, deficient DNA mismatch repair; MSI-H, microsatellite instability-high.

Citation: Journal of the National Comprehensive Cancer Network 22, 3; 10.6004/jnccn.2023.7096

Table 1.

Patient Baseline Characteristics (N=24)

Table 1.
Table 2.

Details of Patients Who Received PD-1 Blockade (N=24)

Table 2.

Treatment and Outcome

All patients received at least 2 cycles of PD-1 inhibitors, including pembrolizumab, nivolumab, sintilimab, camrelizumab, tislelizumab, and toripalimab, and the median course of treatment was 8.5 (range, 2.0–36.0) for the entire cohort. Most patients (83.3%) received at least 8 cycles of treatment. Two patients (8.3%) received PD-1 blockades after failure of neoadjuvant treatment with chemotherapy or chemoradiotherapy. Fifteen patients (62.5%) received PD-1 blockades as monotherapy, and the remaining patients received combined therapy (PD-1 blockade in combination with CTLA-4 inhibitor, chemotherapy, or targeted therapy; Table 2).

The median treatment course was 6.0 (range, 1.0–12.0), and median time to reach cCR was 5.0 months (range, 0.7–9.5 months). The majority of patients (21/24; 87.5%) experienced cCR after at most 8 courses of anti–PD-1 blockades. Notably, 9 (37.5%) patients discontinued their treatments after achieving cCR, with a median treatment course of 8.0 (range, 2.0–10.0). For those who continued to receive PD-1 blockades after cCR, the median overall treatment course was 17.0 (range, 3.0–36.0), and median treatment duration was 13.9 months (range 2.1–26.6 months). All patients avoided surgery for the reason of organ preservation and were subsequently managed with a WW strategy after treatment completion.

The occurrence of any grade of treatment-related toxicities was 62.5% (Table 3), which was acceptable. Two patients experienced grade ≥3 adverse events and therefore had treatment interruptions. It is worth noting that patient #3 developed refractory dermatitis 30 months after completion of the treatment, which was finally diagnosed as immunotherapy-related dermatitis. This patient experienced symptom relief after treatment with halometasone and localized symptomatic treatment.

Table 3.

Treatment-Related Adverse Events (N=24)

Table 3.

Follow-Up

The median follow-up after the first dose of PD-1 blockade was 34.5 months (range, 19.1–51.3 months), and the median follow-up after achievement of cCR was 29.1 months (range, 12.6–48.5 months). All patients remained alive at the cutoff of follow-up (Figure 2). In patient #22, suspected para-aortic and common iliac artery lymph node metastases were detected by CT scan 14 months after cCR (Figure 3), but the CT-guided biopsy found inflammation rather than viable tumor cells. Those lymph nodes decreased in size on PET/CT scan 8 months later, which was further considered no evidence of disease, although their standardized uptake values (SUVs) were slightly elevated. Thus, no local regrowth or distant metastasis was observed during the follow-up, and therefore the 3-year disease-free and overall survivals were both 100%.

Figure 2.
Figure 2.

Swimmer plot of the patients receiving PD-1 blockade in this cohort (N=24).

Abbreviation: CR, complete response.

Citation: Journal of the National Comprehensive Cancer Network 22, 3; 10.6004/jnccn.2023.7096

Figure 3.
Figure 3.

Radiologic and pathologic images of an abnormal node in patient #22. Axial CT images showing (A) area of the left common iliac artery at baseline, (B) timepoint at which cCR was achieved, and (C) 14 months and (E) 22 months after cCR was achieved. (D) Fine-needle aspiration image of the node found no tumor cells but did find evidence of infiltration of lymphocytes and inflammation (hematoxylin-eosin; original magnification ×10). (E) Axial CT image and (F) 18F-FDG PET/CT image showing the decrease in nodal size and the FDG uptake at the left common iliac artery. Red arrows indicate the enlarged node.

Abbreviation: cCR, clinical complete response.

Citation: Journal of the National Comprehensive Cancer Network 22, 3; 10.6004/jnccn.2023.7096

Discussion

In the current study, we presented an exceptional long-term outcome of the WW approach for patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who experienced cCR after anti–PD-1 treatment. Our results reinforced that a WW approach could be a safe treatment alternative for patients with dMMR/MSI-H rectal cancer.

Previous studies36,16 have shown that PD-1 blockades were highly effective for dMMR/MSI-H metastatic CRC (mCRC), and the benefit was durable. In CheckMate 142, ongoing responses were observed in 48% of responders with a median follow-up of 50.9 months, with responses lasting ≥36 months in 52% of these patients.5 In the final analysis of KEYNOTE-177, 76% of the patients who received first-line anti–PD-1 treatment had ongoing responses after 36 months.4 These long-lasting benefits in mCRC strongly suggest the curative potential of ICI treatment, motivating further investigation in the neoadjuvant setting. Cercek et al13 reported that 12 patients had cCR after completing 9 cycles of single-agent PD-1 blockades, after which a WW approach was used. No progression or recurrence was observed in a median follow-up time of 12 months from enrollment. Similarly, in a multicenter cohort, we observed no local or distant recurrence in 19 patients with dMMR/MSI-H LARC who achieved cCR after anti–PD-1 treatment, with a median follow-up of 17.1 months from the date of cCR.11 Similar results were later observed in several smaller cohorts.14,17,18 These promising short-term outcomes provided preliminary evidence of the role of neoadjuvant ICI as a curative therapy. Herein, we expanded upon these findings, demonstrating no progression or recurrence during a median follow-up of 29.1 months (range, 12.6–48.5 months) from the date of cCR in a multicenter cohort of 24 patients who achieved cCR after ICI treatment. This provides robust evidence for nonoperative management in patients with dMMR/MSI-H rectal cancer who achieve cCR following anti–PD-1 therapy.

The treatment of patients with dMMR/MSI-H rectal cancer who achieve cCR after neoadjuvant anti–PD-1 treatment presents another intriguing question. Patients with dMMR/MSI-H mCRC were recommended to receive PD-1 blockade for up to 2 years according to KEYNOTE-164 and KEYNOTE-177.4,16 In the scenario of neoadjuvant treatment in the study by Cercek et al,13 all patients discontinued their treatment after 9 cycles of PD-1 inhibitors and were then managed with a WW strategy. In our study, 15 (62.5%) patients continued to receive PD-1 inhibitors after experiencing cCR, whereas 9 patients stopped the treatment. There are several possible explanations for the discrepancy in duration of treatment after achieving cCR. First, there is still no consensus on real-world practices regarding the duration of treatment. Second, it remains difficult to precisely evaluate a pCR. A cCR usually falls behind a pCR. Furthermore, it might take much longer for a bulky tumor to achieve cCR compared with a small tumor. In the current study, patient #22 presented initially with a stage T4b tumor and experienced cCR after 12 cycles of treatment. Subsequently, the patient received an additional 5 cycles of treatment. Third, the regimens might have had an impact. In the NICHE study, the combination of CTLA-4 and PD-1 inhibitors demonstrated the potential to accelerate the responses,7 and for patients who receive dual immunotherapy, fewer courses of immunotherapy after cCR may be needed than for patients who receive monotherapy. To date, the optimal duration of treatment still needs to be determined. Further research is needed to explore the necessity of continuous use of treatment beyond achieving cCR and a shorter duration of treatment even before achieving cCR.

The optimal surveillance strategy after cCR remains largely unknown. Although a proportion of patients experience cCR after chemoradiotherapy and can then be managed with a WW strategy,1921 local regrowth is a concern, with a 15% to 34% risk reported for these patients.2124 Most of the local regrowth occurred within 1 year from attaining cCR,21,25 and Fernandez et al26 reported that the probability of remaining free from local regrowth within 2 years after achieving cCR was 88.1% for patients who sustained cCR for 1 year. These results indicate that the intensity of surveillance for these patients could be reduced if they achieve and maintain cCR for 3 years. For patients managed with a WW approach after ICI treatment, the current surveillance strategy follows the strategy implemented after chemoradiotherapy. The response patterns for these 2 treatments are different, but whether they have similar local recurrence patterns remains unclear. In mCRC, the final results of KEYNOTE-177 indicated that most of the disease progression or death occurred within the first 2 years after randomization, but evidence in the neoadjuvant setting was limited. In the current study, no local regrowth or distant recurrence was observed within a median follow-up of 29.1 months after achieving cCR, and preliminarily demonstrated that the risk of local recurrence was low in the first 2 years and, consequently, the intensive surveillance might not be necessary after 2 years of achieving cCR. Further evidence is still required to establish appropriate follow-up strategies.

It should be noted that pseudoprogression might occur during surveillance, which is quite different from the observation in patients achieving cCR following chemoradiotherapy. In the current study, patient #22 had suspected para-aortic and common iliac artery lymph node metastases detected by CT scan and an elevated serum CEA level (11.6 ng/mL) during surveillance 14 months after achieving cCR and 11 months after treatment was discontinued. However, the CT-guided biopsy found no viable tumor cells, but rather inflammation with immune cell infiltration. Furthermore, the retroperitoneal lymph nodes were slightly smaller after 8 months of observation and the serum CEA level decreased (8.87 ng/mL), which further excluded the possibility of recurrence. Enlarged lymph nodes after immunotherapy have been reported to be granulomatous/sarcoid-like lesions (GSLs)2730 or nodal immune flare (NIF),31 which were also considered to be immune-related adverse events. These granulomas are associated with the aggregation of immune cells such as giant cells and macrophages due to the activation of effector T cells and the increase of immune-active cytokines after administration of ICIs. According to Cascone et al,31 the incidence of GSLs or NIF is not rare after neoadjuvant ICI treatment in non–small cell lung cancer, occurring in 16% (7/44) of their cohort, which was remarkably higher than in patients with melanoma.32 Reports of GSLs or NIF in the ICI treatment of CRC were scarce. Unlike most lesions located in the thoracic lymph nodes in previous reports,28,31,33 the enlarged lymph nodes of patient #22 were found in para-aortic and common iliac artery lymph nodes, indicating the different pattern of GSLs or NIF in patients with CRC who receive ICIs. Given that GSLs or NIF also have higher SUVs on PET/CT scans,28,31 invasive biopsy is recommended to distinguish real tumor recurrence from GSLs or NIF. For patient #22, although core needle biopsy did not confirm retroperitoneal lymph node metastasis, the CEA level (8.87 ng/mL) did not return to normal and the SUV was still slightly elevated on PET/CT scan, suggesting that metastasis could be completely ruled out and that long-term close follow-up is essential.

The occurrence of GSLs or NIF suggests that radiologic pseudoprogression may also occur during posttreatment surveillance and more biologic markers should be explored to help optimize monitoring. Circulating tumor DNA (ctDNA) has shown promising potential as a predictor of recurrence in several tumors, including CRC.3437 The dynamic changes in ctDNA could reflect residual tumor burden,38 suggesting that it may be a valuable approach for detecting molecular residual disease to support treatment decisions and early detection of relapse.3941 Nevertheless, the efficacy of ctDNA requires further validation by clinical trials.

There are several limitations to our study. First, this study is a retrospective cohort study, which is subject to inherent biases, such as heterogeneity of regimens, selection bias, and confounding bias. Second, the sample size of the study cohort was relatively small, which may limit the generalizability of the findings. Nevertheless, to our knowledge, this is the largest cohort with the longest follow-up in patients with dMMR/MSI-H locally advanced or low-lying rectal cancer treated with a WW approach after experiencing cCR from neoadjuvant anti–PD-1 treatment.

Conclusions

Our results indicated that patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR after anti–PD-1–based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate our findings.

References

  • 1.

    Glynne-Jones R, Wyrwicz L, Tiret E, et al. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(Suppl 4):iv22–40.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Benson AB III, Venook AP, Adam M, et al. NCCN Clinical Practice Guidelines on Oncology: Rectal Cancer. Version 6.2023. Accessed November 20, 2023. To view the most recent version, visit https://www.nccn.org

    • PubMed
    • Export Citation
  • 3.

    André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383:22072218.

  • 4.

    Diaz LA Jr, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol 2022;23:659670.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    André T, Lonardi S, Wong K, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142. Ann Oncol 2022;33:10521060.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017;18:11821191.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Chalabi M, Fanchi LF, Dijkstra KK, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26:566576.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Hu H, Kang L, Zhang J, et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2022;7:3848.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Zhang J, Cai J, Deng Y, et al. Complete response in patients with locally advanced rectal cancer after neoadjuvant treatment with nivolumab. Oncoimmunology 2019;8:e1663108.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Demisse R, Damle N, Kim E, et al. Neoadjuvant immunotherapy-based systemic treatment in MMR-deficient or MSI-high rectal cancer: case series. J Natl Compr Canc Netw 2020;18:798804.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Wang QX, Xiao BY, Cheng Y, et al. Anti-PD-1-based immunotherapy as curative-intent treatment in dMMR/MSI-H rectal cancer: a multicentre cohort study. Eur J Cancer 2022;174:176184.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Xiao BY, Zhang X, Cao TY, et al. Neoadjuvant immunotherapy leads to major response and low recurrence in localized mismatch repair-deficient colorectal cancer. J Natl Compr Canc Netw 2023;21:6066.e5.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022;386:23632376.

  • 14.

    Chen G, Jin Y, Guan WL, et al. Neoadjuvant PD-1 blockade with sintilimab in mismatch-repair deficient, locally advanced rectal cancer: an open-label, single-centre phase 2 study. Lancet Gastroenterol Hepatol 2023;8:422431.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228247.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Le DT, Kim TW, Van Cutsem E, et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol 2020;38:1119.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Yang R, Wu T, Yu J, et al. Locally advanced rectal cancer with dMMR/MSI-H may be excused from surgery after neoadjuvant anti-PD-1 monotherapy: a multiple-center, cohort study. Front Immunol 2023;14:1182299.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Ludford K, Ho WJ, Thomas JV, et al. Neoadjuvant pembrolizumab in localized microsatellite instability high/deficient mismatch repair solid tumors. J Clin Oncol 2023;41:21812190.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004;240:711717; discussion 717–718.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Martens MH, Maas M, Heijnen LA, et al. Long-term outcome of an organ preservation program after neoadjuvant treatment for rectal cancer. J Natl Cancer Inst 2016;108:djw171.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Renehan AG, Malcomson L, Emsley R, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol 2016;17:174183.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Dossa F, Chesney TR, Acuna SA, et al. A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2017;2:501513.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Dattani M, Heald RJ, Goussous G, et al. Oncological and survival outcomes in watch and wait patients with a clinical complete response after neoadjuvant chemoradiotherapy for rectal cancer: a systematic review and pooled analysis. Ann Surg 2018;268:955967.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    van der Valk MJM, Hilling DE, Bastiaannet E, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet 2018;391:25372545.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Smith JJ, Strombom P, Chow OS, et al. Assessment of a watch-and-wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy. JAMA Oncol 2019;5:e185896.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Fernandez LM, São Julião GP, Figueiredo NL, et al. Conditional recurrence-free survival of clinical complete responders managed by watch and wait after neoadjuvant chemoradiotherapy for rectal cancer in the International Watch & Wait Database: a retrospective, international, multicentre registry study. Lancet Oncol 2021;22:4350.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Tetzlaff MT, Jazaeri AA, Torres-Cabala CA, et al. Erythema nodosum-like panniculitis mimicking disease recurrence: a novel toxicity from immune checkpoint blockade therapy—report of 2 patients. J Cutan Pathol 2017;44:10801086.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Tetzlaff MT, Nelson KC, Diab A, et al. Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients. J Immunother Cancer 2018;6:14.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Cornejo CM, Haun P, English J 3rd, et al. Immune checkpoint inhibitors and the development of granulomatous reactions. J Am Acad Dermatol 2019;81:11651175.

  • 30.

    Danlos FX, Pagès C, Baroudjian B, et al. Nivolumab-induced sarcoid-like granulomatous reaction in a patient with advanced melanoma. Chest 2016;149:e133136.

  • 31.

    Cascone T, Weissferdt A, Godoy MCB, et al. Nodal immune flare mimics nodal disease progression following neoadjuvant immune checkpoint inhibitors in non-small cell lung cancer. Nat Commun 2021;12:5045.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Eljilany I, Noor A, Paravathaneni M, et al. Granulomatous and sarcoid-like immune-related adverse events following CTLA4 and PD1 blockade adjuvant therapy of melanoma: a combined analysis of ECOG-ACRIN E1609 and SWOG S1404 phase III trials and a literature review. Cancers (Basel) 2023;15:2561.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Paydas S. Sarcoid-like reaction in cases treated by checkpoint inhibitors. Med Oncol 2021;38:29.

  • 34.

    Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov 2017;7:13941403.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Tie J, Cohen JD, Wang Y, et al. Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer. JAMA Oncol 2019;5:17101717.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Tie J, Cohen JD, Lahouel K, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med 2022;386:22612272.

  • 37.

    Krebs MG, Malapelle U, André F, et al. Practical considerations for the use of circulating tumor DNA in the treatment of patients with cancer: a narrative review. JAMA Oncol 2022;8:18301839.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Cabel L, Proudhon C, Romano E, et al. Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy. Nat Rev Clin Oncol 2018;15:639650.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Vellanki PJ, Ghosh S, Pathak A, et al. Regulatory implications of ctDNA in immuno-oncology for solid tumors. J Immunother Cancer 2023;11:e005344.

  • 40.

    Magbanua MJM, Swigart LB, Wu HT, et al. Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival. Ann Oncol 2021;32:229239.

  • 41.

    Chen G, Peng J, Xiao Q, et al. Postoperative circulating tumor DNA as markers of recurrence risk in stages II to III colorectal cancer. J Hematol Oncol 2021;14:80.

Submitted August 1, 2023; final revision received September 27, 2023; accepted for publication October 9, 2023. Published online March 18, 2024

Author contributions: Study concept and design: Yu, Liao, X. Zhang, Wu, Cheng, Pan, Y.F. Li, X.S. Zhang, Ding. Data acquisition: Yu, Liao, Xiao, X. Zhang, Wu, Cheng, Mei, Hong, Yang. Data analysis and interpretation: Yu, Liao, Xiao, X. Zhang. Funding acquisition: Jiang, Ding. Project administration: X. Zhang, Wu, Cheng, Pan, Y.F. Li, X.S. Zhang, Ding. Resources: Yu, Liao, Xiao, X. Zhang, Wu, Cheng, Tang, Jiang, Kong, Han, Mei, Hong, Yang, Y.F. Li. Supervision: Pan, X.S. Zhang, Ding. Manuscript preparation: All authors. Pei-Rong Ding had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Data availability statement: Due to patient privacy, patient-related data is not available for public access but can be obtained from Pei-Rong Ding at dingpr@sysucc.org.cn upon reasonable request. The key raw data have been uploaded to the Research Data Deposit public platform at www.researchdata.org.cn

Disclosures: The authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This study was supported by the National Natural Science Foundation of China under grant number 82073159 and Guangdong Basic and Applied Basic Research Foundation under grant number 2020A1515110544.

Correspondence: Pei-Rong Ding, MD, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, No. 651, Dongfeng East Road, Guangzhou 510060, P. R. China. Email: dingpr@sysucc.org.cn;
Xiao-Shi Zhang, MD, Department of Biotherapy, Sun Yat-sen University Cancer Center, No. 651, Dongfeng East Road, Guangzhou 510060, P. R. China. Email: zhangxsh@sysucc.org.cn;
Yun-Feng Li, MD, Department of Colorectal Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, No. 519 Kunzhou Road, Kunming 650100, China, P. R. China. Email: liyunfeng@kmmu.edu.cn; and
Zhi-Zhong Pan, MD, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, No. 651, Dongfeng East Road, Guangzhou 510060, P. R. China. Email: panzhzh@sysucc.org.cn
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  • Figure 1.

    Study profile.

    Abbreviations: cCR, clinical complete response; dMMR, deficient DNA mismatch repair; MSI-H, microsatellite instability-high.

  • Figure 2.

    Swimmer plot of the patients receiving PD-1 blockade in this cohort (N=24).

    Abbreviation: CR, complete response.

  • Figure 3.

    Radiologic and pathologic images of an abnormal node in patient #22. Axial CT images showing (A) area of the left common iliac artery at baseline, (B) timepoint at which cCR was achieved, and (C) 14 months and (E) 22 months after cCR was achieved. (D) Fine-needle aspiration image of the node found no tumor cells but did find evidence of infiltration of lymphocytes and inflammation (hematoxylin-eosin; original magnification ×10). (E) Axial CT image and (F) 18F-FDG PET/CT image showing the decrease in nodal size and the FDG uptake at the left common iliac artery. Red arrows indicate the enlarged node.

    Abbreviation: cCR, clinical complete response.

  • 1.

    Glynne-Jones R, Wyrwicz L, Tiret E, et al. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(Suppl 4):iv22–40.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Benson AB III, Venook AP, Adam M, et al. NCCN Clinical Practice Guidelines on Oncology: Rectal Cancer. Version 6.2023. Accessed November 20, 2023. To view the most recent version, visit https://www.nccn.org

    • PubMed
    • Export Citation
  • 3.

    André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383:22072218.

  • 4.

    Diaz LA Jr, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol 2022;23:659670.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    André T, Lonardi S, Wong K, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142. Ann Oncol 2022;33:10521060.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017;18:11821191.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Chalabi M, Fanchi LF, Dijkstra KK, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26:566576.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Hu H, Kang L, Zhang J, et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2022;7:3848.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Zhang J, Cai J, Deng Y, et al. Complete response in patients with locally advanced rectal cancer after neoadjuvant treatment with nivolumab. Oncoimmunology 2019;8:e1663108.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Demisse R, Damle N, Kim E, et al. Neoadjuvant immunotherapy-based systemic treatment in MMR-deficient or MSI-high rectal cancer: case series. J Natl Compr Canc Netw 2020;18:798804.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Wang QX, Xiao BY, Cheng Y, et al. Anti-PD-1-based immunotherapy as curative-intent treatment in dMMR/MSI-H rectal cancer: a multicentre cohort study. Eur J Cancer 2022;174:176184.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Xiao BY, Zhang X, Cao TY, et al. Neoadjuvant immunotherapy leads to major response and low recurrence in localized mismatch repair-deficient colorectal cancer. J Natl Compr Canc Netw 2023;21:6066.e5.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022;386:23632376.

  • 14.

    Chen G, Jin Y, Guan WL, et al. Neoadjuvant PD-1 blockade with sintilimab in mismatch-repair deficient, locally advanced rectal cancer: an open-label, single-centre phase 2 study. Lancet Gastroenterol Hepatol 2023;8:422431.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228247.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Le DT, Kim TW, Van Cutsem E, et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol 2020;38:1119.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Yang R, Wu T, Yu J, et al. Locally advanced rectal cancer with dMMR/MSI-H may be excused from surgery after neoadjuvant anti-PD-1 monotherapy: a multiple-center, cohort study. Front Immunol 2023;14:1182299.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Ludford K, Ho WJ, Thomas JV, et al. Neoadjuvant pembrolizumab in localized microsatellite instability high/deficient mismatch repair solid tumors. J Clin Oncol 2023;41:21812190.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004;240:711717; discussion 717–718.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Martens MH, Maas M, Heijnen LA, et al. Long-term outcome of an organ preservation program after neoadjuvant treatment for rectal cancer. J Natl Cancer Inst 2016;108:djw171.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Renehan AG, Malcomson L, Emsley R, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol 2016;17:174183.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Dossa F, Chesney TR, Acuna SA, et al. A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2017;2:501513.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Dattani M, Heald RJ, Goussous G, et al. Oncological and survival outcomes in watch and wait patients with a clinical complete response after neoadjuvant chemoradiotherapy for rectal cancer: a systematic review and pooled analysis. Ann Surg 2018;268:955967.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    van der Valk MJM, Hilling DE, Bastiaannet E, et al. Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet 2018;391:25372545.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Smith JJ, Strombom P, Chow OS, et al. Assessment of a watch-and-wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy. JAMA Oncol 2019;5:e185896.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Fernandez LM, São Julião GP, Figueiredo NL, et al. Conditional recurrence-free survival of clinical complete responders managed by watch and wait after neoadjuvant chemoradiotherapy for rectal cancer in the International Watch & Wait Database: a retrospective, international, multicentre registry study. Lancet Oncol 2021;22:4350.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Tetzlaff MT, Jazaeri AA, Torres-Cabala CA, et al. Erythema nodosum-like panniculitis mimicking disease recurrence: a novel toxicity from immune checkpoint blockade therapy—report of 2 patients. J Cutan Pathol 2017;44:10801086.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Tetzlaff MT, Nelson KC, Diab A, et al. Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients. J Immunother Cancer 2018;6:14.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Cornejo CM, Haun P, English J 3rd, et al. Immune checkpoint inhibitors and the development of granulomatous reactions. J Am Acad Dermatol 2019;81:11651175.

  • 30.

    Danlos FX, Pagès C, Baroudjian B, et al. Nivolumab-induced sarcoid-like granulomatous reaction in a patient with advanced melanoma. Chest 2016;149:e133136.

  • 31.

    Cascone T, Weissferdt A, Godoy MCB, et al. Nodal immune flare mimics nodal disease progression following neoadjuvant immune checkpoint inhibitors in non-small cell lung cancer. Nat Commun 2021;12:5045.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Eljilany I, Noor A, Paravathaneni M, et al. Granulomatous and sarcoid-like immune-related adverse events following CTLA4 and PD1 blockade adjuvant therapy of melanoma: a combined analysis of ECOG-ACRIN E1609 and SWOG S1404 phase III trials and a literature review. Cancers (Basel) 2023;15:2561.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Paydas S. Sarcoid-like reaction in cases treated by checkpoint inhibitors. Med Oncol 2021;38:29.

  • 34.

    Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov 2017;7:13941403.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Tie J, Cohen JD, Wang Y, et al. Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer. JAMA Oncol 2019;5:17101717.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Tie J, Cohen JD, Lahouel K, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med 2022;386:22612272.

  • 37.

    Krebs MG, Malapelle U, André F, et al. Practical considerations for the use of circulating tumor DNA in the treatment of patients with cancer: a narrative review. JAMA Oncol 2022;8:18301839.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Cabel L, Proudhon C, Romano E, et al. Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy. Nat Rev Clin Oncol 2018;15:639650.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Vellanki PJ, Ghosh S, Pathak A, et al. Regulatory implications of ctDNA in immuno-oncology for solid tumors. J Immunother Cancer 2023;11:e005344.

  • 40.

    Magbanua MJM, Swigart LB, Wu HT, et al. Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival. Ann Oncol 2021;32:229239.

  • 41.

    Chen G, Peng J, Xiao Q, et al. Postoperative circulating tumor DNA as markers of recurrence risk in stages II to III colorectal cancer. J Hematol Oncol 2021;14:80.

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