Neoadjuvant Immunotherapy–Based Systemic Treatment in MMR-Deficient or MSI-High Rectal Cancer: Case Series

Demisse, Rahel; Damle, Neha; Kim, Edward; Gong, Jun; Fakih, Marwan; Eng, Cathy; Oesterich, Leslie; McKenny, Madison; Ji, Jingran; Liu, James H.; Louie, R.V.; Tam, Kit; Gholami, Sepideh; Halabi, Wissam J.; Monjazeb, Arta M.; Dayyani, Farshid; Cho, May

doi:10.6004/jnccn.2020.7558

Cited by 40 publications

(31 citation statements)

References 16 publications

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“…Two of the studies did not present data on the MMR gene test analyses nor the MMR variant identified in the patients, and it remains uncertain how Lynch syndrome was diagnosed in these individuals. 28 , 29 The cases were identified in USA (N=13), Canada (N=3), China (N=3), Japan (N=2), France (N=1), Chile (N=1), UK (N=1), Brazil (N=1), and Australia (N=1). The responses were evaluated using the RECIST criteria (N=13), pathologic complete response with no viable tumor cells after surgery (N=2), tumor decrease with unknown percentage of decrease (N=7), clinical response with proceeded treatment due to no or little tumor progression (N=2), and as a decrease in prostate specific antigen (PSA) (N=2).…”

Section: Resultsmentioning

confidence: 99%

“…Since some of the cohort studies included few variants of unknown significance (VUS) as causative for Lynch syndrome 25 or included Lynch syndrome families based on individuals with dMMR/MSI tumors in families with a cancer history, 8 , 21 we chose to include two case studies with VUS 26 , 27 and two case studies with clinical Lynch syndrome diagnostics, but with unknown germline MMR gene variant. 28 , 29 Lynch syndrome individuals with biallelic MMR variants (also referred to as constitutional MMR deficiency (CMMR-D) syndrome) were also included in this study, since these tumors show the same molecular phenotype as monoallelic Lynch syndrome tumors (N=1). There were no selection criteria regarding tumor type and no restrictions in period.…”

Section: Methodsmentioning

confidence: 99%

“…In summary, 10 cases were included with a colorectal cancer (three with multiple cancers in other organs as well) and one patient with liver metastases from a previously removed colorectal cancer. 18,24,26,28,29,[34][35][36][37][38] Two cases obtained CR, two showed PR, three had SD, and three showed PD giving an ORR of 40% and disease control rate of 70%. All the patients, who showed positive response, were given immunotherapy as first (N=3) or second (N=1) line treatment.…”

Section: Colorectal Cancermentioning

confidence: 96%

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An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome

Therkildsen¹,

Jensen

Rasmussen³

et al. 2021

CEG

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During the recent years, immune checkpoint-based therapy has proven highly effective in microsatellite instable (MSI) solid tumors irrespective of organ site. MSI tumors are associated with a defective mismatch repair (MMR) system and a highly immune-infiltrative tumor microenvironment—both characteristics of Lynch syndrome. Lynch syndrome is a multi-tumor syndrome that not only confers a high risk of colorectal and endometrial cancer but also cancer in, eg the upper urinary tract, ovaries, and small bowel. Since the genetic predisposition for Lynch syndrome are pathogenic variants in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2 , most of the Lynch syndrome cancers show MMR deficiency, MSI, and activation of the immune response system. Hence, Lynch syndrome cancer patients may be optimal candidates for immune checkpoint-based therapies. However, molecular differences have been described between sporadic MSI tumors (developed due to MLH1 promoter hypermethylation) and Lynch syndrome tumors, which may result in different treatment responses. Furthermore, the response profile of the rare Lynch syndrome cases may be masked by the more frequent cases of sporadic MSI tumors in large clinical trials. With this review, we systematically collected response data on Lynch syndrome patients treated with FDA- and EMA-approved immune checkpoint-based drugs (pembrolizumab, atezolizumab, durvalumab, avelumab, ipilimumab, and nivolumab) to elucidate the objective response rate and progression-free survival of cancer in Lynch syndrome patients. Herein, we report Lynch syndrome-related objective response rates between 46 and 71% for colorectal cancer and 14–100% for noncolorectal cancer in unselected cohorts as well as an overview of the Lynch syndrome case reports. To date, no difference in the response rates has been reported between Lynch syndrome and sporadic MSI cancer patients.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Colorectal Cancermentioning

confidence: 96%

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An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome

Therkildsen¹,

Jensen

Rasmussen³

et al. 2021

CEG

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“…There is a case series of 3 patients with rectal cancer that was just reported this year. 1 Here we not only report a case of an advanced rectal cancer, but also a case of an advanced esophageal cancer who have achieved dramatic responses with no evidence of disease on repeated sampling. It is rare for surgery or radiation to be deferred in these situations.…”

mentioning

confidence: 88%

24 Utility of tumor-informed molecular residual disease assays in patients with complete response to immune checkpoint blockade

Kasi

2020

Regular and Young Investigator Award Abstracts

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BackgroundRecent data suggests that responses in patients with mismatch repair deficient (dMMR) tumors tend to be durable and potentially curative. Typically immunotherapy is employed and approved only in metastatic settings. However, it is not uncommon now to consider usage in patients with dMMR tumors secondary to the hypermutated nature of these malignancies alongside the concerns that these do not respond to therapy either through a clinical trial or off-label compassionate access programs. As noted, in patients who have these dramatic and durable responses, the question of foregoing surgery and/or radiation comes up. There is no great test to help predict or guide who are these complete responders. Assessment of molecular residual disease or minimal residual disease through tumor-informed assays is one potential test that can be employed in this setting. We here show the feasibility of such an approach in patients with dMMR tumors who got immunotherapy in the advanced but not metastatic setting.MethodsWe identified patients who were enrolled in the serial tumor informed molecular residual disease BESPOKE expanded access ctDNA testing program (Signatera 16-plex bespoke mPCR NGS assay) who got immunotherapy in the neoadjuvant setting and were also enrolled in our biobanking program.ResultsWe were able to serially do ctDNA analysis in 2 patients (1 with advanced but not metastatic esophageal adenocarcinoma and another patient with advanced but not metastatic nearly obstructing rectal adenocarcinoma with extensive nodal metastases in both situations) who got immunotherapy off-label per physician discretion and tumor board discussion. Of note both these patients also had germline lynch syndrome. Both of them had robust, dramatic and ongoing responses to immune checkpoint blockade. Of note, while they both had some radiographic question of residual disease, repeated endoscopic ultrasounds and random biopsies have yielded no tumor and all just scarred tissue. Circulating tumor DNA in these instances quickly declined to become undetectable and has remained not detectable to date (figure 1). Surgery and radiation is deferred and close follow up alongside serial endoscopic/radiographic assessment in addition to novel usage of ctDNA MRD assays is being employed.Abstract 24 Figure 1Ongoing response and negative ctDNA minimal residual disease to PD-1 blockade added to standard of care chemotherapy for a patient with advanced rectal cancerConclusionsData regarding neoadjuvant usage of immunotherapy is scarce pertaining to mismatch repair deficient tumors. There is a case series of 3 patients with rectal cancer that was just reported this year.1 Here we not only report a case of an advanced rectal cancer, but also a case of an advanced esophageal cancer who have achieved dramatic responses with no evidence of disease on repeated sampling. It is rare for surgery or radiation to be deferred in these situations. However, with added utility of ctDNA MRD assays, it gives us one more tool in our toolbox in terms of applying it to patients suitable for these ‘watch-&-wait’ approaches.Ethics ApprovalThe study has been approved by University of Iowa’s Institutional Review Board IRB#201202743.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferenceDemisse 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(7):798–804. doi:10.6004/jnccn.2020.7558

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“…The 5-year survival prognosis is highly dependent on the tumor stage of CRC: over 90% survival for stage I CRC and nearly 10% survival for stage IV CRC ( 2 ). CRC treatments consist mainly of surgery combined with adjuvant chemotherapy and neoadjuvant radiotherapy ( 3 ). However, these therapies have not been proven to effectively cure CRC with many side effects.…”

Section: Introductionmentioning

confidence: 99%

Identification of the Effects of Chondroitin Sulfate on Inhibiting CDKs in Colorectal Cancer Based on Bioinformatic Analysis and Experimental Validation

Zhou

Morita

et al. 2021

Front. Oncol.

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With a high occurrence rate and high mortality, the treatment of colorectal cancer (CRC) is increasingly attracting the attention of scholars. Hub genes that determine the phenotypes of CRC become essential for targeted therapy. In the present study, the importance of cyclin-dependent kinases (CDKs) on the occurrence of CRC was identified by data mining of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The results showed that the gene expression levels of CDK1, CDK4, and CDK6 were obviously changed in different stages of CRC. Among the CDKs, CDK4 was suggested as an independent risk factor for CRC based on Cox analysis. Furthermore, chondroitin sulfate (CS), a kind of dietary supplement to treat osteoarthritis, was predicted to treat CRC based on its chemical structure and GEO datasets. Cell assay experiments with the human CRC cell line HCT-116 also verified this prediction. CS inhibited the gene and protein expression levels of CDKs and increased the ratios of apoptotic or dead HCT-116 cells by regulating mitogen-activated protein (MAP) kinase pathways. Our data highlight the essential roles of CDKs in CRC carcinogenesis and the effects of CS on treating CRC, both of which will contribute to the future CRC treatment.

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Neoadjuvant Immunotherapy–Based Systemic Treatment in MMR-Deficient or MSI-High Rectal Cancer: Case Series

Cited by 40 publications

References 16 publications

An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome

An Update on Immune Checkpoint Therapy for the Treatment of Lynch Syndrome

24 Utility of tumor-informed molecular residual disease assays in patients with complete response to immune checkpoint blockade

Identification of the Effects of Chondroitin Sulfate on Inhibiting CDKs in Colorectal Cancer Based on Bioinformatic Analysis and Experimental Validation

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