Clinical and molecular characterization of patients with metastatic colorectal cancer harbouring DNA mismatch repair deficiency.

3563 Background: Prognosis of patients (pts) with metastatic colorectal cancer (mCRC) harboring microsatellite instability (MSI) is poorly characterized. We aimed to assess the clinical relevance of distinguishing sporadic (SP) from Lynch syndrome (LS)-related mismatch repair deficiency (dMMR). Methods: Pts with diagnostic of dMMR and/or MSI mCRC between 1998 and 2016 were retrospectively identified in 6 French hospitals. Tumor samples were systematically collected and screened for RAS/RAF mutations and MLH1 promotor methylation. dMMR and MSI statuses were confirmed using immunohistochemistry and Pentaplex© PCR assay. Sporadic cases were molecularly defined as those displaying MLH1 loss of expression with BRAFV600E mutation and/or MLH1 hypermethylation. Clinical data (demographic data, metastatic sites, therapeutic strategies) were recorded. Results: 129 pts, of which 48 SP and 81 LS, were included. Compared with LS, SP were associated with female (P < .001), older age at diagnostic (P < .001), proximal colon (P = 0.002), and less liver metastasis (25% vs 47%, P = .02). For initially localized CRC, median disease free survivals (DFS) were 9.1 months (m) for SP (n = 22) and 12.3 m for LS (n = 47) (hazard ratio (HR) = 0.5, 95%CI 0.28-0.90, P = .02). Median overall survivals (OS) from stage IV diagnosis were 43.9 m in the overall population, 23 m for SP and not reached for LS (HR = 0.23, 95%CI 0.10-0.52, P < .001). BRAF mutation was harbored by 29 SP tumors (60%) and did not impact OS among SP pts (P = .52). Metastatic disease was less frequently resectable for SP than LS (21% vs 56%, P < .001). Median DFS for pts with resected metastatic disease (n = 55) were respectively 6.7 and 10.5 m (HR = 0.28, 95%CI 0.10-0.73, P = .01). At the data cut-off date, 16 pts (15 LS and 1 SP) were still in complete remission. Median progression free survivals with first-line chemotherapy for pts with unresectable metastasis (n = 61) were 3.9 m for SP and 5.0 m for LS (P = .71). Conclusions: This retrospective study suggests a worse prognosis of pts with SP MSI mCRC compared to these with LS-related mCRC.

Download Full-text

Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status

JAMA Oncology ◽

10.1001/jamaoncol.2018.4942 ◽

2019 ◽

Vol 5 (4) ◽

pp. 551 ◽

Cited By ~ 39

Author(s):

Romain Cohen ◽

Elisabeth Hain ◽

Olivier Buhard ◽

Agathe Guilloux ◽

Armelle Bardier ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Metastatic Colorectal Cancer ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Mismatch Repair Deficiency ◽

Primary Resistance ◽

Repair Deficiency

Download Full-text

Assessment of local clinical practice for testing of mismatch repair deficiency in metastatic colorectal cancer: The need for new diagnostic guidelines prior to immunotherapy

Annals of Oncology ◽

10.1093/annonc/mdy281.083 ◽

2018 ◽

Vol 29 ◽

pp. viii179-viii180 ◽

Cited By ~ 1

Author(s):

R. Cohen ◽

E. Hain ◽

O. Buhard ◽

A. Guilloux ◽

A. Bardier ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Practice ◽

Metastatic Colorectal Cancer ◽

Mismatch Repair ◽

Mismatch Repair Deficiency ◽

Repair Deficiency

Download Full-text

23 Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA4 rescue in patients with mismatch repair deficient metastatic colorectal cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0023 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A22-A22

Author(s):

Pashtoon Kasi ◽

Carlos Chan

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Circulating Tumor Dna ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Mismatch Repair Deficiency ◽

Repair Deficiency ◽

Tumor Dna

BackgroundPatients with mismatch repair deficient/microsatellite instability high (dMMR/MSI-High) tumors respond well to immune checkpoint blockade.1 2 Pembrolizumab was the first drug to be approved by the FDA in an agnostic fashion for any tumor type with dMMR/MSI-High for the very same reason. The responses in dMMR/MSI-High tumors tend to be brisk, dramatic and durable to the point that the word ‘cure’ is being used for patients who do respond to PD-1 blockade. This year, pembrolizumab now got approval as 1st line therapy for dMMR/MSI-High metastatic colorectal cancers as well. However, a third of patients do not respond.3 Predictive markers and data for subsequent therapy options are lacking. Here we present for the first time a series of dMMR/MSI-High patients who not only had serial circulating tumor DNA (ctDNA) monitoring during PD-1 blockade/progression, but also were able to get anti-CTLA4 in conjunction with an anti-PD1 (‘CTLA4-rescue’), with ctDNA trends predicting responses weeks ahead of standard imaging.MethodsMetastatic colorectal cancer patients enrolled in the expanded access program for tumor informed circulating tumor DNA monitoring (Signatera 16-plex bespoke mPCR NGS assay) who were noted to be dMMR/MSI-High colorectal cancers were identified. Serial monitoring results while they were receiving immune checkpoint blockade therapy is presented. This only includes patients who had progression on PD-1 blockade whereby CTLA-4 rescue was done as part of their treatment strategy.ResultsSerial monitoring and trends of progression followed by responses are depicted in the patients who had CTLA-4 rescue post PD-1 progression (figure 1). This correlated with radiographic responses in all the patients. The ctDNA decreases in patients showing responses as well as ctDNA increases earlier during progression on PD-1 blockade happened within administration of a single dose.Abstract 23 Figure 1Example of a patient with serial tumor-informed ctDNA monitoring showing initial response and subsequent progression on PD-1 blockade followed by ‘CTLA-4 rescue’.ConclusionsTo date there is only 1 case report published earlier this year showing the value of ‘immunotherapy after immunotherapy’ in patients with dMMR/MSI-High tumors. Here we not only present a series of patients but also in parallel provide a snapshot on serial ctDNA trends whereby this could serve as a dynamic predictive marker of early response or progression to therapy.4 5 Finally, ‘CTLA4-rescue’ needs to be formally included in NCCN and other respective guidelines. Even though nivolumab/ipilimumab is listed as an option for dMMR/MSI-High tumors in addition to single agent pembrolizumab or nivolumab, it is not listed as an option post-PD-1 progression. For all the patients, we have had to fight to get peer to peer approval.Ethics ApprovalThe study is approved at University of Iowa and part of IRB#201202743.ConsentWritten informed consent was obtained from the patients 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.ReferencesLe DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409–13. [Crossref] [PubMed]Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–20. [Crossref] [PubMed]Andre T, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. J Clin Oncol 2020;38:LBA4.Anagnostou V, Forde PM, White JR, et al. Dynamics of tumor and immune responses during immune checkpoint blockade in non-small cell lung cancer. Cancer Res 2019;79:1214–25. [Crossref] [PubMed]Phallen J, Leal A, Woodward BD, et al. Early noninvasive detection of response to targeted therapy in non-small cell lung cancer. Cancer Res 2019;79:1204–13.

Download Full-text

Gender difference for mismatch repair deficiency in human colorectal cancer

Gastroenterology ◽

10.1053/gast.2001.28585 ◽

2001 ◽

Vol 121 (4) ◽

pp. 1026-1027 ◽

Cited By ~ 8

Author(s):

Alex Duval ◽

Barry Iacopetta ◽

Lin Thorstensen ◽

Gunn Iren Meling ◽

Ragnhild A. Lothe ◽

...

Keyword(s):

Colorectal Cancer ◽

Gender Difference ◽

Mismatch Repair ◽

Mismatch Repair Deficiency ◽

Human Colorectal Cancer ◽

Repair Deficiency

Download Full-text

DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer

Cancer ◽

10.1002/cncr.30790 ◽

2017 ◽

Vol 123 (19) ◽

pp. 3732-3743 ◽

Cited By ~ 9

Author(s):

Charité N. Ricker ◽

Diana L. Hanna ◽

Cheng Peng ◽

Nathalie T. Nguyen ◽

Mariana C. Stern ◽

...

Keyword(s):

Colorectal Cancer ◽

Mismatch Repair ◽

Dna Mismatch Repair ◽

Mismatch Repair Deficiency ◽

Dna Mismatch ◽

Hereditary Syndromes ◽

Repair Deficiency ◽

Dna Mismatch Repair Deficiency

Download Full-text

Perioperative therapy in patients with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e18231 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e18231-e18231

Author(s):

Olatunji B. Alese ◽

Katerina Mary Zakka ◽

Xingyue Huo ◽

Renjian Jiang ◽

Walid Labib Shaib ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Multivariate Analyses ◽

Stage Iv ◽

Tumor Location ◽

Primary Site ◽

Perioperative Therapy ◽

Younger Age ◽

Male Preponderance ◽

Metastatic Sites

e18231 Background: Knowledge about perioperative systemic therapy in metastatic colorectal cancer (mCRC) is limited. We aim to describe the nationwide pattern of use and survival outcomes of patients with mCRC treated with surgical resection. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Univariate and multivariate analyses was done to identify factors associated with patient outcome. Results: A total of 61,940 patients with stage IV CRC older than 18 years were identified. Mean age was 63.4 years (SD±14), with a male preponderance (54.8%). About 80% were Caucasian and 69.9% had colon cancer. Compared to medical treatment only, resection of both primary and metastatic sites (13.5%; HR 0.40; 0.37-0.44; p < 0.001), or primary site resection alone (49.2%; HR 0.52; 0.48-0.56; p < 0.001) were associated with improved overall survival (OS). Other co-variates associated with improved survival included younger age group, year of diagnosis (2009-2013), colon tumor location, and < 3 metastatic sites (Table). Five-year OS for resection of primary and metastatic site (28.2%) was higher than for primary site resection alone (14.9%) or no surgical treatment (4.7%). Conclusions: Resection of metastatic sites or primary tumor was associated with improved survival in patients with stage IV CRC.[Table: see text]

Download Full-text