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26 september 2017:J Clin Invest. 2016 Jun 1; 126(6): 2334–2340. 

De laatste jaren worden veel studies gepubliceerd waarin kankerpatiënten met veel verschillende vormen van kanker alsnog goed reageren op immuuntherapie met een anti-PD medicijn, zoals de inmiddels voor sommige vormen van kanker goedgekeurde pembrolizumab, nivolumab, atezolizumab, avelumab enz.. En wie zoekt in clinical trials ziet dat er nog tientallen andere vergelijkbare medicijnen in onderzoek zijn, allemaal meestal in naam eindigend op......mab.

Deze vormen van immuuntherapie met zogeheten antilichamen zijn gericht op het zogeheten immune checkpoint receptor programmed cell death protein 1 (PD-1). Deze receptor (P1-ligand) zorgt ervoor dat er geen apoptose - zelfdoding plaatsvindt van beschadigde kankercellen of als cellen hun werk hebben verricht, die daardoor uit kunnen groeien tot tumoren want ze blijven maar delen. De immuuntherapie met anti-PD medicijnen schakelt die receptoren (PD-1 ligand) als het ware weer in zodat het immuunsysteem de beschadigde of uitgewerkte cellen kan vernietigen / verwijderen.

Uit studies blijkt dat als deze vorm van immuuntherapie aanslaat er langdurige complete remissies kunnen ontstaan met vaak ook echt genezing. Echter een anti-PD-1 therapie heeft niet bij alle patiënten een goed en volledig effect en kan soms ook tot nadelige bijwerkingen leiden. De factoren die bepalen waarom patiënten gevoelig of juist resistent zijn voor een anti-PD aanpak, worden nog niet helemaal begrepen. Maar wordt wel steeds verder via genomische profilering - receptoren en DNA mutatie onderzoek - onderzocht en de onderzoekers komen steeds verder daarmee.

Bv. in deze studie, gepresenteerd op ESMO 2016: Mutations in the POLE proofreading domain identifiy a subset of colorectal cancers that have enhanced immunogenicity blijkt dat ook andere mutaties een prognose kunnen geven op aanslaan of niet. En vooral dat deze darmkankerpatiënten langere ziektevrije tijd en overall overleving hadden. Onder grafiek andere studie bij darmkanker en twee casestudies van vrouwen met darmkanker en buikvliestumoren met bepaalde mutaties.

pole mutatie bij darmkanker

Interessant is bv. dat een andere mutatie, de POLE mutatie genoemd (DNA polymerase epsilon), een belangrijk inzicht kan geven in het eventueel wel of niet reageren op een anti-PD behandeling.

Zo werd onlangs deze studie gepresenteerd: Immunotherapy for Colorectal Cancer waarin wordt beschreven welke mutaties een rol spelen bij immuuntherapie met anti-PD medicijnen.  Op dit moment wordt de MSI-H bij darmkanker gezien als een voorspeller voor aanslaan van immuuntherapie met anti-PD medicijnen (checkpointremmers) maar er zijn er dus meer:

Uit dit studierapport: The majority of colorectal cancers demonstrate activation of the wnt/B-catenin pathway, in part due to inactivation of the tumor suppressor gene, APC. Relevant to therapeutic targeting, in metastatic disease RAS (KRAS or NRAS), mutations are seen in over 50% of patients, with BRAF mutations seen in 5–10% [3,4]. Additional emerging targets include HER-2 amplifications, seen in 2–5% of all colorectal cancers [5]. ............

A subset of colorectal cancers possesses markedly elevated mutational rates. Predominantly, these tumors are characterized by dysfunction of the mismatch repair genes (microsatellite high or MSI-H). MSI-H tumors make up a minority of colorectal cancers, with decreasing frequency in more advanced stage disease. The prevalence of MSI-H in stage II, III and IV colorectal cancers stands at 22%, 12%, and 3%, respectively [7,8]. A small fraction of hyper-mutated tumors possesses polymerase mutations, specifically within the catalytic domain of DNA polymerase epsilon (POLE) or delta (POLD1). These hypermutated tumors are of great relevance in our current understanding of colorectal cancer subtyping and the role of immunotherapy.

Hier een overzicht van enkele belangrijke studies van afgelopen jaren bij darmkanker met bepaalde mutaties van immuuntherapie met anti-PD medicijnen. (Tekst gaat verder onder grafiek)

TABLE 1:
Key immunotherapy trials in metastatic colorectal cancer (CRC).

Drug(s)TargetPopulationPatientsResponse RateIdentifier
Trials for MSI-H CRC
Pembrolizumab PD-1 Refractory MSI-H CRC 25 57% Le et al. [30]
Nivolumab Nivolumab + Ipilimumab PD-1 Refractory MSI-H CRC 47 26% NCT02060188 [31]
PD-1 + CTLA-4 Refractory MSI-H CRC 30 33%
Trials for MSS CRC
Pembrolizumab PD-1 Refractory MSS CRC 28 0% Le et al. [30]
Nivolumab + Ipilimumab PD-1 + CTLA-4 Refractory MSS CRC 20 5% NCT02060188 [31]
Trials of Various CRC Sub-Types
Tremelimumab CTLA-4 Refractory CRC 49 2% Chung et al. [28]
Nivolumab PD-1 Refractory CRC 19 0% Topalian et al. [32]
BMS-936559 PD-L1 Refractory CRC 18 0% Brahmer et al. [33]
Atezolizumab + Bevacizumab PD-L1 Refractory CRC 14 7% NCT01633970 [34]
Atezolizumab + FOLFOX/bev Metastatic CRC
(70% first line)
30 40% (total)
48% (first-line)
Atezolizumab + Cobimetinib PD-L1 MEK Refractory CRC (30% MSS, 70% unknown) 23 17% (3 MSS, 1 unknown) NCT01988896 [35]

Op ESMO 2017 werd een studie gepresenteerd waarin onderzoekers een vrouw met een geschiedenis van kanker met buikvliestumoren analyseerden. Zij reageerde uiteindelijk na vele chemokuren heel goed op immuuntherapie met het anti-PD-1 medicijn pembrolizumab. Een analyse van de Cancer Genome Atlas (TCGA) liet zien dat de aanwezigheid van een POLE mutatie gerelateerd bleek aan een verhoogde expressie van verschillende checkpoint controle genen. Samen tonen deze gegevens aan dat tumoren die POLE-mutaties bevatten, goede kandidaten zijn voor immuuntherapie met anti-PD medicijnen.

Het volledige studierapport van deze vrouw, een casestudie: Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer  is gratis in te zien. Onderaan dit artikel het abstract plus referentielijst.

Een ander voorbeeld van een vrouw met gevorderde darmkanker met een POLE mutatie die uitstekend reageerde is dit studierapport: Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1  dat ook gratis is in te zien. Abstract eveneens onderaan dit artikel.

POLE mutatie

Hier de abstracten van eerder genoemde studies met referentielijsten enz.

Here, we review the contemporary understanding of the immune and molecular landscape in colorectal cancer and discuss ongoing clinical trials evaluating novel combination regimens based on immune checkpoint inhibitors.

Cancers (Basel). 2017 May; 9(5): 50.
Published online 2017 May 11. doi:  10.3390/cancers9050050
PMCID: PMC5447960

Immunotherapy for Colorectal Cancer

Vita Golubovskaya, Academic Editor

Abstract

The recent success of anti-PD1 drugs in metastatic colorectal cancer patients with mismatch repair deficiency generated overwhelming enthusiasm for immunotherapy in the disease. However, patients with mismatch repair deficient colorectal cancer represent only a small subset of the metastatic population. Current research focuses on advancing immunotherapy to earlier stages of the disease including adjuvant and first-line metastatic settings, and on inducing sensitivity to immune checkpoint inhibitor therapy through a combinatorial approach. Here, we review the contemporary understanding of the immune and molecular landscape in colorectal cancer and discuss ongoing clinical trials evaluating novel combination regimens based on immune checkpoint inhibitors.

5. Conclusions

The American Society of Clinical Oncology (ASCO) declared Immunotherapy to be the 2016 Clinical Cancer Advance of the Year. In 2017, the advance of the year has already been announced to be Immunotherapy 2.0. Despite years of frustration, we are beginning to see some success through the use of the immunotherapy approach in colorectal cancer, namely PD-1 inhibition in MSI-H cancers. However, the successful targeting of MSS cancers and non-hypermutated tumors appears to be not too far off on the horizon. MEK and PD-L1 combinations are being rigorously tested, multiple agents and combinations are in development and multiple companies have shifted their focus and investments toward immunotherapeutics. Neglected in this review, but also of note, a case of remarkable success has been witnessed utilizing adoptive cell therapy via tumor infiltrating lymphocytes (TILs) in colorectal cancer [52]. Thus, cancer immunotherapy strategies appear to be moving full speed ahead. Despite the knowledge that many further failures lie in our paths, reason for great optimism remains.

Conflicts of Interest

Patrick M. Boland has received research funding from Merck. Wen Wee Ma has no conflicts of interest to declare.

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Articles from Cancers are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. This association underscores the importance of rare biomarkers in precision cancer medicine, but also raises important questions about how to identify and implement them in practice.

Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study

Enric Domingo, PhD
,
Luke Freeman-Mills, BA
,
Emily Rayner, BSc
,
Mark Glaire, MBBS
,
Sarah Briggs, MBBS
,
Louis Vermeulen, MD
,
Evelyn Fessler, MSc
,
Prof Jan Paul Medema, PhD
,
Arnoud Boot, MSc
,
Prof Hans Morreau, PhD
,
Tom van Wezel, PhD
,
Gerrit-Jan Liefers, MD
,
Prof Ragnhild A Lothe, PhD
,
Stine A Danielsen, PhD
,
Anita Sveen, PhD
,
Prof Arild Nesbakken, MD
,
Prof Inti Zlobec, MD
,
Prof Alessandro Lugli, MD
,
Viktor H Koelzer, MD
,
Martin D Berger, MD
,
Sergi Castellví-Bel, PhD
,
Jenifer Muñoz, MSc
, The Epicolon consortium*,
Marco de Bruyn, PhD
,
Prof Hans W Nijman, MD
,
Prof Marco Novelli, PhD
,
Kay Lawson, MBBS
,
Dahmane Oukrif, MSc
,
Eleni Frangou, MSc
,
Peter Dutton, MSc
,
Sabine Tejpar, MD
,
Mauro Delorenzi, PhD
,
Prof Rachel Kerr, MBBS
,
Prof David Kerr, MBChB
,
Prof Ian Tomlinson, PhD
,
Dr David N Church, DPhil,'Correspondence information about the author Dr David N Church
*List of Epicolon investigators is provided in the appendix
Contributed equally
Show all authors

Summary

Background

Precision cancer medicine depends on defining distinct tumour subgroups using biomarkers that may occur at very modest frequencies. One such subgroup comprises patients with exceptionally mutated (ultramutated) cancers caused by mutations that impair DNA polymerase epsilon (POLE) proofreading.

Methods

We examined the association of POLE proofreading domain mutation with clinicopathological variables and immune response in colorectal cancers from clinical trials (VICTOR, QUASAR2, and PETACC-3) and colorectal cancer cohorts (Leiden University Medical Centre 1 and 2, Oslo 1 and 2, Bern, AMC-AJCC-II, and Epicolon-1). We subsequently investigated its association with prognosis in stage II/III colorectal cancer by Cox regression of pooled individual patient data from more than 4500 cases from these studies.

Findings

Pathogenic somatic POLE mutations were detected in 66 (1·0%) of 6517 colorectal cancers, and were mutually exclusive with mismatch repair deficiency (MMR-D) in the 6277 cases for whom both markers were determined (none of 66 vs 833 [13·4%] of 6211; p<0·0001). Compared with cases with wild-type POLE, cases with POLE mutations were younger at diagnosis (median 54·5 years vs 67·2 years; p<0·0001), were more frequently male (50 [75·8%] of 66 vs 3577 [55·5%] of 6445; p=0·0010), more frequently had right-sided tumour location (44 [68·8%] of 64 vs 2463 [39·8%] of 6193; p<0·0001), and were diagnosed at an earlier disease stage (p=0·006, χ2 test for trend). Compared with mismatch repair proficient (MMR-P) POLE wild-type tumours, POLE-mutant colorectal cancers displayed increased CD8+ lymphocyte infiltration and expression of cytotoxic T-cell markers and effector cytokines, similar in extent to that observed in immunogenic MMR-D cancers. Both POLE mutation and MMR-D were associated with significantly reduced risk of recurrence compared with MMR-P colorectal cancers in multivariable analysis (HR 0·34 [95% CI 0·11–0·76]; p=0·0060 and 0·72 [0·60–0·87]; p=0·00035), although the difference between the groups was not significant.

Interpretation

POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. This association underscores the importance of rare biomarkers in precision cancer medicine, but also raises important questions about how to identify and implement them in practice.

Funding

Cancer Research UK, Academy of Medical Sciences, Health Foundation, EU, ERC, NIHR, Wellcome Trust, Dutch Cancer Society, Dutch Digestive Foundation.

Analysis of The Cancer Genome Atlas (TCGA) revealed that the presence of POLE mutation associates with high mutational burden and elevated expression of several immune checkpoint genes. Together, these data suggest that cancers harboring POLE mutations are good candidates for immune checkpoint inhibitor therapy.

J Clin Invest. 2016 Jun 1; 126(6): 2334–2340.
Published online 2016 May 9. doi:  10.1172/JCI84940
PMCID: PMC4887167

Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer

Abstract

Antibodies that target the immune checkpoint receptor programmed cell death protein 1 (PD-1) have resulted in prolonged and beneficial responses toward a variety of human cancers. However, anti–PD-1 therapy in some patients provides no benefit and/or results in adverse side effects. The factors that determine whether patients will be drug sensitive or resistant are not fully understood; therefore, genomic assessment of exceptional responders can provide important insight into patient response. Here, we identified a patient with endometrial cancer who had an exceptional response to the anti–PD-1 antibody pembrolizumab. Clinical grade targeted genomic profiling of a pretreatment tumor sample from this individual identified a mutation in DNA polymerase epsilon (POLE) that associated with an ultramutator phenotype. Analysis of The Cancer Genome Atlas (TCGA) revealed that the presence of POLE mutation associates with high mutational burden and elevated expression of several immune checkpoint genes. Together, these data suggest that cancers harboring POLE mutations are good candidates for immune checkpoint inhibitor therapy.

Reference information:J Clin Invest. 2016;126(6):2334–2340. doi:10.1172/JCI84940.

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Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

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