Introducing VENTANA MMR RxDx Panel


The first MMR IHC-based assay FDA approved as an aid to identify
endometrial carcinoma patients eligible for treatment with JEMPERLI (dostarlimab-gxly).

MMR

Endometrial cancer is the most common type of cancer that affects the female reproductive organs with over 65,000 new cases diagnosed in 20201.  Endometrial cancer has the highest rates of DNA mismatch Repair (MMR) deficiency of all tumors (20-40%). Multiple studies have demonstrated that MMR deficiency correlate with higher expression of PD-1 or PD-L1, possibly due to the increased neoantigen expression associated with tumor mutation burden that results from replication errors.2,3 Thus, MMR proteins may be useful as predictive biomarkers for PD-1 targeted therapy; specifically, a loss of expression of one or more MMR proteins might predict an increased likelihood of response to such therapy.4,5,6 With the increased understanding of the role MMR may play in endometrial cancer, universal testing of endometrial carcinomas for MMR/MSI is recommended by NCCN7.

MMR slide

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About DNA Mismatch Repair (MMR)

DNA mismatch repair (MMR) is a conserved molecular mechanism that functions to correct the improper base substitutions that spontaneously occur during DNA replication.8 Defects in the MMR machinery have been attributed to mutations in the MMR proteins, most commonly MLH1, PMS2, MSH2, and MSH6.

The MLH1 and PMS2 proteins normally function together in a heterodimeric complex, as do the MSH2 and MSH6 proteins. When MMR is functioning normally, the MSH6/MSH2 heterodimer binds to mismatched DNA. This binding induces a conformational change that allows the MLH1/PMS2 heterodimer to bind the DNA-bound MSH6/MSH2 complex, resulting in excision repair of the affected DNA.9,10 Mutations or deficiencies in these proteins result in frequent MSI and somatic mutation due to replication error. MMR immunohistochemistry (IHC) testing can be useful in identifying MMR genes likely to contain germline or a somatic alterations.11

MMR infographic

Figure 1: MMR proteins and their interactions with DNA. The MSH2-MSH6 complex recognizes mismatches and insertion/deletion loops. The MLH1-PMS2 complex facilitates excision and repair of the mutant bases(s).

 

 

 

 

 

A loss of expression of any of the essential MMR proteins, including MLH1, PMS2, MSH2, or MSH6, in the presence of evaluable internal controls identifies MMR deficiency.

MMR figure 1

Figure 1: VENTANA anti-MLH1 (M1) Mouse Monoclonal Primary Antibody staining with Intact (left) or Loss (right) of expression in the presence of evaluable internal controls in endometrial carcinoma tissue.

MMR figure 3

Figure 3: VENTANA anti-MSH2 (GS19-1129) Mouse Monoclonal Primary Antibody staining with Intact (left) or Loss (right) of expression in the presence of evaluable internal controls in endometrial carcinoma tissue.

MMR figure 2

Figure 2: VENTANA anti-MSH6 (SP93) Rabbit Monoclonal Primary Antibody staining with Intact (left) or Loss (right) of expression in the presence of evaluable internal controls in endometrial carcinoma tissue.

MMR figure 4

Figure 4: VENTANA anti-PMS2 (A16-4) Rabbit Monoclonal Primary Antibody staining with Intact (left) or Loss (right) of expression in the presence of evaluable internal controls in endometrial carcinoma tissue.

1. https://www.cancer.org/cancer/endometrial-cancer/about/key-statistics.html

2. Yamashita H, Nakayama K, Ishikawa M, et al. Microsatellite instability is a biomarker for immune checkpoint inhibitors in endometrial cancer. Oncotarget. 2017:9(5):5652-5664.

3. Xiao X, Dong D, He W, et al. Mismatch repair deficiency is associated with MSI phenotype, increased tumor-infiltrating lymphocytes and PD-L1 expression in immune cells in

ovarian cancer. Gynecol Oncol. 2018;149(1):146-154.

4. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.

5. Sloan EA, Ring KL, Willis BC, et al. PD-L1 expression in mismatch repair-deficient endometrial carcinomas, including Lynch syndrome-associated and MLH1 promoter

hypermethylated tumors. Am J Surg Pathol. 2017;41(3):326-333.

6. Dudley JC, Lin MT, Le DT, et al. Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 2016;22(4):813-820.

7. NCCN Guidelines Version 1. 2020, Endometrial Carcinoma

8. Hsieh P, Yamane K. DNA mismatch repair: Molecular mechanism, cancer, and ageing. Mech Ageing Dev. 2008;129(7-8):391-407.

9. Buza N, Ziai J, Hui P. Mismatch repair deficiency testing in clinical practice. Expert Rev Mol Diagn. 2016;16(5):591-604.

10. Silva FCC, Torrezan GT, Ferreira JRO, et al. Germline mutations in MLH1 leading to isolated loss of PMS2 expression in Lynch syndrome: implications for diagnostics in the clinic.

Am J Surg Pathol. 2017;41(6):861-864.

11. Cunningham JM, Tester DJ, Thibodeau SN. Mutation detection in colorectal cancers: direct sequencing of DNA mismatch repair genes. Methods Mol Med. 2001;50:87-98.

 

 

Intended Use

VENTANA MMR RxDx Panel is a qualitative immunohistochemistry test intended for use in the assessment of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2 and MSH6) in formalin-fixed, paraffin-embedded (FFPE) endometrial carcinoma tissue by light microscopy. The OptiView DAB IHC Detection Kit is used for MLH1, MSH2 and MSH6, and the OptiView DAB IHC Detection Kit with the OptiView Amplification Kit is used for PMS2 on a VENTANA BenchMark ULTRA instrument.

VENTANA MMR RxDx Panel includes VENTANA anti-MLH1 (M1) Mouse Monoclonal Primary Antibody, VENTANA anti-PMS2 (A16-4) Mouse Monoclonal Primary Antibody, VENTANA anti-MSH2 (G219-1129) Mouse Monoclonal Primary Antibody and VENTANA anti-MSH6 (SP93) Rabbit Monoclonal Primary Antibody.

VENTANA MMR RxDx Panel is indicated as an aid in identifying patients eligible for treatment with JEMPERLI (dostarlimab-gxly) as listed in Table 1 in accordance with the approved therapeutic product labeling.

Table 1. VENTANA MMR RxDx Panel companion diagnostic indications.

 

Indication for use Therapy MMR Status
Endometrial Cacinoma (EC) JEMPERLI (dostarlimab-gxly) Defiicient MMR (dMMR)
 

VENTANA MMR RxDx Demonstrates Predictive Power in Identifying MMR Deficiency in Endometrial Cancer

Clinical data

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Clinical data

JEMPERLI Efficacy Results in GARNET Mismatch Repair Endometrial Cancer Population*

 

Objective Response Summary
Endpoint JEMPERLI N = 71
Confirmed ORR
Overall response rate 42.3%
95% CI (30.6, 54.6)
Complete response rate 12.7%
Partial response rate 29.6%
Duration of Response
Median in months Not reached
(range)(a) (2.6, 22.4+)
Patients with duration ≥ 6 months 93.3%
 
Note: CI = Confidence interval, + = ongoing at last assessment
(a) Median follow-up for DOR was 14.1 months, measured from time of first response.
*JEMPERLI Package Insert

MMR status concordance between GARNET study Clinical Trial Assay* and VENTANA MMR RxDx Panel (IU Population**)

 

VENTANA MMR RxDx Panel Status(b) IU Concordance ITD Concordance
n/N (95% CI)(a) n/N (95% CI)(a)
PPA 51/55 92.7 (82.7, 97.1) 70/76 92.1 (83.8, 96.3)
NPA 68/68 100.0 (94.7, 100.0) 90/91 98.9 (94.0, 99.8)
OPA 119/123 96.7 (91.9, 98.7) 160/167 95.8 (91.6, 98.0)
(a) Two-sided 95% CIs were calculated using the Wilson score method.
(b) For the purpose of the analyses, a pMMR status was considered negative, and dMMR status was considered positive.
PPA = positive percent agreement; NPA = negative percent agreement; OPA = overall percent agreement
*MMR by IHC, not necessarily Roche
**Intended Use (IU) population includes only the subset of patients for whom VENTANA MMR RxDx Panel testing attempt was performed according to the requirements of the Dx protocol
Analyses were performed in the Concordance population (all patients in the Safety Population with an evaluable VENTANA MMR RxDx Panel (CDx) staining result). The intent-to-Diagnose (ITD) and the Concordance populations were equivalent in this study. The Intended Use (IU) Concordance population includes only the subset of patients who are also in the IU population (ie, for whom VENTANA MMR RxDx Panel testing attempt was performed according to the requirement of the diagnostic protocol).

Ordering Information: Ordering codes for VENTANA MMR RxDx Panel

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Ordering Information: Ordering codes for VENTANA MMR RxDx Panel

 

Product name Catalog number Ordering Code Quantity
VENTANA anti-MLH1 (M1) Mouse Monoclonal Primary Antibody 790-5091 07862237001 50 tests
VENTANA anti-PMS2 (A16-4) Mouse Monoclonal Primary Antibody 790-5094 07862261001 50 tests
VENTANA anti-MSH2 (G219-1129) Mouse Monoclonal Primary Antibody 790-5093 07862253001 50 tests
VENTANA anti-MSH6 (SP93) Rabbit Monoclonal Primary Antibody 790-5092 07862245001 50 tests
OptiView DAB IHC Detection Kit 760-700 06396500001 250 tests
OptiView Amplification Kit* 860-099 06718663001 250 tests
*Required with VENTANA anti-PMS2 (A16-4) Mouse Monoclonal Primary Antibody