Microsatellite Instability as a Biomarker for PD-1 Blockade

DOI: 10.1158/1078-0432.CCR-15-1678 Published February 2016

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Figure 1.
Proposed relationship between MSI status and immunologic response. Tumor cell (top) and T cell (bottom) in the absence (A) or presence (B) of immunotherapy. For simplicity, the tumor cell is drawn as the source for the PD-L1; however, in some tumors, such as MSI colorectal cancer, the dominant source may be macrophages or other tumor-infiltrating lymphocytes and myeloid cells (6). In the absence of functional MMR, nascent strand slippage (green base) goes unrepaired, producing frameshift mutations (red bases) and resulting in proteins (blue diamond) containing a mutation-associated neoantigen (MANA, red square). MANA-MHC complexes are presented to T cells. MANAs can also arise from missense mutations (not shown). MHC, major histocompatibility complex; TCR, T-cell receptor.
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Figure 2.
MSI testing algorithm proposed in 2012 by the Association for Molecular Pathology. Reprinted with permission from ref. 29. This figure was published in The Journal of Molecular Diagnostics, Vol. 14, Funkhouser WK, Jr, Lubin IM, Monzon FA, Zehnbauer BA, Evans JP, Ogino S, et al. Relevance, pathogenesis, and testing algorithm for mismatch repair-defective colorectal carcinomas: a report of the Association for Molecular Pathology, 91–103. Copyright Elsevier 2012.

Table 1.

Cancers with an MSI-H frequency greater than 10%

Table 2.

Cancers with an MSI-H frequency between 2% and 10%

Abbreviation: SCC, squamous cell carcinoma.

↵^aThis number represents an aggregate of studies with different definitions of MSI-H, not all of which meet the Bethesda guidelines.
↵^bMSI-H was defined as positivity in at least 2/8 markers.

Table 3.

Cancers with an MSI-H frequency less than 2%

Tumor type	Frequency, % (n)	Study
Skin (squamous cell)	0% (30), 0% (56)	Reuschenbach et al. (89)^a
Skin (basal cell)	0% (53), 2% (104)	Reuschenbach et al. (89)^a
Prostate	1% (79)	Burger et al. (90)
Lung	0% (80), 2% (55)	Okuda et al. (91), Ninomiya et al. (92)
Osteosarcoma	0% (68)	Entz-Werle et al. (93)
Glioblastoma	0% (109)	Martinez et al. (94)
Pancreatic ductal adenocarcinoma	0%–2% (338)	Laghi et al (95)
Breast	0% (267), 0% (34), 0% (52), 1% (100)	Anbazhagan et al. (96), Adem et al. (97), Kuligina et al. (98), Toyama et al. (99)
Bladder	1% (84)	Catto et al. (100)
Testicular germ cell	0% (100)	Mayer et al. (70)

↵^aThe first percentage given resulted from looking at a series of cases with three mononucleotide markers (BAT25, BAT26, and CAT25).The second number was derived by the authors by summing the results of several other studies, not all of which defined MSI-H in a manner consistent with the Bethesda guidelines.