1
IMMUNE CHECKPOINT
INHIBITOR BIOMARKERS
Programmed cell death ligand 1 (PDL1)
immunohistochemistry (IHC) uses various
scoring systems and cutoffs for particular
antibody clones to quantify PDL1 expression as
a predictive biomarker for specic FDA
approved ICI. For example:
- The PDL1 pharmDX 22C3 immunostain is
a companion diagnostic for non small cell
lung carcinoma (NSCLC) patients eligible for
pembrolizumab immunotherapy.
- The tumor proportion score (TPS) is calcu-
lated by dividing the total number of PDL1
positive tumor cells by the total number of
tumor cells (
1% positive cutoff).
- The combined positive score (CPS) is based
on dividing the number of PDL1 positive
cells (tumor cells, lymphocytes, macrophages)
by the number of tumor cells to predict
pembrolizumab efcacy in metastatic gastric
and gastroesophageal junctional carcinoma,
Issue 17 || February 2022
WHAT’S NEW IN
MOLECULAR GENETIC
PATHOLOGY 2022:
IMMUNE CHECKPOINT
INHIBITOR BIOMARKERS
AND SELECT SOLID
TUMORS
Patricia C. Tsang, MD
1
and Guoli Chen, MD
2
1
MedStar Washington Hospital Center, Pathology &
Laboratory Medicine, Washington, DC, USA
2
Geisinger Medical Laboratories, Geisinger Health,
Danville, Pennsylvania, USA
Corresponding Author: Patricia C. Tsang, MD
MedStar Washington Hospital Center, Pathology &
Laboratory Medicine, Washington, DC, USA
E-mail: patctsang@hotmail.com
ORCID
Patricia C. Tsang
https://orcid.org/0000-0003-0523-9793
Guoli Chen
https://orcid.org/0000-0002-4426-6156
Abstract
Predictive biomarker testing plays a critical role
in targeted immuno-oncology, including the use
of immune checkpoint inhibitors (ICI) for various
solid tumors. Molecular advancements in cancers
of the breast, kidney and brain have continued to
propel tumor classication and precision therapy.
GENE FUSION NOMENCLATURE
The HUGO Gene Nomenclature Committee has
released a new recommendation to denote gene
fusion with a double colon, e.g., BCR::ABL
(Leukemia 2021;35:3040).
bladder cancer and cervical cancer (Fig. 1). It
has the same cutoff of
1%, using the 22C3
antibody clone.
- The PDL1 SP142 clone is an FDA approved
complementary diagnostic to predict response
of metastatic NSCLC to atezolizumab. The
evaluation is based on either the proportion
of tumor area occupied by PDL1 expressing
tumor inltrating immune cells of any
intensity or the percentage of PDL1 express-
ing tumor cells of any intensity.
Decient mismatch repair (dMMR) / high mic-
rosatellite instability (MSI-H) is predictive of
ICI efcacy in colorectal cancers and other solid
tumors. While it is commonly tested by IHC,
assays based on PCR or next generation
sequencing (NGS) are available.
High tumor mutational burden (TMB) may
also serve as a predictor of immunotherapy
response. TMB reects the number of somatic
mutations per megabase of tumor genomic
sequence. It can be determined by whole exome
sequencing (WES) or targeted sequencing of
gene panels (usually
200 genes). Cutoff values
have not yet been unied and may vary in
respect to different assay platforms and ICI
drug targets. Recently, Foundation Medicine’s
FoundationOne
®
CDx, which includes MSI
and TMB assessment, was approved as a
companion diagnostic for pembrolizumab with
a cutoff of
10 mutations per megabase,
regardless of solid tumor type.
BREAST CARCINOMA
NGS can simultaneously detect alterations of
multiple genes involved in breast cancers.
Clinically actionable genomic changes include
ERBB2 (HER2) amplication (prevalence
~15%), BRCA1/BRCA2 mutations (5%–
10%), PIK3CA mutations (30%–40%) and
ETV6::NTRK3 fusion in secretory breast
carcinoma (< 0.2% of breast cancers).
- BRCA1 and BRCA2 inactivating mutations
carry a lifetime cumulative risk of 60% and
55% to develop breast cancer, respectively.
PathologyOutlines.com
WHAT’S NEW
IN PATHOLOGY?
Sponsored by an unrestricted grant from Geisinger Medical Laboratories: Dedicated to Laboratory Excellence
Fig. 1. Esophagogastric adenocarcinoma. (A) H&E
stain, 40 x. (B) PD-L1 22C3 immunostain demonstrat-
ing a combined positive score of close to 20% (posi-
tive: > 1%), indicating response to pembrolizumab.
A
B