pISSN 1598-2998, eISSN 2005-9256
https://doi.org/10.4143/crt.2021.828
Cancer Res Treat. 2022;54(4):1200-1208
Original Article
Frequency of Mismatch Repair Deficiency/High Microsatellite Instability and
Its Role as a Predictive Biomarker of Response to Immune Checkpoint Inhibitors
in Gynecologic Cancers
Joseph J. Noh
Chan Lee3
1
, Min Kyu Kim
2
, Min Chul Choi
3
, Jeong-Won Lee
1
, Hyun Park3, Sang Geun Jung3, Won Duk Joo3, Seung Hun Song3,
1
Gynecologic Cancer Center, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Samsung Changwon Hospital, Sungkyunkwan University School of
Medicine, Changwon, 3Comprehensive Gynecologic Cancer Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
2
Purpose This study was to investigate the frequency of mismatch repair deficiency/high microsatellite instability (MMRd/MSI-H)
in gynecologic malignancies and the efficacy of immune checkpoint inhibitors (ICIs) in patients with recurrent gynecologic cancers
according to MMR/MSI status.
Materials and Methods We conducted a multi-center retrospective review on the patients who were diagnosed with gynecologic
cancers between 2015 and 2020. Their clinicopathologic information, results of immunohistochemistry staining for MLH1/MSH2/
MSH6/PMS2 and MSI analysis, tumor response to treatment with ICIs were investigated.
Results Among 1,093 patients included in the analysis, MMRd/MSI-H was most frequent in endometrial/uterine cancers (34.8%,
164/471), followed by ovarian, tubal, and peritoneal cancers (12.8%, 54/422) and cervical cancer (11.3%, 21/186). When assessed
by histology without regard for cancer types, the frequency of MMRd/MSI-H was 11.0% (38/345) in high-grade serous adenocarcinoma, 38.6% (117/303) in endometrioid adenocarcinoma, and 30.2% (16/53) in carcinosarcoma. A total of 114 patients were treated
with ICIs at least once. The objective response rate (ORR) was 21.6% (8/37) in cervical cancer, 4.7% (2/43) in ovarian cancer, and
25.8% (8/31) in endometrial/uterine cancers. Univariate regression analysis identified MMRd/MSI-H as the only significant factor
associated with the ORR (28.9% [11/38] vs. 11.8% [9/76]; odds ratio, 3.033; 95% confidence interval, 1.129 to 8.144; p=0.028).
Conclusion The frequency of MMRd/MSI-H is moderate to high in gynecologic cancers in the Korean population. MMRd/MSI-H could
be effective predictive biomarkers in gynecologic cancers of any type.
Key words Gynecologic neoplasms, Immune checkpoint inhibitors, Microsatellite instability, Mismatch repair, Recurrence
Introduction
The introduction of immune checkpoint inhibitors (ICIs)
has led to a revolutionary change in the oncology field far
beyond their remarkable clinical efficacy. In recent years, various ICIs have resulted in an improvement in the overall survival (OS) of patients with a broad range of advanced cancers
[1,2]. However, for most types of cancer, only a minority of
patients experience a durable response from such treatments
while most patients do not benefit significantly. Therefore,
attention has been paid to the identification and development of predictive biomarkers of response to ICIs, and more
in-depth and comprehensive studies have been conducted in
recent years [3,4]. Among the most widely investigated preCorrespondence: Min Chul Choi
Comprehensive Gynecologic Cancer Center, CHA Bundang Medical Center,
CHA University, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea
Tel: 82-31-780-6191 Fax: 82-31-780-6194 E-mail: oursk79@cha.ac.kr
Received July 18, 2021 Accepted December 10, 2021
Published Online December 13, 2021
1200 Copyright
dictive biomarkers of response to ICIs, microsatellite instability (MSI) and defective mismatch repair (MMRd), universal
screening tools for identifying Lynch syndrome [5], have
been shown to be significant biomarkers for a favorable response to ICIs [6-8].
Mismatch repair deficient tumors have a unique genetic
signature, harboring hundreds to thousands of somatic mutations that encode potential neoantigens. These susceptible
mutations in repetitive DNA sequences, termed microsatellites, result in high levels of microsatellite instability (MSIH) [9]. This signature results from primary bi-allelic defects
in genes that govern DNA mismatch repair. These tumors
arise in individuals with hereditary genetic syndromes, the
so-called Lynch syndrome, or more often as sporadic diseasCo-correspondence: Jeong-Won Lee
Gynecologic Cancer Center, Department of Obstetrics and Gynecology,
Samsung Medical Center, Sungkyunkwan University School of Medicine,
81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
Tel: 82-2-3410-1382 Fax: 82-2-3410-0630 E-mail: garden.lee@samsung.com
*Joseph J. Noh and Min Kyu Kim contributed equally to this work.
2022 by the Korean Cancer Association
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
│ https://www.e-crt.org │
Joseph J. Noh, MMRd and MSI-H in Gynecologic Cancers
es. Tumors with MMRd represent approximately 4% of all
diagnosed cancers [10,11]. These tumors vary in frequency
across different cancer types. Also, in patients with gynecologic cancers, they occur at a rate of 17%-31% in endometrial
cancer, 1%-3% in ovarian cancer, and 2%-4% in cervical cancer [10,11].
The phase II KEYNOTE-158 study of pembrolizumab,
an anti–programmed death-1 (PD-1) monoclonal antibody
and an ICI, in patients with previously treated, advanced
non-colorectal MSI-H/MMRd cancers reported an objective
response rate (ORR) of 34.3% (80/233) [7]. In a meta-analysis
of 14 studies comprising 939 patients with pre-treated MSIH tumor, ICIs showed high efficacy that was independent of
the tumor type and specific ICI type used, showing a pooled
ORR of 41.5% [12]. Pembrolizumab was approved by the
United States Food and Drug Administration in May 2017
for the treatment of patients with any type of MSI-H/MMRd
solid tumors that have progressed following prior treatment.
This marked the first approval of a tumor-agnostic cancer
therapy in which treatment is based on a common tumor
biomarker rather than the anatomic site of origin. Therefore,
it became clear that accurate identification of patients with
MMRd/MSI-H tumors is essential for not only screening the
genetic background of patients, but also making appropriate
therapeutic decisions during disease recurrence.
The frequencies of MMRd/MSI-H in pan-cancer have been
reported in several studies [10] and there have been some
reports of their frequency in gynecologic cancer patients.
However, real-world data comparing the ORR according to
MMR/MSI status have not yet been reported in gynecologic
cancers. In the present study, we retrospectively assessed the
frequency of MMRd/MSI-H in Korean gynecologic cancer
patients, and investigated the effect of ICI therapy in recurrent gynecologic cancer with MMRd/MSI-H.
Materials and Methods
1. Study design and patients
We conducted a multi-center, retrospective study at three
tertiary academic medical institutions in South Korea. We
reviewed the medical records of patients who were diagnosed with gynecologic cancers between January 2015 and
December 2020. The collected data included the patient
demographics and clinical data on pathologic results, including the results of immunohistochemistry (IHC) staining for
MLH1/MSH2/MSH6/PMS2, and MSI analysis. A total of
1,093 patients were included in investigating the frequency
of MMRd/MSI-H in gynecologic cancers. Among these patients, we further reviewed the clinicopathologic and radiologic records of those diagnosed with recurrent or persistent
gynecologic cancer who underwent treatment with ICIs for
at least one cycle. Patients who were treated with ICIs underwent intravenous administration of 200 mg of pembrolizumab every 3 weeks or 3 mg/kg of nivolumab every 2 weeks
until disease progression, unacceptable toxicity, or patient
withdrawal. The study protocol was approved by the institutional review board of each participating institution (CHA
IRB 2020-12-034).
2. Tumor testing
The tumor MMR status was determined by examining
the loss of protein expression via IHC staining of four MMR
enzymes. Tumors with loss of MMR expression in at least
one of those four markers were defined as MMRd. MSI status was determined by the polymerase chain reaction (PCR)–
based MSI analysis of DNA from normal and tumor tissues.
The analysis was performed using five mononucleotide loci
(BAT25, BAT26, NR21, NR24, and Mono27) or five mixed
mononucleotide and dinucleotide loci (BAT25, BAT26, D17S250, D2S123, and D5S346) according to the institution’s
established method. Specimens were classified as MSI-H if
at least two allelic loci sizes shifted among the five microsatellite markers analyzed. Tumors were classified as MMRd/
MSI-H if either MMRd and/or MSI-H were seen. Tumor programmed death-ligand 1 (PD-L1) expression was analyzed
using the PD-L1 IHC 22C3 antibody (Agilent Technologies,
Inc., Santa Clara, CA) to determine the tumor proportion
score (TPS), defined as the percentage of viable tumor cells,
or using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Inc., Carpinteria, CA) to determine the combined
positive score (CPS), defined as the ratio of PD-L1–positive
cells (tumor cells, lymphocytes, and macrophages) to the
total number of viable tumor cells multiplied by 100. PD-L1
positivity was defined as a TPS ≥ 1% or a CPS > 1.
3. Assessments of response and safety
Baseline tumor assessment was performed before the start
of treatment, and response was evaluated via abdominopelvic and/or chest computed tomography scans performed
at least every 3 months. Additional imaging studies were
performed at the clinician’s discretion if a patient’s clinical
symptoms deteriorated. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors
(RECIST) ver. 1.1 by a gynecologic oncologist at each institution. Safety was assessed by retrospectively reviewing charts
of laboratory test results and physical examination to detect
any possible adverse events (AEs), which were evaluated
according to the Common Terminology Criteria for AEs, ver.
4.03.
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Table 1. Frequency of MMRd and/or MSI-H in gynecologic cancers by origin
No.
Cervix/Vulvar/Vagina cancer
Cervix cancer
Vulvar cancer
Vagina cancer
Ovarian/Peritoneal/Tubal cancer
Ovarian
Epithelial ovarian cancer
Non-epithelial ovarian cancer
Peritoneal cancer
Fallopian tubal cancer
Endometrial/Uterine cancer
Endometrial cancer
Uterine sarcoma
Gestational trophoblastic neoplasia
Total
MMRd/MSI-H
Frequency (%)
25
21
2
2
54
50
50
0
3
1
164
139
25
2
245
12.8
11.3
33.3
66.7
12.8
13.0
13.3
0.0
12.0
8.3
34.8
37.3
25.5
40.0
22.4
No.
MMRd/MSI-H
Frequency (%)
345
303
74
53
52
51
36
31
30
20
14
13
12
10
38
117
7
16
10
14
8
7
3
5
2
0
7
1
11.0
38.6
9.5
30.2
19.2
27.5
22.2
22.6
10.0
25.0
14.3
0.0
58.3
10.0
195
186
6
3
422
385
377
8
25
12
471
373
98
5
1,093
MMRd, mismatch repair deficiency; MSI-H, microsatellite high.
Table 2. Frequency of MMRd and/or MSI-H in gynecologic cancers by histology regardless of origin
High-grade serous carcinoma
Endometrioid adenocarcinoma
Squamous cell carcinoma
Carcinosarcoma
Endocervical adenocarcinoma
Clear cell carcinoma
Mucinous carcinoma
Leiomyosarcoma
Neuroendocrine carcinoma
Mixed adenocarcinoma
Endometrial stromal sarcoma
Adenosquamous carcinoma
Mesonephric adenocarcinoma
Low grade serous carcinoma
MMRd, mismatch repair deficiency; MSI-H, microsatellite high.
4. Outcomes
The primary endpoints were the frequency of MMRd/
MSI-H tumors in gynecologic cancers and the ORR, defined
as the proportion of patients with complete response (CR)
or partial response (PR), as assessed using RECIST ver. 1.1.
The secondary endpoints included the duration of response,
defined as the time from the response to tumor progression
or death, whichever occurred first; progression-free survival (PFS), defined as the time from the start of treatment to
tumor progression or death, whichever occurred first; and
the OS, defined as the time from the start of treatment to
death from any cause.
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5. Statistical analysis
Efficacy and safety profile analyses included all patients
who underwent at least one cycle of treatment. The data
were summarized using descriptive statistics or contingency tables for demographic and baseline characteristics, response measurements, and safety. Patients without response
data were considered to be non-responders. The duration
of response, PFS, and OS were estimated using the KaplanMeier method. Univariate logistic regression analyses were
performed to identify factors affecting the ORR. All statistical analyses were performed using SPSS ver. 18.0 (SPSS Inc.,
Chicago, IL). Analysis items with p-values less than 0.05
Joseph J. Noh, MMRd and MSI-H in Gynecologic Cancers
were considered statistically significant.
Results
1. Frequency of MMRd/MSI-H
A total of 1,093 patients were included in the analysis.
According to the origin of cancer, the frequencies of MMRd/
MSI-H were 11.3% in cervical cancer (21/186), 12.8% in ovarian, tubal and peritoneal cancers (54/422), and 37.3% in
endometrial cancer (139/373) (Table 1). When assessed by
the types of histology regardless of the anatomical cancer
origin, the frequency was the highest in mesonephric adenocarcinoma (58.3%, 7/12), 38.6% in endometrioid adenocarcinoma (117/303), 30.2% in carcinosarcoma (16/53), and 27.5%
in clear cell carcinoma (14/51) (Table 2). The frequencies of
MMRd/MSI-H were 22.1% (216/976) in tumors with nonsarcoma histology, 24.1% (27/112) in tumors with sarcoma
histology, and 40% (2/5) in gestational trophoblastic neoplasia (GTN) (S1 Table).
2. Clinicopathologic characteristics
A total of 114 out of 1,093 patients were treated with ICIs for
recurrence at least once. The clinicopathologic characteristics
of these patients are listed in Table 3. The median age was 54
years (range, 21 to 86 years). Among them, 41.2% (47/114)
had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 1, and 73.7% (84/114) had stage
III or IV disease at the initial diagnosis. In total, eight tumor
types were represented among the patients, most commonly
ovarian, cervical, endometrial, and uterine corpus (mainly
uterine sarcoma) cancers. PD-L1 expression was assessed in
93 patients (81.6%), 65 (69.9%) of whom were PD-L1 positive.
Thirty-eight patients (33.3%) had MMRd/MSI-H tumors.
The remaining 76 patients were identified as MMR proficient
(MMRp)/microsatellite stable (MSS), but received ICI either
because their tumor profiles showed PD-L1 positivity or
their tumor histology types corresponded to those that have
demonstrated response to ICI. The median sum of the target
lesions size was 60 mm (range, 10 to 1,230 mm). The median
number of lines of prior chemotherapy, including neoadjuvant chemotherapy, was two (range, 1 to 7). The specific
agents of ICIs administered were pembrolizumab (88.6%,
101/114) and nivolumab (11.4%, 13/114). As of February 28,
2021, at the time of data cutoff, the median follow-up time
was 4.9 months (range, 0.1 to 36.8 months). Eighty-five patients (74.6%) had discontinued ICIs, most commonly due to
disease progression. The patients underwent a median of 4
cycles (range, 1 to 40 cycles) of chemotherapy with ICIs.
Table 3. Baseline clinico-pathologic characteristics of the patients treated with immune checkpoint inhibitors (n=114)
No. (%)
Age, median (range, yr)
ECOG performance status
0-1
2-4
FIGO stage at diagnosis
I/II
III/IV
N/A
Origin of cancer
Cervix
Vulvar
Ovary/Peritoneum/Fallopian tube
Endometrium
Uterine corpus
Gestational trophoblast
PD-L1 expressiona)
≥1
<1
N/A
MMRd and/or MSI-H
MMRp and/or MSS
Target lesion size, median (range, mm)b)
No. of previous lines of chemotherapy
1
2
3
4
≥5
Type of immune checkpoint inhibitors
Pembrolizumab
Nivolumab
54 (21-86)
47 (41.2)
67 (58.8)
22 (19.3)
84 (73.7)
8 (7.0)
37 (32.5)
1 (0.9)
43 (37.7)
23 (20.2)
8 (7.0)
2 (1.8)
65 (57.1)
28 (24.6)
21 (18.4)
38 (33.3)
76 (66.7)
60 (10-1,230)
29 (25.4)
39 (34.2)
18 (15.8)
15 (13.2)
13 (11.4)
101 (88.6)
13 (11.4)
ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; MMRd, mismatch repair deficiency; MMRp, mismatch repair proficiency;
MSI-H, microsatellite high; MSS, microsatellite stable; N/A, nonavailable; PD-L1, programmed death-ligand 1. a)Determined by
either the tumor proportion score (TPS) or the combined positive
score (CPS), b)Sum of the diameters of the target lesions.
3. Antitumor activity
In the total population (n=114), five patients (4.4%)
achieved CR and 15 (13.2%) achieved PR, resulting in an
ORR of 17.5% (Table 4). Among the patients who achieved
an objective response, the median time to response was 2.4
months (range, 0.8 to 17.3 months) and the median duration of response was not reached (range, 2.2 to 33.0 months).
Among patients with MMRd/MSI-H tumors (n=38), the
ORR was 28.9% (3 CRs and 8 PRs). Among patients with
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Table 4. Tumor responses assessed by RECIST v.1.1 (n=114)
Antitumor activity
Best overall response
CR
PR
SD
PD
Not able to be assessed
Objective response rate
Disease control rate
Time to response (mo)
Median (range)
Duration of response (mo)
Median (range)
Total population
MMRd/MSI-H group
MMRp/MSS group
114
38
76
5 (4.4)
15 (13.2)
23 (20.2)
58 (50.9)
13 (11.4)
20 (17.5)
43 (37.7)
3 (7.9)
8 (21.1)
4 (10.5)
16 (42.1)
7 (18.4)
11 (28.9)
15 (39.5)
2 (2.6)
7 (9.2)
19 (25.0)
42 (55.3)
6 (7.9)
9 (11.8)
28 (36.8)
2.4 (0.8-17.3)
3.7 (0.8-17.3)
1.9 (1.4-3.5)
Not reached
(2.2-33.0)
Not reached
(2.3-33.0)
Not reached
(2.2-32.0)
Values are presented as number (%) unless otherwise indicated. CR, complete response; MMRd, mismatch repair deficiency; MMRp,
mismatch repair proficiency; MSI-H, microsatellite high; MSS, microsatellite stable; PD, progressive disease; PR, partial response; RECIST,
Response Evaluation Criteria in Solid Tumor; SD, stable disease.
A
B
1.0
0.8
0.8
Overall survival
Progression-free survival
1.0
0.6
0.4
0.2
0
0.6
0.4
0.2
0
0
12
24
36
Time (mo)
0
12
24
36
Time (mo)
Fig. 1. Kaplan-Meier estimates of survival in the total study population (n=114): progression-free survival (A) and overall survival (B).
MMRp/MSS tumors (n=76), the ORR was 11.8% (2 CRs and
7 PRs) (Table 4).
The response to treatment with ICIs was assessed by anatomical cancer origins and the results are summarized in S2
Table. The ORR was 4.7% (2/43) in ovarian cancer, 21.6%
(8/37) in cervical cancer, 26.1% (6/23) in endometrial cancer, 25.0% (2/8) in uterine corpus cancer, and 100.0% (2/2) in
GTN. Among patients with MMRd/MSI-H tumors (n=38),
the ORR was 33.3% for endometrial cancer (5/15), 33.3%
(2/6) for uterine corpus cancer, 14.3% (1/7) for ovarian cancer, and 12.5% (1/8) for cervical cancer (S3 Table).
At the time of data cutoff, 86 (75.4%) patients in the total
population had experienced disease progression or death.
The median PFS was 2.8 months (95% confidence interval [CI], 2.4 to 3.2), and the estimated PFS rates at 6 and 12
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months were 30.1% and 21.4%, respectively (Fig. 1A). Thirtythree patients (28.9%) in the total population had died. The
median OS was 35.9 months (95% CI, 16.1 to 55.7) in the total
population (Fig. 1B). The OS rates at 6 and 12 months were
77.1% and 61.1%, respectively.
4. Prognostic factors
We compared the ORR according to different clinical parameters, including age, tumor origin, the number of previous lines of chemotherapy, ECOG status, PD-L1 positivity,
MMRd/MSI-H status, and tumor size (Table 5). MMRd/
MSI-H status was the only significant factor found in the univariate regression analyses (odds ratio, 3.033; 95% CI, 1.129
to 8.144; p=0.028).
Joseph J. Noh, MMRd and MSI-H in Gynecologic Cancers
Table 5. Logistic regression analysis of predictive factors for the
objective response rate
Univariate analysis
Age (yr)
< 60
≥ 60
Origin of tumor
Cervix
Ovary
Uterine
No. of prior lines of
chemotherapy
≤2
>2
ECOG performance status
≤1
>1
MMRd/MSI-H
MMRp and/or MSS
MMRd and/or MSI-H
PD-L1 status
<1
≥1
Tumor burden (cm)a)
<2
≥ 2 and < 5
≥ 5 and < 10
≥ 10
OR (95% CI)
p-value
1(
0.711 (0.236-2.139)
0.544
1(
0.274 (0.067-1.122)
1.467 (0.490-4.392)
0.072
0.493
1(
0.759 (0.278-2.077)
0.592
1(
0.554 (0.196-1.567)
0.266
1(
3.033 (1.129-8.144)
0.028
1(
3.569 (0.754-16.899)
0.109
1(
1.739 (0.299-10.104)
1.538 (0.266-8.890)
2.207 (0.417-11.669)
0.538
0.630
0.352
CI, confidence interval; ECOG, Eastern Cooperative Oncology
Group; MMRd, mismatch repair deficiency; MMRp, mismatch
repair proficiency; MSI-H, microsatellite high; MSS, microsatellite stable; OR, odds ratio; PD-L1, programmed death-ligand 1.
a)
Sum of the diameters of the target lesion.
5. Safety
Treatment-related AEs of any grade and treatment-related
AEs of grade ≥ 3 were reported in 42.1% and 4.4% of patients,
respectively (S4 Table). There were no treatment-related
deaths. The most common AEs of any grade were hypothyroidism (10.5%), anemia (8.8%), fatigue (7.0%), and skin rash
(3.5%). The AEs of grades 3/4 were hypothyroidism, anemia,
renal insufficiency, colitis, and thrombocytopenia.
Discussion
In two previous studies that evaluated MSI with next-generation sequencing-based methods using data from the Cancer Genome Atlas [10], the frequency of MSI-H was reported
to be 3.5%-3.8% for all carcinomas. The frequencies of MSI-H
ranged from 28.3% (75/265) to 31.4% (170/542) in endometrial cancer, 1.4% (6/437) to 3.2% (14/436) in ovarian cancer,
and 2.3% (7/305) to 2.6% (8/305) in cervical cancer. In the
present study, the frequencies of MMRd/MSI-H were 37.3%
(139/373) in endometrial cancer, 13.3% (50/377) in epithelial
ovarian cancer, and 11.3% (21/186) in cervical cancer (Table
1). The frequency of MMRd and/or MSI-H in endometrial
cancer was comparable to those reported in previous studies,
and the frequency of ovarian and cervical cancers was higher
than that previously reported. However, a previous study
which used the classical PCR-based MSI method, which is
the same method used in the present study, reported MSIH rates of 10% for ovarian cancer [13] and 8% for cervical
cancer [14]. Therefore, it is possible that these results could
be influenced by the difference in MSI analysis methods and
reporting methods. Overall, it is noteworthy that endometrial cancer has the highest MMRd/MSI-H frequency.
Mesonephric adenocarcinoma is a rare malignant tumor of
the female genital tract, which originates from Wolffian duct
remnants. It has been reported to carry a worse prognosis
even in the early stages [15,16]. Although the MMRd/MSIH frequency in mesonephric adenocarcinoma in the present
study was 58.3% (7/12), previous studies reported that the
frequency of MMRd or MSI-H in mesonephric adenocarcinoma was low [15,16]. This discordance might arise from the
small number of cases and the absence of a central pathology
review in the present study. Although data are lacking on the
response rates of mesonephric adenocarcinoma to ICIs, treatment with ICIs in MMRd/MSI-H mesonephric adenocarcinoma can be considered.
Previous studies reported that the frequency of MMRd/
MSI-H in uterine carcinosarcoma was as low as 3.5% (2/57)
[11]. However, in the present study, the frequencies of MMRd
/MSI-H were 30.2% (16/53) in carcinosarcoma and 22.6%
(7/31) in leiomyosarcoma, which were relatively higher
(Table 2). In the treatment of gynecologic sarcoma which
usually carries a poor prognosis and has no effective therapeutic options at recurrence, it would be helpful to assess
the MMRd/MSI-H status and consider treatment using ICIs.
GTN comprises a unique group of diseases that arise from
the malignant transformation of fetal trophoblasts, cells that
originate from the placenta. Recent studies found strong
expression of PD-L1 in GTN [17,18] and the frequency of
MMRd/MSI-H was 40% (2/5) in the present study (Table 1).
The therapeutic response to ICIs in treating chemo-resistant
GTN was reported to be favorable [19,20], and there are two
ongoing clinical trials on the treatment of chemo-resistant
GTN with ICIs (NCT03135769 and NCT04303884).
The mismatch repair pathway plays a crucial role in repairing DNA replication errors. Deficiencies in MMR proteins
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that cause MSI-H lead to the accumulation of mutations
and the generation of neoantigens that might stimulate the
antitumor immune response [7]. Tumors with MMRd could
induce immune evasion by immune checkpoints, allowing
them to escape from the tumor-specific T-cell response [21].
Therefore, using a monoclonal antibody to inhibit immune
checkpoints might be an effective therapeutic approach to
reversing immune suppression and re-activating the immune system in MMRd/MSI-H tumors regardless of cancer
type.
In gynecological cancers regardless of MMRd/MSI-H
status, the ORR of anti-PD-1 inhibitors was reported to be
low (4%-23%). The respective rates were 4%-12% in cervical
cancer [22], 8%-15% in ovarian cancer [23,24], and 13%-23%
in endometrial cancer [25,26]. A meta-analysis of 14 studies comprising 939 patients with pre-treated MSI-H cancer
reported that the pooled ORR of ICIs was 41.5% (95% CI,
34.9 to 48.4), the pooled median PFS was 4.3 months (95% CI,
3.0 to 6.8), and the pooled median OS was 24 months (95%
CI, 20.1 to 28.5) [12]. Another previous study reported that
the ORR was 34.3% with a median PFS of 4.1 months and a
median OS of 23.5 months among 233 patients representing
27 MMRd/MSI-H tumor types [7]. In that study, the ORRs in
endometrial cancer and ovarian cancer were 57.1% (28/49)
and 33.3% (5/15), respectively.
In the present study, the ORR of the total population
(n=114) was 17.5% and that of the MMRd/MSI-H group
(n=38), representing five gynecologic cancer types, was
28.9% (Table 4). The ORRs were 33.3% (5/15) for endometrial cancer with MMRd/MSI-H and 14.3% (1/7) for ovarian
cancer with MMRd/MSI-H (S3 Table). The median PFS of
MMRd/MSI-H group (n=38) was 2.3 months (95% CI, 0.6 to
4.1), and the median OS was not reached (data not provided).
Although it is difficult to directly compare the results of this
study with those of other prospective studies, we observed
a low overall ORR of ICIs for MMRd/MSI-H tumors. This
difference could be influenced by the difference between
prospective and retrospective study designs, and by the
relatively high MMRd/MSI-H rates observed in the present
study. Despite this difference, it was possible to confirm the
statistical difference in ORR between MMRd/MSI-H and
MMRp/MSS patients.
In the present study, we examined the effects of several factors on ORR: age, cancer type, number of prior lines of chemotherapy, ECOG status, MMRd/MSI-H status, PD-L1 positivity, and tumor size. MMRd/MSI-H was shown to be the
only significant factor in the univariate analysis (odds ratio,
3.033; 95% CI, 1.129 to 8.144; p=0.028). Other factors showed
no statistically significant associations (Table 5). PD-L1 protein expression on tumor or immune cells has also emerged
as a potential predictive biomarker for sensitivity to ICIs [27].
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CANCER RESEARCH AND TREATMENT
In the present study, the association between PD-L1 expression and ORR could not be confirmed (Table 5). A high tumor
mutational burden is another emerging agnostic biomarker
with a wider range than MMRd/MSI-H in cancers of any
type [28]. Further investigations on such potential biomarker
and others are warranted to expand the understanding of
profound immune response in malignant diseases.
According to a recent meta-analysis [29], AEs of any grade
occurred in 65.8% of patients receiving an ICI, and 16.6% of
patients experienced AEs of grade ≥ 3. In the present study,
AEs of any grade occurred in 42.1% of patients, and 4.4% of
patients experienced AEs of grade ≥ 3. The frequency of AEs
in this study was relatively low, which is likely due to the
limitations of a retrospective study conducted using chart
reviews. Minor AEs might not have been recorded.
The limitations of this study mainly stem from its retrospective design. The lack of independent central pathologic review could also be a confounding factor. Accordingly,
there may have been differences in the methods of MMRd/
MSI testing and the interpretation of the results among the
pathologists at each institution. The frequency of MMRd/
MSI-H was higher than those reported in previous studies.
The absence of a difference in disease control rate between
the MMRd/MSI-H and MMRp/MSS groups (Table 4) might
be due to the high MMRd/MSI-H frequency in this study.
In addition, MMRd and MSI tests were not performed in
all patients. Some patients underwent only one of the two
tests. Therefore, it is difficult to conclude that the accurate
MMRd/MSI-H frequency was reflected in the present study.
Also, the response assessment could not be centralized
by an independent central radiologic review. We did not
assess the immune response based on the immune RECIST or
immune-related RECIST. Although none of the 114 patients
raised concerns regarding potential pseudoprogression or
hyperprogression even when assessed by the RECIST, the
implementation of immune-related response criteria might
have portrayed different results. There may also have been
differences in the interpretation of the results depending on
the types of ICI (pembrolizumab or nivolumab) although
both agents belong to the same category and act as antiPD-1 antibodies. The potential discrepancy between the TPS
and CPS to predict response to anti–PD-1/PD-L1 therapy is
another limitation. Due to practical issues, the institutions in
the present study have adopted different scoring methods.
The relatively short follow-up period (median, 4.9 months)
is another limitation of the study. Unlike prospective studies,
in real-world practice, patients with poor general condition
(ECOG PS ≥ 2) are treated with ICIs as the last attempt with
short life expectancies. In the present study, more than half
(58.8%, 67/114) of the patients had an ECOG PS ≥ 2 (Table 3).
As non-responders with poor general condition mostly died
Joseph J. Noh, MMRd and MSI-H in Gynecologic Cancers
soon after treatment with ICIs, the study resulted in a short
follow-up period.
Nevertheless, to the best of our knowledge, the present retrospective study of a relatively large, mainly Asian cohort,
is the first to evaluate MMRd/MSI-H status as a predictive
biomarker for ICIs in gynecologic cancers in a real-world setting. Compared to the known very low MMRd/MSI-H frequencies of ovarian and cervical cancer, in the present study, a
relatively high frequency of > 10% was observed. This shows
that treatment with ICIs is a potential therapeutic alternative
in patients with gynecologic cancers with MMRd/MSI-H.
Recently, the combination of ICI and multi-kinase inhibitors has received attention in the treatment of MSS/MMRp
tumors, which have a much higher proportion compared
to MMRd/MSI-H tumors. Combined therapy comprising
pembrolizumab and lenvatinib (an oral multi-kinase inhibitor) for MSS/MMRp recurrent endometrial cancer has been
found to yield favorable outcomes among 37.2% (35/94) of
patients [30]. As such study, new combination therapeutic
strategies are also being specified for MSS/MMRp tumors.
The present study has shown that the frequency of MMRd/
MSI-H in gynecologic cancers is moderate to high in Korea.
MMRd/MSI-H status was confirmed to be a predictive biomarker for ICI therapy in gynecologic cancers. Further studies are warranted to discover other predictive biomarkers for
ICI therapy in gynecologic cancer.
Electronic Supplementary Material
Supplementary materials are available at Cancer Research and
Treatment website (https://www.e-crt.org).
Ethical Statement
This study was approved by the institutional review board (CHA
IRB 2020-12-034) and adhered to the principles in the Declaration of
Helsinki. A waiver to require informed consent was obtained.
Author Contributions
Conceived and designed the analysis: Choi MC, Lee JW, Lee C.
Collected the data: Noh JJ, Kim MK, Choi MC, Lee JW, Park H, Jung
SG, Joo WD, Song SH, Lee C.
Contributed data or analysis tools: Noh JJ, Kim MK, Choi MC, Lee
JW.
Performed the analysis: Choi MC, Lee JW, Park H, Jung SG, Joo WD.
Wrote the paper: Noh JJ, Kim MK, Choi MC, Lee JW.
ORCID iDs
Joseph Noh : https://orcid.org/0000-0002-3132-8709
Min Kyu Kim : https://orcid.org/0000-0002-1937-3611
Min Chul Choi : https://orcid.org/0000-0003-4509-6731
Jeong-Won Lee : https://orcid.org/0000-0002-6945-0398
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
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