Introduction: Cisplatin-based standardized therapy has been established for metastatic testicular germ cell tumors (TGCTs). However, the patient prognosis is considerably less favorable if the disease recurs following failure of first-line therapies. There is a need for novel treatment options for patients with recurrent or metastatic TGCTs, notably for those that are not sensitive to first-line chemotherapy. With the development of next-generation sequencing technologies, an increasing number of gene mutations has been identified in TGCTs. Previously published research studies have established a link between KRAS mutations and chemotherapy resistance, and have demonstrated that KRAS mutations are associated with inflammatory tumor microenvironment and tumor immunogenicity, leading to an improved response to inhibition of programmed death (PD-1) protein expression. Previous studies have reported that the tumor immune microenvironment of TGCT influences therapeutic efficacy. Case Presentation: A 65-year-old metastatic patient with TGCT and a KRAS-12 valine-for-glycine gene mutation was described. This patient initially underwent inguinal orchiectomy and received two prior chemotherapeutic regimens. Following the rapid progression of the disease, the patient was treated with anti-PD-1 therapy and nab-paclitaxel chemotherapy, and his condition was successfully controlled by this combination treatment. Conclusion: To the best of our knowledge, this is the first successful case of KRAS-mutation patient with TGCT who achieved partially and sustained disease remission by combining immune checkpoint inhibitors with chemotherapy. This case provides an excellent example for personalized treatment of metastatic TGCTs.

1.
Bray
F
,
Ferlay
J
,
Soerjomataram
I
,
Siegel
R
,
Torre
L
,
Jemal
A
.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
.
CA Cancer J Clin
.
2018
;
68
(
6
):
394
424
.
2.
Gilligan
T
,
Lin
DW
,
Aggarwal
R
,
Chism
D
,
Cost
N
,
Derweesh
IH
, et al
.
Testicular cancer, version 2.2020, NCCN clinical practice guidelines in oncology
.
J Natl Compr Canc Netw
.
2019
;
17
(
12
):
1529
54
.
3.
Beyer
J
,
Kramar
A
,
Mandanas
R
,
Linkesch
W
,
Greinix
A
,
Droz
JP
, et al
.
High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables
.
J Clin Oncol
.
1996
;
14
(
10
):
2638
45
.
4.
Sonpavde
G
,
Hutson
T
,
Roth
B
.
Management of recurrent testicular germ cell tumors
.
Oncologist
.
2007
;
12
(
1
):
51
61
.
5.
Motzer
R
,
Sheinfeld
J
,
Mazumdar
M
,
Bains
M
,
Mariani
T
,
Bacik
J
, et al
.
Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer
.
J Clin Oncol
.
2000
;
18
(
12
):
2413
8
.
6.
Gilligan
T
,
Lin
D
,
Aggarwal
R
,
Chism
D
,
Cost
N
,
Derweesh
I
, et al
.
Testicular cancer, version 2.2020, NCCN clinical practice guidelines in oncology
.
J Natl Compr Canc Netw
.
2019
;
17
(
12
):
1529
54
.
7.
Hanna
NH
,
Einhorn
LH
.
Testicular cancer--discoveries and updates
.
N Engl J Med
.
2014
;
371
(
21
):
2005
16
.
8.
Brink
M
,
de Goeij
AFPM
,
Weijenberg
MP
,
Roemen
GMJM
,
Lentjes
MHFM
,
Pachen
MMM
, et al
.
K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands cohort study
.
Carcinogenesis
.
2003
;
24
(
4
):
703
10
.
9.
Necchi
A
,
Bratslavsky
G
,
Corona
RJ
,
Chung
JH
,
Millis
SZ
,
Elvin
JA
, et al
.
Genomic characterization of testicular germ cell tumors relapsing after chemotherapy
.
Eur Urol Focus
.
2020
;
6
(
1
):
122
30
.
10.
Meng
J
,
Gao
J
,
Li
X
,
Gao
R
,
Lu
X
,
Zhou
J
, et al
.
TIMEAS, a promising method for the stratification of testicular germ cell tumor patients with distinct immune microenvironment, clinical outcome and sensitivity to frontline therapies
.
Cell Oncol
.
2023
;
46
(
3
):
745
59
.
11.
Zhang
C-F
,
Liu
C
,
Shi
Q-L
,
Ma
J
,
Ma
H-H
,
Zhou
H-B
.
[Clinicopathological analysis of testicular mixed germ cell tumor]
.
Zhonghua Nan Ke Xue
.
2011
;
17
(
4
):
336
41
.
12.
Gillessen
S
,
Sauvé
N
,
Collette
L
,
Daugaard
G
,
de Wit
R
,
Albany
C
, et al
.
Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): results from the IGCCCG update consortium
.
J Clin Oncol
.
2021
;
39
(
14
):
1563
74
.
13.
Shen
H
,
Shih
J
,
Hollern
D
,
Wang
L
,
Bowlby
R
,
Tickoo
S
, et al
.
Integrated molecular characterization of testicular germ cell tumors
.
Cell Rep
.
2018
;
23
(
11
):
3392
406
.
14.
Chang
Y
,
Wang
X
,
Xu
Y
,
Yang
L
,
Qian
Q
,
Ju
S
, et al
.
Comprehensive characterization of cancer-testis genes in testicular germ cell tumor
.
Cancer Med
.
2019
;
8
(
7
):
3511
9
.
15.
Woldu
SL
,
Amatruda
JF
,
Bagrodia
A
.
Testicular germ cell tumor genomics
.
Curr Opin Urol
.
2017
;
27
(
1
):
41
7
.
16.
Sommerer
F
,
Hengge
U
,
Markwarth
A
,
Vomschloss
S
,
Stolzenburg
J
,
Wittekind
C
, et al
.
Mutations of BRAF and RAS are rare events in germ cell tumours
.
Int J Cancer
.
2005
;
113
(
2
):
329
35
.
17.
Olie
R
,
Looijenga
L
,
Boerrigter
L
,
Top
B
,
Rodenhuis
S
,
Langeveld
A
, et al
.
N- and KRAS mutations in primary testicular germ cell tumors: incidence and possible biological implications
.
Genes, Chromosomes Cancer
.
1995
;
12
(
2
):
110
6
.
18.
de Vries
G
,
Rosas-Plaza
X
,
van Vugt
MATM
,
Gietema
JA
,
de Jong
S
.
Testicular cancer: determinants of cisplatin sensitivity and novel therapeutic opportunities
.
Cancer Treat Rev
.
2020
;
88
:
102054
.
19.
Oing
C
,
Kollmannsberger
C
,
Oechsle
K
,
Bokemeyer
C
.
Investigational targeted therapies for the treatment of testicular germ cell tumors
.
Expert Opin Investig Drugs
.
2016
;
25
(
9
):
1033
43
.
20.
Keohavong
P
,
DeMichele
MA
,
Melacrinos
AC
,
Landreneau
RJ
,
Weyant
RJ
,
Siegfried
JM
.
Detection of K-ras mutations in lung carcinomas: relationship to prognosis
.
Clin Cancer Res
.
1996
;
2
:
411
8
.
21.
Renaud
S
,
Falcoz
P-E
,
Schaëffer
M
,
Guenot
D
,
Romain
B
,
Olland
A
, et al
.
Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases
.
Br J Cancer
.
2015
;
113
(
8
):
1206
15
.
22.
Moore
AR
,
Rosenberg
SC
,
McCormick
F
,
Malek
S
.
RAS-targeted therapies: is the undruggable drugged?
.
Nat Rev Drug Discov
.
2020
;
19
(
8
):
533
52
.
23.
Adderley
H
,
Blackhall
F
,
Lindsay
CR
.
KRAS-mutant non-small cell lung cancer: converging small molecules and immune checkpoint inhibition
.
EBioMedicine
.
2019
;
41
:
711
6
.
24.
Kim
D
,
Xue
JY
,
Lito
P
.
Targeting KRAS (G12C): from inhibitory mechanism to modulation of antitumor effects in patients
.
Cell
.
2020
;
183
(
4
):
850
9
.
25.
Hong
D
,
Fakih
M
,
Strickler
J
,
Desai
J
,
Durm
G
,
Shapiro
G
, et al
.
KRAS (G12C) inhibition with sotorasib in advanced solid tumors
.
N Engl J Med
.
2020
;
383
(
13
):
1207
17
.
26.
Canon
J
,
Rex
K
,
Saiki
A
,
Mohr
C
,
Cooke
K
,
Bagal
D
, et al
.
The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity
.
Nature
.
2019
;
575
(
7781
):
217
23
.
27.
Velado-Eguskiza
A
,
Gomez-Santos
L
,
Badiola
I
,
Sáez
F
,
Alonso
E
.
Testicular germ cell tumours and proprotein convertases
.
Cancers
.
2022
;
14
(
7
):
1633
.
28.
Pinzani
M
,
Failli
P
,
Ruocco
C
,
Casini
A
,
Milani
S
,
Baldi
E
, et al
.
Fat-storing cells as liver-specific pericytes. spatial dynamics of agonist-stimulated intracellular calcium transients
.
J Clin Invest
.
1992
;
90
(
2
):
642
6
.
29.
Jennewein
L
,
Bartsch
G
,
Gust
K
,
Kvasnicka
H
,
Haferkamp
A
,
Blaheta
R
, et al
.
Increased tumor vascularization is associated with the amount of immune competent PD-1 positive cells in testicular germ cell tumors
.
Oncol Lett
.
2018
;
15
(
6
):
9852
60
.
30.
Chieffi
P
,
De Martino
M
,
Esposito
F
.
Further insights into testicular germ cell tumor oncogenesis: potential therapeutic targets
.
Expert Rev Anticancer Ther
.
2020
;
20
(
3
):
189
95
.
31.
Kalavska
K
,
Schmidtova
S
,
Chovanec
M
,
Mego
M
.
Immunotherapy in testicular germ cell tumors
.
Front Oncol
.
2020
;
10
:
573977
.
32.
Chen
N
,
Fang
W
,
Lin
Z
,
Peng
P
,
Wang
J
,
Zhan
J
, et al
.
KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma
.
Cancer Immunol Immunother
.
2017
;
66
(
9
):
1175
87
.
33.
Champiat
S
,
Dercle
L
,
Ammari
S
,
Massard
C
,
Hollebecque
A
,
Postel-Vinay
S
, et al
.
Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1
.
Clin Cancer Res
.
2017
;
23
(
8
):
1920
8
.
34.
Pan
L-N
,
Ma
Y-F
,
Li
Z
,
Hu
J-A
,
Xu
Z-H
.
KRAS G12V mutation upregulates PD-L1 expression via TGF-β/EMT signaling pathway in human non-small-cell lung cancer
.
Cell Biol Int
.
2021
;
45
(
4
):
795
803
.
35.
Dong
Z-Y
,
Zhong
W-Z
,
Zhang
X-C
,
Su
J
,
Xie
Z
,
Liu
S-Y
, et al
.
Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma
.
Clin Cancer Res
.
2017
;
23
(
12
):
3012
24
.
36.
Rizvi
N
,
Hellmann
M
,
Snyder
A
,
Kvistborg
P
,
Makarov
V
,
Havel
J
, et al
.
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
.
Science
.
2015
;
348
(
6230
):
124
8
.
37.
Zhang
L
,
Mai
W
,
Jiang
W
,
Geng
Q
.
Sintilimab: a promising anti-tumor PD-1 antibody
.
Front Oncol
.
2020
;
10
:
594558
.
38.
Wang
J
,
Fei
K
,
Jing
H
,
Wu
Z
,
Wu
W
,
Zhou
S
, et al
.
Durable blockade of PD-1 signaling links preclinical efficacy of sintilimab to its clinical benefit
.
mAbs
.
2019
;
11
(
8
):
1443
51
.
39.
Cierna
Z
,
Mego
M
,
Miskovska
V
,
Machalekova
K
,
Chovanec
M
,
Svetlovska
D
, et al
.
Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors
.
Ann Oncol
.
2016
;
27
(
2
):
300
5
.
40.
Semaan
A
,
Haddad
FG
,
Eid
R
,
Kourie
HR
,
Nemr
E
.
Immunotherapy: last bullet in platinum refractory germ cell testicular cancer
.
Future Oncol
.
2019
;
15
(
5
):
533
41
.
41.
Yarchoan
M
,
Albacker
LA
,
Hopkins
AC
,
Montesion
M
,
Murugesan
K
,
Vithayathil
TT
, et al
.
PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers
.
JCI insight
.
2019
;
4
(
6
).
42.
Hato
SV
,
Khong
A
,
de Vries
IJM
,
Lesterhuis
WJ
.
Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics
.
Clin Cancer Res
.
2014
;
20
(
11
):
2831
7
.
43.
Peng
J
,
Hamanishi
J
,
Matsumura
N
,
Abiko
K
,
Murat
K
,
Baba
T
, et al
.
Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-κb to foster an immunosuppressive tumor microenvironment in ovarian cancer
.
Cancer
.
2015
;
75
(
23
):
5034
45
.
44.
Motzer
RJ
,
Mazumdar
M
,
Sheinfeld
J
,
Bajorin
DF
,
Macapinlac
HA
,
Bains
M
, et al
.
Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients
.
J Clin Oncol
.
2000
;
18
(
6
):
1173
80
.
45.
Schettini
F
,
Giuliano
M
,
De Placido
S
,
Arpino
G
.
Nab-paclitaxel for the treatment of triple-negative breast cancer: rationale, clinical data and future perspectives
.
Cancer Treat Rev
.
2016
;
50
:
129
41
.
46.
Zhang
F
,
Huang
D
,
Zhao
L
,
Li
T
,
Zhang
S
,
Zhang
G
, et al
.
Efficacy and safety of PD-1/PD-L1 inhibitors plus nab-paclitaxel for patients with non-small cell lung cancer who have progressed after platinum-based chemotherapy
.
Ther Adv Med Oncol
.
2020
;
12
:
1758835920936882
.
47.
Lian
B
,
Zhang
W
,
Wang
T
,
Yang
Q
,
Jia
Z
,
Chen
H
, et al
.
Clinical benefit of sorafenib combined with paclitaxel and carboplatin to a patient with metastatic chemotherapy-refractory testicular tumors
.
Oncologist
.
2019
;
24
(
12
):
e1437
42
.
48.
Hacioglu
BM
,
Kodaz
H
,
Erdogan
B
,
Cinkaya
A
,
Tastekin
E
,
Hacibekiroglu
I
, et al
.
K-RAS and N-RAS mutations in testicular germ cell tumors
.
Bosn J Basic Med Sci
.
2017
;
17
:
159
63
.
You do not currently have access to this content.