Introduction: Several studies have implicated the PIK3/AKT pathway in the pathophysiology of cancer progression as its activation seems to be aberrant in several forms of cancer. The purpose of the present systematic review is to evaluate the impact of PIK3CA mutations on survival outcomes of patients with cervical cancer. Methods: We used the Medline (1966–2020), Scopus (2004–2020), ClinicalTrials.gov (2008–2020), EMBASE (1980–2020), Cochrane Central Register of Controlled Trials (CENTRAL) (1999–2020), and Google Scholar (2004–2020) databases in our primary search along with the reference lists of electronically retrieved full-text papers. Statistical meta-analysis was performed with the RevMan 5.3 software. Results: Overall, 12 articles were included in the present study that comprised 2,196 women with cervical cancer. Of those, 3 studies did not report significant differences in survival outcomes among patients with mutated versus wild-type PIK3CA tumors, 5 studies reported decreased survival outcomes, and 3 studies revealed increased survival rates. The meta-analysis revealed that patients with the mutated PIK3CA genotypes had worse overall survival compared to patients with wild-type PIK3CA (HR 2.31; 95% CI: 1.51, 3.55; 95% PI: 0.54, 9.96; data from 3 studies) and the same was observed in the case of DFS rates (HR 1.82; 95% CI: 1.47, 2.25; 95% PI: 1.29, 2.56; data from 4 studies). Conclusion: Current evidence concerning the impact of PIK3CA mutations on survival outcomes of patients with cervical cancer is inconclusive, although the majority of included studies support a potential negative effect, primarily among those with squamous cell carcinoma tumors.

1.
World Health Organization
.
Cancer. Cervical cancer
. .
Retrieved 2020 Jan 10
.
2.
Ferlay
J
,
Shin
HR
,
Bray
F
,
Forman
D
,
Mathers
C
,
Parkin
DM
.
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
.
Int J Cancer
.
2010
;
127
(
12
):
2893
917
.
3.
Movva
S
,
Rodriguez
L
,
Arias-Pulido
H
,
Verschraegen
C
.
Novel chemotherapy approaches for cervical cancer
.
Cancer
.
2009
;
115
(
14
):
3166
80
.
4.
Lorusso
D
,
Petrelli
F
,
Coinu
A
,
Raspagliesi
F
,
Barni
S
.
A systematic review comparing cisplatin and carboplatin plus paclitaxel-based chemotherapy for recurrent or metastatic cervical cancer
.
Gynecol Oncol
.
2014
;
133
(
1
):
117
23
.
5.
Li
M
,
Feng
YM
,
Fang
SQ
.
Overexpression of ezrin and galectin-3 as predictors of poor prognosis of cervical cancer
.
Braz J Med Biol Res
.
2017
;
50
(
4
):
e5356
.
6.
Lin
J
,
Lu
J
,
Wang
C
,
Xue
X
.
The prognostic values of the expression of Vimentin, TP53, and Podoplanin in patients with cervical cancer
.
Canc Cell Int
.
2017
;
17
(
1
):
80
.
7.
Wright
AA
,
Howitt
BE
,
Myers
AP
,
Dahlberg
SE
,
Palescandolo
E
,
Van Hummelen
P
, et al
Oncogenic mutations in cervical cancer: genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix
.
Cancer
.
2013
;
119
(
21
):
3776
83
.
8.
Assad
DX
,
Elias
ST
,
Melo
AC
,
Ferreira
CG
,
De Luca Canto
G
,
Guerra
EN
.
Potential impact of mTOR inhibitors on cervical squamous cell carcinoma: a systematic review
.
Oncol Lett
.
2016
;
12
(
5
):
4107
16
.
9.
Xiang
L
,
Jiang
W
,
Li
J
,
Shen
X
,
Yang
W
,
Yang
G
, et al
PIK3CA mutation analysis in Chinese patients with surgically resected cervical cancer
.
Sci Rep
.
2015
;
5
:
14035
.
10.
Porta
C
,
Paglino
C
,
Mosca
A
.
Targeting PI3K/Akt/mTOR Signaling in Cancer
.
Front Oncol
.
2014
;
4
:
64
.
11.
Siddik
ZH
.
Cisplatin: mode of cytotoxic action and molecular basis of resistance
.
Oncogene
.
2003
;
22
(
47
):
7265
79
.
12.
Liberati
A
,
Altman
DG
,
Tetzlaff
J
,
Mulrow
C
,
Gøtzsche
PC
,
Ioannidis
JPA
, et al
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration
.
J Clin Epidemiol
.
2009
;
62
(
10
):
e1
34
.
13.
Wells
G
,
Shea
B
,
O’Connell
D
,
Peterson
J
,
Welch
V
,
Losos
M
, et al
The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses
. .
14.
Zhu
X
,
Zhou
X
,
Zhang
Y
,
Sun
X
,
Liu
H
,
Zhang
Y
.
Reporting and methodological quality of survival analysis in articles published in Chinese oncology journals
.
Medicine
.
2017
;
96
(
50
):
e9204
.
15.
Borenstein
M
,
Hedges
LV
,
Higgins
JPT
,
Rothstein
HR
.
A basic introduction to fixed-effect and random-effects models for meta-analysis
.
Res Synth Methods
.
2010
;
1
(
2
):
97
111
.
16.
IntHout
J
,
Ioannidis
JPA
,
Borm
GF
.
The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method
.
BMC Med Res Methodol
.
2014
;
14
(
1
):
25
.
17.
Smith
CT
.
Meta-analysis of time-to-event data
.
Cochrane Training Center
.
Available from:
https://training.cochrane.org/meta-analysis-time-event-data.
Retrieved March 12 2020
.
18.
Souza
JP
,
Pileggi
C
,
Cecatti
JG
.
Assessment of funnel plot asymmetry and publication bias in reproductive health meta-analyses: an analytic survey
.
Reprod Health
.
2007
;
16
(
4
):
3
.
19.
Cui
B
,
Zheng
B
,
Zhang
X
,
Stendahl
U
,
Andersson
S
,
Wallin
KL
.
Mutation of PIK3CA: possible risk factor for cervical carcinogenesis in older women
.
Int J Oncol
.
2009
;
34
(
2
):
409
16
.
20.
McIntyre
JB
,
Wu
JS
,
Craighead
PS
,
Phan
T
,
Köbel
M
,
Lees-Miller
SP
, et al
PIK3CA mutational status and overall survival in patients with cervical cancer treated with radical chemoradiotherapy
.
Gynecol Oncol
.
2013
;
128
(
3
):
409
14
.
21.
Hou
MM
,
Liu
X
,
Wheler
J
,
Naing
A
,
Hong
D
,
Coleman
RL
, et al
Targeted PI3K/AKT/mTOR therapy for metastatic carcinomas of the cervix: a phase I clinical experience
.
Oncotarget
.
2014
;
5
(
22
):
11168
79
.
22.
Guo
L
,
Wu
H
,
Zhu
J
,
Zhang
C
,
Ma
J
,
Lan
J
, et al
Genetic variations in the PI3K/AKT pathway predict platinum-based neoadjuvant chemotherapeutic sensitivity in squamous cervical cancer
.
Life Sci
.
2015
;
15
(
143
):
217
24
.
23.
Wang
J
,
Chai
YL
,
Wang
T
,
Liu
JH
,
Dai
PG
,
Liu
Z
.
Genetic alterations of PIK3CA and tumor response in patients with locally advanced cervical squamous cell carcinoma treated with cisplatin-based concurrent chemoradiotherapy
.
Exp Mol Pathol
.
2015
;
98
(
3
):
407
10
.
24.
Spaans
VM
,
Trietsch
MD
,
Peters
AA
,
Osse
M
,
ter Haar
N
,
Fleuren
GJ
, et al
Precise classification of cervical carcinomas combined with somatic mutation profiling contributes to predicting disease outcome
.
PLoS One
.
2015
;
10
(
7
):
e0133670
.
25.
Chung
TKH
,
Cheung
TH
,
Yim
SF
,
Yu
MY
,
Chiu
RWK
,
Lo
KWK
, et al
Liquid biopsy of PIK3CA mutations in cervical cancer in Hong Kong Chinese women
.
Gynecol Oncol
.
2017
;
146
(
2
):
334
9
.
26.
Grigsby
P
,
Elhammali
A
,
Ruiz
F
,
Markovina
S
,
McLellan
MD
,
Miller
CA
, et al
Clinical outcomes and differential effects of PI3K pathway mutation in obese versus non-obese patients with cervical cancer
.
Oncotarget
.
2018
;
9
(
3
):
4061
73
.
27.
Lachkar
B
,
Minaguchi
T
,
Akiyama
A
,
Liu
S
,
Zhang
S
,
Xu
C
, et al
Prognostic significance of PIK3CA mutation in stage IIB to IVA cervical cancers treated by concurrent chemoradiotherapy with weekly cisplatin
.
Medicine
.
2018
;
97
(
31
):
e11392
.
28.
Razia
S
,
Nakayama
K
,
Nakamura
K
,
Ishibashi
T
,
Ishikawa
M
,
Minamoto
T
, et al
Clinicopathological and biological analysis of PIK3CA mutation and amplification in cervical carcinomas
.
Exp Ther Med
.
2019
;
18
(
3
):
2278
84
.
29.
Scholl
S
,
Popovic
M
,
de la Rochefordiere
A
,
Girard
E
,
Dureau
S
,
Mandic
A
, et al
Clinical and genetic landscape of treatment naive cervical cancer: alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome
.
EBioMedicine
.
2019
;
43
:
253
60
.
30.
Janku
F
,
Tsimberidou
AM
,
Garrido-Laguna
I
,
Wang
X
,
Luthra
R
,
Hong
DS
, et al
PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors
.
Mol Cancer Ther
.
2011
;
10
(
3
):
558
65
.
31.
Janku
F
,
Wheler
JJ
,
Westin
SN
,
Moulder
SL
,
Naing
A
,
Tsimberidou
AM
, et al
PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations
.
J Clin Oncol
.
2012
;
30
(
8
):
777
82
.
32.
Hou
MM
,
Liu
X
,
Wheler
J
,
Naing
A
,
Hong
D
,
Bodurka
D
, et al
Outcomes of patients with metastatic cervical cancer in a phase I clinical trials program
.
Anticancer Res
.
2014
;
34
(
5
):
2349
55
.
33.
Bumrungthai
S
,
Munjal
K
,
Nandekar
S
, et al
Epidermal growth factor receptor pathway mutation and expression profiles in cervical squamous cell carcinoma: therapeutic implications
.
J Transl Med
.
2015
;
24
(
13
):
244
.
34.
Arjumand
W
,
Merry
CD
,
Wang
C
,
Saba
E
,
McIntyre
JB
,
Fang
S
, et al
Phosphatidyl inositol-3 kinase (PIK3CA) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells
.
Oncotarget
.
2016
;
7
(
50
):
82424
39
.
35.
Frumovitz
M
,
Burzawa
JK
,
Byers
LA
,
Lyons
YA
,
Ramalingam
P
,
Coleman
RL
, et al
Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer
.
Gynecol Oncol
.
2016
;
141
(
3
):
588
91
.
36.
Hasegawa
K
,
Kagabu
M
,
Mizuno
M
,
Oda
K
,
Aoki
D
,
Mabuchi
S
, et al
Phase II basket trial of perifosine monotherapy for recurrent gynecologic cancer with or without PIK3CA mutations
.
Invest New Drugs
.
2017
;
35
(
6
):
800
12
.
37.
Hodgson
A
,
Amemiya
Y
,
Seth
A
,
Cesari
M
,
Djordjevic
B
,
Parra-Herran
C
.
Genomic abnormalities in invasive endocervical adenocarcinoma correlate with pattern of invasion: biologic and clinical implications
.
Mod Pathol
.
2017
;
30
(
11
):
1633
41
.
38.
Juric
D
,
Rodon
J
,
Tabernero
J
,
Janku
F
,
Burris
HA
,
Schellens
JHM
, et al
Phosphatidylinositol 3-kinase alpha-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: results from the first-in-human study
.
J Clin Oncol
.
2018
;
36
(
13
):
1291
9
.
39.
Liu
JF
,
Gray
KP
,
Wright
AA
,
Campos
S
,
Konstantinopoulos
PA
,
Peralta
A
, et al
Results from a single arm, single stage phase II trial of trametinib and GSK2141795 in persistent or recurrent cervical cancer
.
Gynecol Oncol
.
2019
;
154
(
1
):
95
101
.
40.
Sarris
EG
,
Saif
MW
,
Syrigos
KN
.
The biological role of PI3K pathway in lung cancer
.
Pharmaceuticals
.
2012
;
5
(
11
):
1236
64
.
41.
McCubrey
JA
,
Steelman
LS
,
Abrams
SL
,
Lee
JT
,
Chang
F
,
Bertrand
FE
, et al
Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance
.
Adv Enzyme Regul
.
2006
;
46
:
249
79
.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.