Highlights
- •Women previously exposure to cytomegalovirus and high C-reactive protein have worse RFS and OS vs. not previously exposed.
- •CMV+ but CRP- had the longest OS, indicating CMV exposure, in the absence of inflammation, may have protective properties.
- •Inflammation and CMV serostatus at the time of surgery appear to impact survival and may influence the immune response.
Abstract
Objectives: Cytomegalovirus (CMV) is a common infection that establishes latency in
healthy people. CMV has been associated with alterations of the immune compartment
leading to improved responses, while inflammation has been shown to adversely impact
outcomes. We investigated whether CMV serostatus predicts outcomes in ovarian cancer
in the presence or absence of inflammation.
Methods: A total of 106 patients with serous ovarian cancer from 2006 to 2009 were
analyzed. CMV and systemic inflammation was measured using CMV immunoglobulin G (IgG)
and C-reactive protein (CRP), respectively, in serum collected prior to cytoreduction.
Patients were stratified by CMV IgG (non-reactive, reactive/borderline) and CRP (≤10,
>10 mg/L) status. Overall survival (OS) and recurrence-free survival (RFS) were compared
by group using log-rank tests and Cox proportional hazards regression models adjusting
for age at surgery.
Results: Of 106 eligible patients, 40 (37.7%) were CMV+/CRP+, 24 (22.6%) CMV+/CRP-,
19 (17.9%) CMV−/CRP+, and 23 (21.7%) CMV−/CRP−. CRP+ had higher CA-125 levels (P = 0.05) and higher rates of suboptimal debulking (P = 0.03). There were no other significant differences in demographic, surgical, or
pathologic factors between groups. CMV+/CRP+ patients median RFS and OS were 16.9 months
(95% CI: 9.0–21.1) and 31.7 months (95% CI: 25.0–48.7), respectively, with a significantly
worse RFS (aHR: 1.85, 95% CI: 1.05–3.24, P = 0.03) and OS (aHR: 2.12, 95% CI: 1.17–3.82, P = 0.01) compared to CMV−/CRP− (RFS = 31.2 months (95% CI: 16.0–56.4) and OS = 63.8 months
(95% CI: 50.7–87.0)). CMV+/CRP− group displayed the longest OS (89.3 months).
Conclusions: Previous exposure to CMV and high CRP at surgery portended worse RFS
and OS compared to women who tested negative. The CMV+/CRP− group had the longest
OS, indicating that CMV status alone, in the absence of inflammation, may be protective.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Gynecologic OncologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cancer statistics, 2020.CA Cancer J. Clin. 2020; 70: 7-30
- Ovarian cancer statistics, 2018.CA Cancer J. Clin. 2018; 68: 284-296https://doi.org/10.3322/caac.21456
- The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded.Am. J. Pathol. 2016; 186: 733-747
- Ovarian cancer and the immune system.Gynecol. Oncol. Rep. 2017; 19: 57-58
- Immunobiology of human cytomegalovirus: from bench to bedside.Clin. Microbiol. Rev. 2009; 22 (Table of Contents): 76-98
- Seroprevalence of cytomegalovirus infection in the United States, 1988-1994.Clin. Infect. Dis. 2006; 43: 1143-1151
- Decoding human cytomegalovirus.Science. 2012; 338: 1088-1093
- Is HCMV a tumor promoter?.Virus Res. 2011; 157: 193-203
- Human cytomegalovirus and mucoepidermoid carcinoma of salivary glands: cell-specific localization of active viral and oncogenic signaling proteins is confirmatory of a causal relationship.Exp. Mol. Pathol. 2012; 92: 118-125
- Cytomegalovirus infection leads to pleomorphic rhabdomyosarcomas in Trp53+/− mice.Cancer Res. 2012; 72: 5669-5674
- High prevalence of human cytomegalovirus proteins and nucleic acids in primary breast cancer and metastatic sentinel lymph nodes.PLoS One. 2013; 8e56795
- High prevalence of human cytomegalovirus in brain metastases of patients with primary breast and colorectal cancers.Transl. Oncol. 2014; 7: 732-740
- Detection and genotyping of CMV and HPV in tumors and fallopian tubes from epithelial ovarian cancer patients.Sci. Rep. 2019; 9: 19935
- Viral and bacterial aetiologies of epithelial ovarian cancer.Eur. J. Clin. Microbiol. Infect. Dis. 2012; 31: 2311-2317
- Human cytomegalovirus in high grade serous ovarian cancer possible implications for patients survival.Medicine (Baltimore). 2018; 97: e9685
- Serum C-reactive protein as independent prognostic variable in patients with ovarian cancer.Clin. Cancer Res. 2008; 14: 710-714
- High levels of C-reactive protein are associated with an increased risk of ovarian cancer: results from the ovarian cancer cohort consortium.Cancer Res. 2019; 79: 5442-5451
- Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein.J. Clin. Invest. 1997; 99: 2930-2940
- Interleukin 4 inhibits the production of some acute-phase proteins by human hepatocytes in primary culture.FEBS Lett. 1993; 336: 215-220
- Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins.J. Immunol. 1992; 149: 2021-2027
- Serum C-reactive protein as a prognostic factor in patients with epithelial ovarian cancer.Eur. J. Obstet. Gynecol. Reprod. Biol. 1999; 82: 107-110
- What should we regard as an "elevated" C-reactive protein level?.in: Ann Intern Med.2015: 326 (United States)
- Inflammation and ovarian cancer.Cytokine. 2012; 58: 133-147
- Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function.Immunity. 2015; 42: 443-456
- CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT.Leukemia. 2016; 30: 456-463
- Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans.Clin. Exp. Immunol. 2016; 185: 239-251
- Leucine-rich alpha-2-glycoprotein-1 is upregulated in sera and tumors of ovarian cancer patients.J. Ovarian Res. 2010; 3: 21
- The prognostic value of the preoperative c-reactive protein/albumin ratio in ovarian cancer.BMC Cancer. 2017; 17: 285
- C-reactive protein concentrations and subsequent ovarian cancer risk.Obstet. Gynecol. 2007; 109: 933-941
- CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?.J. Transl. Med. 2009; 7: 102
- Variability in CRP, regulatory T cells and effector T cells over time in gynaecological cancer patients: a study of potential oscillatory behaviour and correlations.J. Transl. Med. 2014; 12: 179
- Natural killer cell receptors for major histocompatibility complex class I and related molecules in cytomegalovirus infection.Tissue Antigens. 2004; 63: 195-203
- Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen.J. Immunol. 2012; 189: 5082-5088
- Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming.J. Clin. Invest. 2019; 129: 3770-3785
- Adaptive NKG2C.Front. Immunol. 2018; 9: 686
- Impact of human cytomegalovirus infection and its immune response on survival of patients with ovarian cancer.Transl. Oncol. 2018; 11: 1292-1300
- Clinically relevant immune responses against cytomegalovirus: implications for precision medicine.Int. J. Mol. Sci. 2019; 20
Article info
Publication history
Published online: November 07, 2020
Accepted:
October 22,
2020
Received:
August 21,
2020
Identification
Copyright
© 2020 Elsevier Inc. All rights reserved.
