The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort

Esther Roura; Noémie Travier; Tim Waterboer; Silvia de Sanjosé; F Xavier Bosch; Michael Pawlita; Valeria Pala; Elisabete Weiderpass; Núria Margall; Joakim Dillner; Inger T Gram; Anne Tjønneland; Christian Munk; Domenico Palli; Kay-Tee Khaw; Kim Overvad; Françoise Clavel-Chapelon; Sylvie Mesrine; Agnès Fournier; Renée T Fortner; Jennifer Ose; Annika Steffen; Antonia Trichopoulou; Pagona Lagiou; Philippos Orfanos; Giovanna Masala; Rosario Tumino; Carlotta Sacerdote; Silvia Polidoro; Amalia Mattiello; Eiliv Lund; Petra H Peeters; H B(as). Bueno de Mesquita; J Ramón Quirós; María-José Sánchez; Carmen Navarro; Aurelio Barricarte; Nerea Larrañaga; Johanna Ekström; David Lindquist; Annika Idahl; Ruth C Travis; Melissa A Merritt; Marc J Gunter; Sabina Rinaldi; Massimo Tommasino; Silvia Franceschi; Elio Riboli; Xavier Castellsagué

doi:10.1371/journal.pone.0147029

The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort

Esther Roura, Noémie Travier, Tim Waterboer, Silvia de Sanjosé, F Xavier Bosch, Michael Pawlita, Valeria Pala, Elisabete Weiderpass, Núria Margall, Joakim Dillner, Inger T Gram, Anne Tjønneland, Christian Munk, Domenico Palli, Kay-Tee Khaw, Kim Overvad, Françoise Clavel-Chapelon, Sylvie Mesrine, Agnès Fournier, Renée T FortnerJennifer Ose, Annika Steffen, Antonia Trichopoulou, Pagona Lagiou, Philippos Orfanos, Giovanna Masala, Rosario Tumino, Carlotta Sacerdote, Silvia Polidoro, Amalia Mattiello, Eiliv Lund, Petra H Peeters, H B(as). Bueno de Mesquita, J Ramón Quirós, María-José Sánchez, Carmen Navarro, Aurelio Barricarte, Nerea Larrañaga, Johanna Ekström, David Lindquist, Annika Idahl, Ruth C Travis, Melissa A Merritt, Marc J Gunter, Sabina Rinaldi, Massimo Tommasino, Silvia Franceschi, Elio Riboli, Xavier Castellsagué

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Abstract

BACKGROUND: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).

METHODS AND FINDINGS: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥ 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7).

CONCLUSIONS: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.

Original language	English
Article number	e0147029
Journal	PLoS ONE [E]
Volume	11
Issue number	1
DOIs	https://doi.org/10.1371/journal.pone.0147029
Publication status	Published - 2016

Keywords

Adult
Aged
Antibodies, Viral
Carcinoma, Squamous Cell
Case-Control Studies
Cervical Intraepithelial Neoplasia
Chlamydia Infections
Chlamydia trachomatis
Contraceptives, Oral, Hormonal
Female
Follow-Up Studies
Gonadal Steroid Hormones
Herpes Genitalis
Herpesvirus 2, Human
Hormone Replacement Therapy
Humans
Intrauterine Devices
Middle Aged
Papillomaviridae
Papillomavirus Infections
Pregnancy
Prospective Studies
Reproductive History
Risk
Uterine Cervical Neoplasms
Young Adult
Research Support, Non-U.S. Gov't

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Roura, E., Travier, N., Waterboer, T., de Sanjosé, S., Bosch, F. X., Pawlita, M., Pala, V., Weiderpass, E., Margall, N., Dillner, J., Gram, I. T., Tjønneland, A., Munk, C., Palli, D., Khaw, K.-T., Overvad, K., Clavel-Chapelon, F., Mesrine, S., Fournier, A., ... Castellsagué, X. (2016). The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort. PLoS ONE [E], 11(1), Article e0147029. https://doi.org/10.1371/journal.pone.0147029

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title = "The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort",

abstract = "BACKGROUND: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).METHODS AND FINDINGS: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95\% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥ 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95\%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7).CONCLUSIONS: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.",

keywords = "Adult, Aged, Antibodies, Viral, Carcinoma, Squamous Cell, Case-Control Studies, Cervical Intraepithelial Neoplasia, Chlamydia Infections, Chlamydia trachomatis, Contraceptives, Oral, Hormonal, Female, Follow-Up Studies, Gonadal Steroid Hormones, Herpes Genitalis, Herpesvirus 2, Human, Hormone Replacement Therapy, Humans, Intrauterine Devices, Middle Aged, Papillomaviridae, Papillomavirus Infections, Pregnancy, Prospective Studies, Reproductive History, Risk, Uterine Cervical Neoplasms, Young Adult, Research Support, Non-U.S. Gov't",

author = "Esther Roura and No{\'e}mie Travier and Tim Waterboer and \{de Sanjos{\'e}\}, Silvia and Bosch, \{F Xavier\} and Michael Pawlita and Valeria Pala and Elisabete Weiderpass and N{\'u}ria Margall and Joakim Dillner and Gram, \{Inger T\} and Anne Tj{\o}nneland and Christian Munk and Domenico Palli and Kay-Tee Khaw and Kim Overvad and Fran{\c c}oise Clavel-Chapelon and Sylvie Mesrine and Agn{\`e}s Fournier and Fortner, \{Ren{\'e}e T\} and Jennifer Ose and Annika Steffen and Antonia Trichopoulou and Pagona Lagiou and Philippos Orfanos and Giovanna Masala and Rosario Tumino and Carlotta Sacerdote and Silvia Polidoro and Amalia Mattiello and Eiliv Lund and Peeters, \{Petra H\} and \{Bueno de Mesquita\}, \{H B(as).\} and Quir{\'o}s, \{J Ram{\'o}n\} and Mar{\'i}a-Jos{\'e} S{\'a}nchez and Carmen Navarro and Aurelio Barricarte and Nerea Larra{\~n}aga and Johanna Ekstr{\"o}m and David Lindquist and Annika Idahl and Travis, \{Ruth C\} and Merritt, \{Melissa A\} and Gunter, \{Marc J\} and Sabina Rinaldi and Massimo Tommasino and Silvia Franceschi and Elio Riboli and Xavier Castellsagu{\'e}",

year = "2016",

doi = "10.1371/journal.pone.0147029",

language = "English",

volume = "11",

journal = "PLoS ONE [E]",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "1",

}

Roura, E, Travier, N, Waterboer, T, de Sanjosé, S, Bosch, FX, Pawlita, M, Pala, V, Weiderpass, E, Margall, N, Dillner, J, Gram, IT, Tjønneland, A, Munk, C, Palli, D, Khaw, K-T, Overvad, K, Clavel-Chapelon, F, Mesrine, S, Fournier, A, Fortner, RT, Ose, J, Steffen, A, Trichopoulou, A, Lagiou, P, Orfanos, P, Masala, G, Tumino, R, Sacerdote, C, Polidoro, S, Mattiello, A, Lund, E, Peeters, PH, Bueno de Mesquita, HB, Quirós, JR, Sánchez, M-J, Navarro, C, Barricarte, A, Larrañaga, N, Ekström, J, Lindquist, D, Idahl, A, Travis, RC, Merritt, MA, Gunter, MJ, Rinaldi, S, Tommasino, M, Franceschi, S, Riboli, E & Castellsagué, X 2016, 'The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort', PLoS ONE [E], vol. 11, no. 1, e0147029. https://doi.org/10.1371/journal.pone.0147029

TY - JOUR

T1 - The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer

T2 - Results from the EPIC Cohort

AU - Roura, Esther

AU - Travier, Noémie

AU - Waterboer, Tim

AU - de Sanjosé, Silvia

AU - Bosch, F Xavier

AU - Pawlita, Michael

AU - Pala, Valeria

AU - Weiderpass, Elisabete

AU - Margall, Núria

AU - Dillner, Joakim

AU - Gram, Inger T

AU - Tjønneland, Anne

AU - Munk, Christian

AU - Palli, Domenico

AU - Khaw, Kay-Tee

AU - Overvad, Kim

AU - Clavel-Chapelon, Françoise

AU - Mesrine, Sylvie

AU - Fournier, Agnès

AU - Fortner, Renée T

AU - Ose, Jennifer

AU - Steffen, Annika

AU - Trichopoulou, Antonia

AU - Lagiou, Pagona

AU - Orfanos, Philippos

AU - Masala, Giovanna

AU - Tumino, Rosario

AU - Sacerdote, Carlotta

AU - Polidoro, Silvia

AU - Mattiello, Amalia

AU - Lund, Eiliv

AU - Peeters, Petra H

AU - Bueno de Mesquita, H B(as).

AU - Quirós, J Ramón

AU - Sánchez, María-José

AU - Navarro, Carmen

AU - Barricarte, Aurelio

AU - Larrañaga, Nerea

AU - Ekström, Johanna

AU - Lindquist, David

AU - Idahl, Annika

AU - Travis, Ruth C

AU - Merritt, Melissa A

AU - Gunter, Marc J

AU - Rinaldi, Sabina

AU - Tommasino, Massimo

AU - Franceschi, Silvia

AU - Riboli, Elio

AU - Castellsagué, Xavier

PY - 2016

Y1 - 2016

N2 - BACKGROUND: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).METHODS AND FINDINGS: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥ 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7).CONCLUSIONS: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.

AB - BACKGROUND: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).METHODS AND FINDINGS: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥ 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7).CONCLUSIONS: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.

KW - Adult

KW - Aged

KW - Antibodies, Viral

KW - Carcinoma, Squamous Cell

KW - Case-Control Studies

KW - Cervical Intraepithelial Neoplasia

KW - Chlamydia Infections

KW - Chlamydia trachomatis

KW - Contraceptives, Oral, Hormonal

KW - Female

KW - Follow-Up Studies

KW - Gonadal Steroid Hormones

KW - Herpes Genitalis

KW - Herpesvirus 2, Human

KW - Hormone Replacement Therapy

KW - Humans

KW - Intrauterine Devices

KW - Middle Aged

KW - Papillomaviridae

KW - Papillomavirus Infections

KW - Pregnancy

KW - Prospective Studies

KW - Reproductive History

KW - Risk

KW - Uterine Cervical Neoplasms

KW - Young Adult

KW - Research Support, Non-U.S. Gov't

U2 - 10.1371/journal.pone.0147029

DO - 10.1371/journal.pone.0147029

M3 - Article

C2 - 26808155

SN - 1932-6203

VL - 11

JO - PLoS ONE [E]

JF - PLoS ONE [E]

IS - 1

M1 - e0147029

ER -

The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort

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