Cervical cancer and pre-cancer in the EPIC cohort: the role of environmental cofactors = El càncer de coll uterí i els seus precursos en la cohort EPIC: el rol dels cofactors ambientals

Abstract

The objective of this thesis is to estimate prospectively the association between environmental cofactors and the risk of developing cervical cancer and pre-cancer, including tobacco smoking, hormonal and reproductive factors, and serological markers of Human Papillomavirus (HPV), Chlamydia trachomatis (CT) and Human Herpesvirus type 2 (HHV-2) infections. We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. During a mean follow-up of 9 years, 261 invasive cervical cancer (ICC) cases and 804 cervical intraepithelial neoplasia grade 3 (CIN3) or carcinoma in situ (CIS) cases were reported. A nested case-control study within the EPIC cohort was also performed, including the sera from 184 invasive cases, 425 cases of CIN3/CIS, and 1,218 matched control women. They were tested for L1, E6 and E7 antibodies against several HPV types, CT and HHV-2 to allow the adjustment for these variables in the statistical analyses and thus confirm associations obtained in the cohort study. L1 seropositivity to any mucosal HPV type was significantly associated with both CIN3/CIS and ICC. By HPV type, HPVs 11, 16, 18, and 45 L1 were associated with CIN3/CIS whereas only HPVs 11 and 16 L1 were significantly related to invasive cervical cancer risk. Associations with HPV types 16 and 18 E6 and E7 seropositivity were only significant for invasive cancer, being the strongest association with HPV 16 E6 seropositivity (OR=10.2). Previous exposure to CT was strongly associated with ICC and weakly associated with CIN3/CIS, and HHV-2 seropositivity was marginally associated with both CIN3/CIS and ICC risk. Increasing number of sexually transmitted infections (HPV L1, CT and HHV-2) was associated with increasing both CIN3/CIS and ICC risk. Current smokers showed a two-fold increased risk of CIN3/CIS and ICC compared to never smokers. Smoking duration and intensity increased the risk of cervical cancer and pre-cancer, with a clear dose-response among ever smokers. Overall, smoking cessation was associated with a reduced by a half of the risk of both CIN3/CIS and ICC. Consistent associations were observed after adjustment for HPV L1, CT and HHV-2 serostatus in the nested case-control study, confirming the results obtained in the cohort. Being a parous woman was positively associated with CIN3/CIS risk, with magnitudes of two-fold, but not with ICC. The risk of pre-invasive cancer also increased with increasing number of full-term pregnancies. Duration of oral contraceptives use was associated with a significantly increased risk of CIN3/CIS and ICC, with relative risks of 1.6 and 1.8 respectively for more than 15 years of use compared to never use. Quitting the use for more than 5 years reduced the risk for CIN3/CIS to almost a half. Ever use of menopausal hormone therapy was associated with a significantly reduced risk of ICC (HR=0.5). No association was found between cervical cancer risk and ever use of intrauterine device (IUD). Analyses restricted to all cases and HPV seropositive controls were also conducted, yielding similar results for parity, OC use and hormonal therapy use, and emerging a significant inverse association with IUD for combined CIN3/CIS and ICC (OR=0.7). This large prospective study confirms the role of tobacco smoking as an important cofactor for both CIN3/CIS and ICC. The strong beneficial effect of quitting smoking is an important finding that will further support public health policies for smoking cessation. Our results also suggest that several hormonal and reproductive factors, as well as infections of CT and HHV-2, are involved in cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of cervical cancer associated with hormonal risk factors. Our study further identifies HPV 16 E6 seropositivity as a potential marker to predict invasive cervical cancer before the disease development.

L’objectiu d’aquesta tesi és estimar prospectivament les associacions entre els cofactors ambientals i el risc de desenvolupar un càncer cervical invasor (ICC) o pre-invasor (CIN3/CIS) utilitzant les dades de l’estudi EPIC (European Prospective Investigation into Cancer and Nutrition). Hem seguit una cohort de 308.036 dones durant un període mitjà de 9 anys, identificant 261 casos de ICC i 804 casos de CIN3/CIS, i hem realitzat un estudi de casos i controls aniuat dins la cohort, incloent sèrums de 184 casos invasors, 425 CIN3/CIS i 1.218 controls aparellats, testant anticossos del Virus del Papil·loma Humà (VPH), la Chlamydia trachomatis (CT) i el Herpesvirus Humà tipus 2 (HHV-2). Els principals resultats han determinat que la seropositivitat per la proteïna L1 a qualsevol tipus del VPH mucós està associat a CIN3/CIS i ICC. En canvi les associacions per les oncoproteïnes E6 i E7 dels tipus del VPH 16 i 18 només han estat significatives pel càncer invasor, destacant la del VPH 16 E6 (OR=10.2). L'exposició passada a CT, i en menor mesura a HHV-2, s’ha vist associada a un major risc de desenvolupar un càncer invasor o pre-invasor. Les dones fumadores tenen el doble de risc de desenvolupar un CIN3/CIS o ICC en comparació amb les dones que no han fumat mai, risc que augmenta amb la duració i intensitat d’ús; en canvi el fet de deixar de fumar s’ha associat a una reducció del risc a la meitat. Un major nombre d’embarassos s’ha associat a un augment en el risc de tenir un CIN3/CIS. La durada en l'ús d’anticonceptius orals s’ha associat a un risc significativament major de desenvolupar un CIN3/CIS o ICC, mentre que deixar d’utilitzar-los durant com a mínim 5 anys redueix el risc de CIN3/CIS a gairebé la meitat. L'ús de teràpia hormonal substitutiva s’ha associat a un menor risc de patir un càncer cervical invasor, en canvi no s’ha trobat cap associació significativa entre l'ús de dispositius intrauterins i el càncer cervical. Aquesta cohort prospectiva confirma el rol del tabac, i en menor mesura dels factors hormonals i reproductius i de les infeccions per CT i HHV-2, com a cofactors del càncer de coll uterí.