Oral Contraceptive Use and Breast Cancer Risk According to Molecular Subtypes Status: A Meta-Analysis

Abstract Background Breast cancer is a heterogeneous disease with distinct molecular signatures of disease etiology, evidenced by the joint expression of molecular tumor markers. Differential effects of oral contraceptive use on breast cancer risk by molecular subtypes have been reported. This is the first meta-analysis to investigate associations between oral contraceptive use and subsequent breast cancer risk stratified by combined estrogen receptor (ER) and progesterone receptor (PR) status alongside the Luminal A and B subtypes, which additionally consider the human epidermal growth factor receptor 2 (HER2) status. Methods A systematic review and meta-analysis of case-control and cohort studies was conducted in PubMed and Web of Science. The odds ratios (ORs) were summarized using a random-effects model. Results Eleven studies met the inclusion criteria for qualitative and quantitative analysis. Random effects meta-analyses revealed significant risk increasing effects for ever-users of oral contraception on ER-PR- breast cancer compared to never-users (OR = 1.30, 95% CI; 1.07 to 1.56, p < 0.01). Ever-use of oral contraception was not associated with breast cancer risk when stratified by the ER+PR+ breast cancer subtype (OR = 1.00, 95% CI; 0.86 to 1.16, p = 0.99). Data on Luminal A and B subtypes was limited and not suggestive for associations with breast cancer risk in ever-users of OCs compared to never-users. Furthermore, a significant increased risk of ER-PR- breast cancer was observed for OC use duration of > 4 years compared to never-users (OR = 1.74, 95% CI: 1.15 to 2.63, p < 0.01). Conclusions The current state of the evidence suggests that OC use longer than 4 years is associated with an increased breast cancer risk, pertaining to the estrogen and progesterone double negative breast cancer subtype. Large-scale prospective observational studies including more comprehensive molecular signature of breast cancer aetiology, including HER2 status, are needed. Key messages • The use of oral contraception was associated with estrogen and progesterone receptor double negative breast cancer, but not hormone receptive positive cancer. • This is the first meta-analysis to investigate oral contraceptive use and associations with breast cancer risk by combined estrogen and progesterone receptor status.


Introduction:
Italy was one of the first EU countries hit by the COVID-19 pandemic. Currently, Italy has reported 15.5 million cases of COVID-19 and 161000 deaths. Meanwhile, the vaccination campaign against COVID-19 began in Italy at the end of 2020, using mRNA and viral vector vaccines (immunizing people against Spike protein of SARS-CoV-2. The purpose of this study was to estimate, in a representative sample of the Italian population, the prevalence of antibodies against SARS-CoV2 in 2019 (before case zero, identified in Italy in February 2020) and in 2021, after 3 pandemic waves and a vaccination campaign.

Methods:
During October / November 2019: 365 participants were selected in the Piedmontese population among those who went to a hospital for routine blood tests. The population was selected on the basis of age and gender to be representative of the Italian population. The same number of patients was selected in the first quarter of 2021, the inclusion and exclusion criteria remained the same. Sera were searched for spike protein of SARS-CoV-2 and, if positive, tested for antinucleocapsid antibodies.

Results:
Our preliminary data show that half of the sample for both years is female. In the 2019 sample, i.e. before case zero was identified in Italy (Lombardy), five of the sera (4 males and one female) tested positive for anti-Spike,indicating a previous infection (vaccine didn't exist). In the 2021 sample, 152 males and 139 females tested positive for IgG anti-spike, for a total of 291. The prevalence therefore passed from 1.37% to 79.73%. As regards the search for ANti-Nantibodies, one male and one female tested positive in 2019; in 2021 9 males and 13 females.

Conclusions:
The results of our study show that in 2019, before the first official case in Italy was highlighted, coronavirus was already circulating. The prevalence has risen exponentially, going from less than 2% to around 80%.

Background:
Breast cancer is a heterogeneous disease with distinct molecular signatures of disease etiology, evidenced by the joint expression of molecular tumor markers. Differential effects of oral contraceptive use on breast cancer risk by molecular subtypes have been reported. This is the first metaanalysis to investigate associations between oral contraceptive use and subsequent breast cancer risk stratified by combined estrogen receptor (ER) and progesterone receptor (PR) status alongside the Luminal A and B subtypes, which additionally consider the human epidermal growth factor receptor 2 (HER2) status.

Methods:
A systematic review and meta-analysis of case-control and cohort studies was conducted in PubMed and Web of Science. The odds ratios (ORs) were summarized using a randomeffects model.

Results:
Eleven studies met the inclusion criteria for qualitative and quantitative analysis. Random effects meta-analyses revealed significant risk increasing effects for ever-users of oral contraception on ER-PR-breast cancer compared to never-users (OR = 1.30, 95% CI; 1.07 to 1.56, p < 0.01). Ever-use of oral contraception was not associated with breast cancer risk when stratified by the ER+PR+ breast cancer subtype (OR = 1.00, 95% CI; 0.86 to 1.16, p = 0.99). Data on Luminal A and B subtypes was limited and not suggestive for associations with breast cancer risk in ever-users of OCs compared to neverusers. Furthermore, a significant increased risk of ER-PRbreast cancer was observed for OC use duration of > 4 years compared to never-users (OR = 1.74, 95% CI: 1.15 to 2.63, p < 0.01).

Conclusions:
The current state of the evidence suggests that OC use longer than 4 years is associated with an increased breast cancer risk, pertaining to the estrogen and progesterone double negative breast cancer subtype. Large-scale prospective observational studies including more comprehensive molecular signature of breast cancer aetiology, including HER2 status, are needed. Key messages: The use of oral contraception was associated with estrogen and progesterone receptor double negative breast cancer, but not hormone receptive positive cancer. This is the first meta-analysis to investigate oral contraceptive use and associations with breast cancer risk by combined estrogen and progesterone receptor status.