Discussion
This study provided an update on BC incidence and survival among women in Isere Department from 1990 to 2018. The largest increase in the incidence of BC is found in YW. Our results are consistent with several studies: From French registries, Colonna et al. reported + 0.65% per year of the incidence rate between 1983 and 2002 (15–39 years old) and national data show an increase of 0.9% per year on average from 1990 to 2018 among YW.[5,17] Leclère et al. have shown an increase in the incidence rate among YW in seven European countries by 1.19% on average per year between 1990 and 2008.[9] In the USA, Guo et al. have shown a rise in incidence rate among women between ages 20 and 39 years from the Surveillance, Epidemiology, and End Results program's 9-registry areas from 1975 to 2015, with an annual percent change of 0.5%.[18]
We found an increase in the average annual incidence (+ 0,8%) in all age groups over this period. These data are close to those found at the national level in France over the same period, estimated at + 1.1% over the period 1990 to 2018 and + 0.6% between 2010 and 2018.[5] In the USA, there is a rise in incidence by + 0,3% per year between 2009 and 2018.[19]
This trend in incidence seems to be multifactorial: Management practices can influence BC incidence: In France, BC screening programs have been implemented throughout the country since 2004 but started gradually since other 1994. It is recommended only in women aged 50 to 74 years or if there are risk factors such as a family history or a genetic mutation such as BRCA.[6] The introduction of organized screening could lead to this increased incidence in the 50–74 age group but not totally. Indeed, we also find an increase in incidence in the other age categories. The mechanisms that lead screening to vary incidence rates are the advanced diagnosis effect and overdiagnosis.
A possible explanation for the increase in incidence is the modification in exposure to risk factors of BC: Among modifiable risk factors, several studies have proven a relationship between alcohol consumption and the risk of developing BCYW.[20,21] Smoking is associated with the risk of developing BC even if this risk is scarce.[22,23] In France, the increased incidence of smoking in women may partly explain the higher incidence rate of BC.[24] On the other hand, a high BMI is linked to a reduced risk of developing BCYW.[25] Physical activity is also associated with a reduced risk of BC at any age.[26]
Regarding hormonal and reproductive factors, the increase in the incidence of BC in western countries could be explained by the decrease in breastfeeding, the later age of the first child with a decrease in the average number of children per woman. Younger age at puberty and later menopause may also explain this trend.
Considerable advances have been made in BC oncogenetic: genetic factors, more frequent in YW must be considered with great importance even if the majority of BCYW are not explained by cancer susceptibility genes.[27] BC predisposition genes BRCA1 and BRAC2 have been known for over twenty years.[28,29] In the UK POSH cohort, around 12% of women under 41 years old had the BRCA mutation.[30] Therefore, young age alone is sufficient to suggest an oncogenetic consultation. An American cohort study showed that in 2006, 77% of YW with BC had a BRCA test, compared to 95% in 2013, suggesting progress in genetic screening in this category of patients.[31] Later, the mutation of the PALB2 gene was also found to be predisposing to BC.[32] Today in France, the Genetics and Cancer group recommends the analysis of the BRCA 1 and 2, PALB2, TP53, CDH1, and PTEN genes if there is a suspicion of predisposition to BC.[33] Oncogenetic consultation makes it possible to look for predispositions and adapt screening according to these predispositions.
The greatest improvement in survival is found in the 50–74 age group, linked to the implementation of organized screening: Indeed, the diagnosis is made at an earlier stage when treatments are more likely to be effective, but there is also a bias related to the early diagnosis: The date of diagnosis is advanced, and therefore, survival is longer even if the date of death does not change because it is calculated from an earlier date.
We found that YW have lower relative survival than 50–74-year-olds, which is widely described in the literature.[34] However, relative survival is better over time. The latest French national study from the national cancer institute also shows an improvement in survival in all age groups from 1989 to 2018. In YW, the 10-year net survival increases from 72% in 1990 to 85% in 2010.[35] Because the YW category is not targeted by organized screening, improvement of specific survival is not only linked to earlier screening, particularly in patients with a genetic predisposition, but also to therapeutic advances. Increased awareness of early detection is also an explanation for improved survival. This improvement in survival is found in other European countries.[36] Several explanations can be put forward for the poorer survival among YW: In our study, there are about twice more triple negative among YW compared to the 50–74 age group, which is found in several studies.[37] We know triple-negative BC is associated with a poor prognosis. There were more aggressive tumors compared to older women.[38,39] There is more HER2 amplified among YW in our study compared to other age groups, but young age has no impact on the relative survival of this type of tumor.[40,41] Several studies have shown that survival is worse for the luminal subtype in YW.[34,42] Many mechanisms may explain this finding: Young age is associated with poorer compliance with adjuvant endocrine therapy, and limited efficacy of this treatment.[43] In addition, post-chemotherapy amenorrhea related to hormonal impregnation, associated with better outcomes in this subtype, is less common in YW.[44] Women targeted for screening may have less advanced luminal tumors as a result of screening. Finally, the poorer survival could also be explained by a later stage at diagnosis, but this hypothesis is debated.[45,46] The lowest relative survival is found in the over 75 s, which may be explained by the higher proportion of comorbidities in this age category and the lower ability to receive standard treatments.[47]
BC screening was shown to reduce breast cancer mortality in the randomized controlled trials, and the effectiveness of mammography has been demonstrated in modern screening programs. The International Agency for Research on Cancer estimated that mammography screening reduces breast cancer mortality by about 40% in women ages 50–69 who attend screening.[48] However, several factors could make it difficult to estimate the impact of organized screening since it was introduced, such as increased awareness, the increasing effectiveness of treatments, the modification of risk factors over time implying changes in incidence rates, and the gradual introduction and at a variable level of screening in the different French regions. To overcome the influence of these different factors, the evaluation of screening program data utilizing the incidence-rate-of-fatal breast cancer analysis has demonstrated that as expected, both screening and improvements in therapy have contributed to reductions in breast cancer mortality, but that women who regularly attend screening benefit substantially more from modern treatment advances than women who do not attend screening.[49,50] The practice of "individual screening" was already widespread in France before the generalization of organized screening even among YW, which could partly explain the increase in incidence in this category. On the other hand, this hypothesis is not sufficient to explain this trend because the increase is greater among YW. Screening for BC has some limitations: In Europe, the risk of being a false positive is 20% for a woman getting tested every two years from 50 to 69 years old, and the risk of having a biopsy when it is a false positive is 3%.[51] However, false positives do not have an impact on the incidence. Nevertheless, overdiagnosis may be partly responsible for the increased incidence, but our study cannot quantify it. According to Hauge et al., the total lifetime risk of radiation BC and the number of radiation-induced BC death were 10 and 1 per 100,000 women, respectively, by having biennial mammographic screening with a latency time of 10 years.[52] However, the use of a biannual mammogram would avoid one death of BC for every 250 women invited.[53] Radio-induced cancers are more frequent among YW than in older women.[54] There are more false positives, and mammography is less efficient for this age category, where MRI or US should be preferred.[55]
BCYW is still a rare disease, and screening impact on mortality has not been demonstrated. Thus, BC screening is not advisable for this age class.[56] Nevertheless, by observing the current trend, it seems necessary to ask whether the age of screening should be redefined: Indeed, YW have more aggressive cancers and poorer survival. In our study, the incidence rate in 50–74-year-olds is too high compared to YW: Therefore, it will be difficult to show the effect on mortality of organized screening in younger women. In addition, very high participation will be necessary for screening to be effective. Although the 35–39 age group is similar to the 40–44 age group in terms of disease burden, the incidence rate in this age group is too low to recommend screening. However, studies have investigated the effectiveness of screening between the ages of 40 and 49 with interesting results on mortality reduction: Hellquist et al. demonstrated a statistically significant overall mortality reduction of 29% in women invited to screening compared to those who were not, with an average follow-up of 16 years.[57] In women aged 40–44 years, the mortality reduction was less marked (18%). In their study, Jonsson et al.[58] found a 36% reduction in mortality in the 40–49-year-old group at a median follow-up of 11 years.
In this regard, the latest US recommendations suggest the age of 45 years to start screening since the 45–49 age group is very similar to the 50–54 age group on the absolute risk of breast cancer at 5 years, the proportion of incident cases, and distribution of deaths by age at diagnosis.[59]
It could be interesting in the future to consider personalized screening according to the risk of developing BC to screen fewer women at low risk and strengthen the screening of women at higher risk. Indeed, the increase in incidence seen in YW does not result in incidence rates high enough to consider screening in the general population. On a European scale, the MyPeBs study launched in 2019 is evaluating a new BC screening strategy aimed at demonstrating that stratified screening reduces advanced BC and disadvantages of screening (overdiagnosis, false positives). MyPeBs could prepare future screening recommendations in Europe. In France, individualized strategies by screening program for high-risk women were set up in 2014 by the high health authority as part of the 2009–2013 cancer plan. However, no studies have compared multiple screening strategies in different risk groups on mortality reduction.
Our study has several limitations. First, it is a retrospective study with the disadvantages we know. We used data from the Isere register which is not necessarily representative of other French departments. In addition, even if this work allows several hypotheses, it is a descriptive epidemiological study, which makes it difficult to assess the evolution of risk factors and their consequences on our survival and incidence data. We only had tumor subtypes from 2011, which limited the number of cases for a more powerful analysis. Moreover, we did not have tumor grade and Ki67. Thus, we could not divide the luminal category into groups A or B for more accuracy.
The strengths of our work are multiple: The registry information system, based on general population data, allows for the completeness of invasive BC diagnoses. Moreover, the incidence data were calculated over the last three decades, which allows us to have reliable hindsight in our analysis, and a large number of patients included, allowing for significant power. Finally, the data are based on a multicentric population: The registry used includes several medical centers in different cities throughout the department.
Breast Cancer Res. 2022;24(87) © 2022 BioMed Central, Ltd.
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