A French national breast and thyroid cancer screening programme for survivors of childhood, adolescent and young adult (CAYA) cancers - DeNaCaPST programme

Survival of childhood, adolescent and young adult (CAYA) cancers has increased with progress in the management of the treatments and has reached more than 80% at 5 years [1, 2]. Nevertheless, these survivors are at great risk of second cancers and non-malignant co-morbidities in later life [3, 4]. There is paucity of information in the literature regarding tertiary prevention of secondary cancers.

Radiation therapy during childhood or young adulthood is an established risk factor for second breast cancer (SBC) [5]. Cohort studies have shown the cumulative risk of breast cancer to be approximately 10–33%, depending on the dose received by the breast, compared with a lifetime risk in the general population of 11–12%. This increased risk is mostly linearly dependent on the radiation dose received to the breast during radiation therapy, the shape of the dose response being modified by age at exposure and by early menopause [6‐16]. The risk is higher with high dose of radiotherapy delivered at a young age, but is still significant after moderate (3–10 Gy) radiation dose [6, 10, 15]. The definition of a threshold dose is complicated because it depends on other parameters such as the size of the field, the age at treatment and hormonal status. The cumulative risk for a breast cancer after a mediastinal irradiation above 20 Gy is similar to that for BRCA2-mutated women: around 35% at 40 years [17]. Some studies suggest that these cancers are diagnosed at a median age of 35 years, and that they are more often bilateral hormone receptor-negative and high-grade compared with sporadic primary breast cancers [18, 19].

In CAYA cancer survivors, breast cancer screening is the subject of numerous articles, even in this specific population. Recently, Hodgson et al. presented the results of a mathematical model used to evaluate the marginal benefit on SBC mortality of early-initiated breast screening starting at age 25 years compared with screening initiated at age 40 years, which would be even later in France without any organized program (national breast screening starts at the age of 50) [20]. Their findings indicate that early MRI-based screening (starting at the age of 25 years) should reduce SBC mortality at the age of 75 from 16.65% with no early screening to 15.38% in the case of same-day annual mammography and MRI (16.28% with annual mammography, 15.40% annual MRI), leading to prevention of one SBC death for every approximately 80 patients screened. Many institutions, COG (Children’s Oncology Group), UK CCSG (Children’s Cancer and Leukaemia Group), NCI (National Cancer Institute), ACS (American Cancer Society) and HAS (French High Authority of Health), recommend breast screening for women at high and early risk; nevertheless, in the absence of any national program, these recommendations are not followed [21‐23]. A harmonization has recently been published and recommends screening for women who have been exposed to chest irradiation above 20 Gy [24]. This screening should start at a minimum age of 25 years and a minimum delay after radiation of 8 years. Apart from the dose, the authors suggest taking into account other factors such as the size of the field, the family history of breast and ovarian cancer, in order to accurately evaluate the risk. The surveillance modalities are still under discussion. Most authors agree on an annual examination based on MRI, but the place of mammography, which delivers additional low doses of radiation, is still debated [18, 25‐27].

The second most frequent cancer described in this population is thyroid cancer. Irradiation in childhood or young adulthood increases the risk of nodules and papillary cancers [28]. The time to onset is usually between 10 and 20 years after radiation exposure, but it has been described earlier or later. The best screening method for irradiated thyroid is still debated. The Scottish Intercollegiate Guidelines Network 2013, based on articles published before 2000, does not recommend systematic screening because of lack of clinical relevance. Nevertheless, an Italian prospective study of 129 subjects with a past history of thyroid irradiation who were monitored by ultrasound every three years found that three of the five patients with confirmed papillary carcinoma had non-palpable nodules at time of diagnosis, and advocated a systematic US-type surveillance [29]. The size of the nodule does not appear to be correlated with the risk of malignancy, but this risk does increase with an increase in the number of nodules [28]. In a retrospective study in Chicago on 1059 cancer survivors who have had a thyroidectomy because of a palpable nodule or radiological abnormality, the risk of cancer was 19.6% for one nodule and 36.4% for four or more.

The natural history of these nodules seems to be slow. Thus, two attitudes emerge from the literature: clinical monitoring followed by ultrasound in case of doubtful palpation, or follow-up by regular ultrasound (every 2–5 years) with an annual clinical examination, starting five to eight years after radiation therapy. If nodule(s) have suspicious imaging characteristics (hypoechogenicity, microcalcifications, irregular contours, or mixed types of vascularization (peripheral and central or penetrating radial), cytology is required regardless of the size of the suspect nodule [30, 31]. Also, in the case of malignant cytology in a nodule equal to or greater than 1 cm, a total thyroidectomy is recommended [32]. For isolated nodules less than 1 cm in diameter, there is no demonstration that immediate surgery may be beneficial in terms of cure rate as compared to delayed surgery performed at the time of progression. Therefore, the interest of routine screening for thyroid nodules remains debated. In addition, for patients whose analysis is in favour of a benign nodule but who have a multinodular thyroid, or for patients whose nodules are too small for cytology, regular monitoring is recommended.

In France, the national breast screening programme starts at the age of 50 and is based on mammography every two years. With this in mind, we conducted two studies:

The first was to analyze the characteristics of the secondary breast cancer (SBC) developed in women under the age of 50 (article in press, presented in part at SIOP and ESLCC congress). This was a multicentre retrospective study on 102 women in nine French centres, treated between 1950 and 1995. The median delay from irradiation to SBC was 20 years, and for five women, SBC occurred in the first decade after the first cancer (respective delay: 3, 5, 7, 7, 8 years after); the dose of irradiation was ≥20 Gy in 76% of the cases. The diagnosis of SBC was made at a symptomatic stage in 88.3% of cases (pain, lump, discharge, or skin retraction). Only 23 women had a follow-up focusing on the breasts before SBC diagnosis, either exclusively clinical (4%), or by annual or biennial mammography (13%), or by biennial echography and mammography for a patient at high risk (50 Gy at the level of mediastinum and three relatives with breast cancer). None was followed by MRI.

The second was a survey of current practice on long-term follow-up care (article in press, presented at the SFCE meeting). This survey was sent to every member of the SFCE (French Society for Childhood Cancer) by mail in 2016. Fifty three doctors from 31 centers answered, 18 doctors were used to prescribe breast screening if needed, and 28 were used to prescribe thyroid screening if needed. This survey confirmed that individual thyroid screening was more widespread, probably due to the facility of the screening procedure (non-ionizing exam) (Additional file 1).

France is lacking a specialized screening programme for irradiated childhood survivors, even if physicians are aware of the increased risk and national recommendations have been issued. Long-term follow-up for adults is challenging and requires time, money and organization. In addition, the possible lack of availability of MRI machines has been pointed out.

A study is therefore required to assess, and if possible overcome, all the possible barriers. This is then the main purpose of the DeNaCaPST study, which is supported by the SFCE.

International guidelines have been put in place because of the evidence for increased lifetime risk of breast and thyroid cancer. DeNaCaPST is based on these international recommendations but it is important to recognize that they are based on expert consensus opinion and are supported by neither nonrandomized observational studies nor prospective randomized trials in this specific population. In the general population, some studies have been designed as blind and randomized studies, but we have to point out that in the field of breast cancer screening data are sometimes distorted or inappropriately used, and that screening is also a theme of passionate debate [36]. The main goal of cancer screening is to reduce the specific mortality from cancer. But expected mortality depends strongly on the mortality rate, which evolves with time. In breast cancer, mortality rate is reducing because of the growing effectiveness of treatments [37]. Thus the endpoint of screening studies should not focus only on reducing specific mortality [38], and the overall effectiveness of a screening program (including the risk of over-diagnosis) can be definitively assessed only through randomized controlled trials. Nevertheless those trials are ethically questionable.

Over-diagnosis is a phenomenon inherent in any screening program. This means that clinicians must be aware of the problem and such programs must be regularly reviewed, given such therapeutic advances and new studies produced, to re-examine the real impact of any program on mortality and the extent of its deleterious effects. Indeed, as it is not possible to predict the evolution of a cancerous lesion at the time it is detected, it is proposed to treat all detected cancers, but this may result in overtreatment for cancers that would have not evolved through time.

Evaluation of over-diagnosis is possible only through randomized studies comparing screened and non-screened populations. Otherwise it must employ assumptions modeled from the rate of non- progressive cancers. The results published for this kind of analysis vary greatly depending on the type of cancer concerned (eg. in breast “infiltrating only” or “infiltrating + in situ”), the methodology, assumptions, indicators and parameters chosen.

For micro-papillary thyroid cancer of less than 1 cm in diameter when they are isolated (without lymph node metastases and without extra-capsular extension), there is no data demonstrating a benefit of immediate surgery as compared to delayed surgery performed at progression. Therefore a programme of active surveillance may be offered to these patients, that may be combined to translational research to discover biological markers that are predictive of future progression.

As survival has greatly improved in childhood cancers, detection of therapy-related malignancies has become a priority even if new radiation techniques will lead to better protection for organs at risk. DeNaCaPST is a multicentre study whose aim is to prove that a screening for thyroid and breast cancers is possible at a national level for at-risk survivors. We hope that it will result in a similar follow-up for those at equal risk across the country. It will also provide additional data on secondary thyroid and breast cancers, and reinforce multidisciplinary cooperation.