Radiotoxicity and breast cancer screening: caution, caution, caution…

 Dr Annette LEXA (PhD Toxicology)

July 2, 2019

In October 2017, I published on this site, an informative article on the risk associated to radiotoxicity[1] explaining that 15 years of research performed by the Radiobiology Community UMR 1052 INSERM (a joint research unit within the National Institute for Health and Medical Research, Lyon) demonstrated that we are not equal when exposed to radiation. Moreover, this issue is not a new one in authorized environments, as the ASN (Nuclear Safety Authority) had already been concerned about it in 2003, calling for study and protection of populations at risk “through the evolution of medical practices with regard to ionizing radiation and an eventual evolution of regulations”.
We are now in 2019, the data is accumulating and nothing is moving. The main reason for this is the lack of disciplinary transversality: while radiotherapists and radiophysicists are regular collaborators, radiobiologists are rare and less involved in therapeutic choices.
Although radiotherapists point out problems with the physical doses received, biological factors are the ones that explain the dramatic reactions of patients, causing them to interrupt the radiotherapy, which is nevertheless necessary.

It should be mentioned that the current regulatory context[2] resulting from the amendments to the Labor Code and the Public Health Code introduced in 2002-2003, is based, in particular, on the monitoring of the 120,000 survivors of Hiroshima-Nagasaki. We are now facing a paradigm shift that is changing our view of radiation-induced events. Advocates of hubris around early cancer screening have not thought for a moment about this paradigm shift: early screening will induce even more medical imaging, overdiagnosis, overtreatment, and radiation-induced cancers in young and healthy women.

It is absolutely necessary that this new paradigm be implemented into legislation, good medical practice, population screening campaigns as well as all in clinical and epidemiological studies (such as the vast European study My PEBs, which enlists women as young as 40 years of age without the slightest precaution, without information or informed consent on this subject[3]). It's no longer a matter of the precautionary principle, it's a matter of prevention, because we can no longer say "we didn't know."

Mechanisms involved

Radiation induces chromosomal effects resulting in well-known anomalies (micronucleus, translocation, insertion) which are the manifestation of double-strand breaks (DSB) of poorly repaired DNA. Poor repair of DSBs is the most serious event that the double helix of DNA can undergo.

For the same dose of absorbed radiation, our cells undergo 40 DSB / Gy (Gray is the unit of measurement used in medicine to quantify irradiation). However, DBSs are already occurring at 1mGy and the effect is significant at around 100-300 mGy, so we talk about hyper-radiosensitivity to low doses. It is the persistence of unrepaired lesions that counts and it is on the signalling and repairing of our DNA that we are not all equal face to radiation.

In humans, there are two ways to repair DSBs: end-joining (predominant) and recombination. This is the model of a perforated sock, explained by Nicolas Foray: either we place the two pieces together and join them together (end joining) or we make a patch when the hole is too large, as our grandmothers used to do (recombination).The end-joining repair model is a source of error that can result in a high radiosensitivity and severe immunodeficiency. Recombination repair pattern necessarily causes breaks in other regions of DNA, as a piece of DNA has to be removed to repair the first break, resulting in DNA chain damage.

There is a distinct category of proteins known as 'tumour suppressors' which are involved in DNA signaling and repair. They function well in homozygous individuals [4] for these proteins such as BRCA1, BRC12, p53, Rb…

  • Heterozygous BRCA1+/- mutations in the BRCA1 protein, responsible for the majority of familial breast and ovarian cancers, increase the risk of cancer by a factor of 6 to 10. BRCA1 is closely related to the ATM[5] protein involved in the signaling of DSBs and would be indispensable for the action of the Rad51[6] protein involved in the repair by recombinant DNA.
  • The heterozygous BRCA2 +/- mutations are implicated in ovarian and male breast cancer. The BRCA2 protein interacts with the RAD51 protein for DNA repair.
  • Overexpression of the Rad51 protein induces hyper-recombinations, a source of high genetic instability leading to tumour processes. We are now aware that radio- sensitive individuals overexpress hyper-recombinations leading to radio-induced cancers.

The research carried out by the Radiobiology Group identified three population groups according to their resistance to radiation:

  • Radioresistant (Group I)75-85% of the population: ATM cytoplasmic protein in dimeric form, very good recognition of DBSs, no predisposition to cancer.
  • Moderate radiosensitivity (Group II) 5-20% of the population: delayed transit of the ATM protein in the nucleus, poor recognition of DBSs, poor repair, moderate radiosensitivity, high risk of cancer.
  • Hyper radiosensitivity (Group III) >1% of the population: mutation of the ATM protein, poor recognition of DBSs, poor repair, hyper-radiosensitivity, high risk of cancer.

Radiosensitivity of DNA to low doses of ionising radiation

We already know that the breast is a radiosensitive organ. Mammography, by performing successive images, results in a repetition of low doses of 2 mGy sent at 3 minutes intervals. These radiations will induce a tissue reaction in some women: cellular apoptosis [7], double-stranded DNA (DSB) breaks with late repair defects which can induce either secondary cancer from improperly repaired cells or cell death. When the control mechanisms are efficient, cell death is more likely than its transformation into an immortal cancer cell line.

This radiosensitivity has been known for a long time in radiotherapy, its late, long-lasting and very difficult to treat expected effects (burns, necrosis, fibrosis, apoptosis) affect 5-15% of patients treated for cancer (8,000-25,000 people per year).

Extreme radiosensitivity exists in several rare genetic deficiency syndromes (ataxia telangiectasia, progeria, xeroderma pigmentosum, Huntington's chorea, Fanconi anaemia, Li-Fraumeni syndrome, etc.): patients who are homozygous for the genes involved are unable to tolerate the doses used in medical imaging. Although these cases are rare but detectable, it is possible that in the general population a large number of heterozygotes may be observed, a source of genomic instability for these carriers and causing problems during repeated radiotherapy and medical imaging.

Radiosusceptibility signs a predisposition to radiation-induced cancers even at low doses

The effect is random, probabilistic and will concern 5% of patients who have received radiotherapy. They are likely to develop with a high probability a secondary radiation-induced cancer, knowing that these patients affected by cancer are already more radiosensitive than the majority of the population.
This radiosusceptibility is increased in mammographic conditions (images delivering 2+2 mGy at intervals of 3 minutes with immediate repetition, preventing the mutated genomes from setting up signalling and successful repair). Women at high family risk of breast cancer (15% of breast cancer cases) have defects in signalling and repairing of their DNA: this is the case of the BRCA1 protein, which is at the heart of the complexes formed to repair the DNA DBSs. But women carrying a mutation of this gene which has thus become defective, and who are therefore more likely to develop cancers because their DNA has not been properly repaired, are encouraged to undergo close monitoring at an early stage, with a combination of mammograms and even tomograms. Some doctors - who do not know anything about radiosusceptibility - require them to undergo examinations every 6 months or every year, while the greatest caution should be applied: spacing of at least ½h at 1 hour from the x-rays (50% of DBSs are normally repaired within 50 minutes), avoid contrast products and x-rays.

Time for conclusion

This knowledge implies a new screening strategy for women at high family risk (such as taking a single mammogram, proposing MRIs and ultrasounds that do not emit ionising radiation). It also calls into question the continuation of organised screening such as outlined in Law 2004-806 of 9 August 2004 on public health policy, consolidated version as of 16 April 2019. No one has ever thought of questioning French radiobiology specialists on this "point of detail".
Work is currently underway to validate predictive tests for radiosensitivity before any radiotherapy.

While awaiting the availability and reimbursement of easy and inexpensive predictive tests for all the tens of millions of women, young and not so young, but above all healthy women, enrolled in mammographic screening, this knowledge of the biological causes of radiosensitivity and radiosusceptibility requires, on the basis of the precautionary principle, that the project of extending mammographic surveillance of young women should be stopped. Radiologists, gynecologists and oncologists must be informed of the risks of radiation-induced cancers to that they are exposing their patients with this regrettable "life-saving screening". Don't we say that hell is paved with good intentions? Don't we also say that "error is human, stubbornness (by arrogance) is diabolical? ».

Read also, in the news :

  1. The Academy of Medicine warns that the risk linked to imaging examinations must be offset against the risks of the disease itself. http://www.academie-medecine.fr/wp-content/uploads/2016/12/16.11.15-DUBOUSSET-rapport-v-16.12.8-AK.pdf page 8 and 9

The incidence of cancer (breast and endometrial) is multiplied by 5 for adolescents treated for scoliosis 25 years earlier (with an average of 16 x-rays per case) in a Danish study in 2016 (26). This work led to the recommendation to take these images with a postero-anterior incidence rather than the reverse, in order to expose less the mammary gland. The new systems, which are unfortunately not widespread enough (EOS)(15), allow a reduction in dose by a factor of 6 to 40 compared with conventional radiographs. Complete monitoring of scoliosis can therefore be carried out for the equivalent of a single conventional radiography. Once the diagnosis has been specified on the initial radiography, the best protection is to monitor this scoliosis using non-irradiating means such as the scoliometer, or surface topography systems (27), with an X-ray check being carried out only if a significant change in surface topography is found.
c) The incidence of cancer in adulthood would be increased. Some populations have a particular radiosensitivity linked to DNA repair disorders (30,31). Obviously, the risk associated with imaging examinations must be weighed against the risks of the disease itself (e.g. mucoviscidosis) and the use of non-irradiating techniques (MRI, ultrasound) should be systematically favoured if possible.

2. https://www.francebleu.fr/infos/sante-sciences/les-nouveaux-cas-de-cancers-en-hausse-surtout-chez-les-femmes-1562060451
https://www.lemonde.fr/sciences/article/2019/07/02/les-nouveaux-cas-de-cancer-en-forte-hausse-en-france_5484200_1650684.html
No reduction in breast cancer despite screening, increase in lung cancer in women. We wonder about the proportion of lung cancers in women attributable to over-diagnosis and thus secondary to over-treatment by unnecessary radiotherapy.

Bibliography

Radiosensibilité et irradiation mammaire, Toxicité des polluants et cancers du sein , Nicolas Foray, Unité UA8 Radiations Défense, Santé et Environnement, Groupement de Recherche sur les Radiations de Lyon (GRRAL) , 2019, Communication personnelle à Cancer Rose
https://its.aviesan.fr/getlibrarypublicfile.php/cd704e89988a4e3bcf2e1217566876cf/inserm/_/collection_library/201800012/0001/J1-098ITS-2017.foray.lyon.ITMO.TS..21.nov.2017.pdf.pdf

La susceptibilité individuelle aux rayonnements ionisants, Pr. Michel Bourguignon Commissaire ASN, 2014
https://www.irsn.fr/GT-CIPR/Documents/15-05-2014/GT-CIPR_15-05-2014_3-Bourguignon.pdf

La radio-susceptibilité individuelle: 3 défis et une vision pour la radioprotection, Pr Michel Bourguignon, ASN, 2015
http://reseau-ramip.fr/wa_files/06-TOULOUSE_20RaMiP_20RSI_20-_204_20Dec_202015_20__5BMode_20de_20compatibilit_C3_A9_5D.pdf

Impact du transit cytonucléaire de la protéine ATM en réponse aux radiations ionisantes : notions de pro- et anti-episkévie, Melanie Ferlazzo, Thèse de doctorat de l’Université de lyon, 2017
https://tel.archives-ouvertes.fr/tel-01588173/file/TH2017FERLAZZOMELANIE.pdf

[1]Test prédictif des réactions à la radiothérapie : des femmes en grand danger, Annette LExa, 2017 .
https://www.cancer-rose.fr/test-predictif-des-reactions-a-la-radiotherapie-des-femmes-en-grand-danger/
[2] La Directive 2013/59/Euratom du Conseil du 5 décembre 2013 fixe les normes de base relatives à la protection sanitaire contre les dangers résultant de l’exposition aux rayonnements ionisants. Une directive regroupe les directives de 1989 à 2003

[3]https://cancer-rose.fr/my-pebs/2019/06/13/argument-english/


4] Homozygotes have 2 functional parental alleles such as BRCA1 +/+ for example. Heterozygous BRCA +/- carriers have a deficient mutated allele resulting in poorer break signalling and therefore poorer repair.

5] The cytoplasmic protein ATM, is a dimer with a signaling function to stimulate DNA repair - See the importance of the transit of this protein in the signalling mechanism for double-stranded breakage repair: https://www.cancer-rose.fr/test-predictif-des-reactions-a-la-radiotherapie-des-femmes-en-grand-danger/

6] In humans, the RAD51 protein plays an essential role in recombination during DNA repair following double-strand breaks.

7] Apoptosis, or programmed cell death, is the process by which cells trigger their self-destruction in response to a signal