Perception and reality

3 jan. 2017

How women perceive the data from screening, influenced by optimistic slogans and presentations, versus reality:

When the authors of the report of the Swiss Medical Board (a Swiss medical commission independent from government authorities) evaluated the relevance of the mammographic screening program for breast cancer (see article), (PDF Article) they looked at one data that had been studied in several countries (4), namely how women perceive the benefits of screening according to what has been communicated about it and the information they have received, and that have made their beliefs on the subject.
The authors have presented a comparative table, with data gathered from the perception survey of American women in Part A, and real, objective data from the most probable scenarios, observed from the most convincing and among the most reliable studies in Part B (1-3)
The authors were astonished by the significant discrepancy between women's beliefs about the benefits of screening and reality.


The projected number of women in their fifties who would survive, develop breast cancer and die from other causes while doing regularly screening over 10 years, was compared to the expected number of women who would survive, develop breast cancer or die from other causes, and not doing screening.

71.5% of these interviewed American women estimated that screening mammography reduced by half the risk of dying from breast cancer, and 72.1% believed that at least 80 deaths would be prevented for every 1,000 women invited for screening.
The presentation of mortality risk reduction as a percentage embellishes the data.
A 20% reduction in mortality (a figure found on public institution websites, women committees websites and in the information brochures distributed to women) does not mean that 20 out of every 100 women will die of breast cancer, but that only one less woman will die of it in the best case (and without considering the other, more numerous women screened, who will at the same time suffer from overdiagnosis and false alarms).
The relative risk reduction of 20% corresponds to a comparison between the screened and unscreened groups. If, for example, 5 out of 1000 unscreened women die and 4 out of 1000 screened women die of breast cancer, the relative risk reduction resulting from the comparison of these two groups corresponds to this 20% ((5-4)/5=0.2 ), but in absolute terms it is only one woman who is saved. The data that the authors have collected for the Swiss population show also these optimistic expectations in a similar way.

The authors legitimately ask the question, how can women make an informed decision if the benefits of the screening program are overestimated?
We asked ourselves the same question…and tried to answer it (see the brochure on the home page).

REFERENCES

1-Gotzsche PC, Jorgensen KJ. Screening for breast cancer with mammography. Cochrane Database Syst Rev 2013;6:CD001877-CD001877
Medline

2-Independent UK Panel on Breast Cancer ScreeningThe benefits and harms of breast cancer screening: an independent review. Lancet 2012;380:1778-1786
Medline

3-Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ 2014;348:g366-g366
Medline

4-Domenighetti G, D'Avanzo B, Egger M, et al. Women's perception of the benefits of mammography screening: population-based survey in four countries. Int J Epidemiol2003;32:816-821
Medline

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Ineffectiveness of mammography screening

Ineffectiveness of mammography screening to detect the most serious cancers

Summary by Cécile Bour, MD

October 1, 2020

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2770959

Published on September, 25, 2020.

Saroj Niraula, MD, MSc1,2Natalie Biswanger, BSc3PingZhao Hu, PhD4; et alPascal Lambert, MSc2Kathleen Decker, PhD2,5

  • 1. Section of Medical Oncology and hematology, University of Manitoba, Winnipeg, Manitoba, Canada
  • 2. Research Institute of Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada
  • 3. Cancer Screening program, CancerCare Manitoba, Winnipeg, Manitoba, Canada
  • 4. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada
  • 5. Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

Study objectives

« Evaluate the differences and similarities in characteristics and outcomes of breast cancers detected by mammographic screening compared to  those detected between screening mammograms (interval cancers) in women participating in a population-based screening program »

Results of study

« In this cohort study of 69 025 women, interval breast cancers accounted for one-fourth of breast cancers in routinely screened women, were 6 times more likely to be grade III, and had 3.5 times increased hazards of breast cancer death compared with screen-detected cancers. »

Meaning

« Heterogeneity in breast cancer defies assumptions necessary for screening mammography in its current form to be maximally effective; strategies beyond routine screening mammography are needed to prevent, detect, and avert deaths from the more lethal interval breast cancers. »

Explanation :

Breast cancer does not follow the linear and mechanistic pattern assumed.

Natural history of cancer

The theory that cancer can be treated because it has been diagnosed when very small, seems to be intuitive, flattering, yet contrary to observation (clinical cases, autopsy studies). In the case of breast cancer screening, we also have to deal with the true belief which is underpinned by frequently repeated mantra such as "cancer can knock on every door," "the smaller the better," "prevention is cure." Is it true?

These clichés are based on a linear and mechanistic  theory of natural history of cancer. Cancer is believed to evolve in an ineluctable way, according to a set pattern. A cancer cell, then a nodule, then a large nodule, then a local invasion, followed by metastases and inevitable death.

But reality is a lot more complex than that.

Small does not mean caught on time, it can simply be a silent cancer, little or never progressive, even regressive, that would have been diagnosed during screening but would never have been killing the woman.

Or, on the contrary, at the time of diagnosis it may already be metastatic, while small or sometimes even occult.

Large does not mean being caught too late, but simply the case of a rapidly growing cancer that, due to its fast development, would be large at the time of diagnosis. In general, it is true that these lesions are on average more aggressive, but this is not absolute. In older women who give up to consult, large cancers may have significant local consequences, such as skin erosions or severe retractions, but without having spread to the distance.

We see these cases in consultation every day, which we consider "paradoxical". 

Not all the cancers evolve and most of them do not become metastatic, they can stagnate, regress, grow so slowly that the patient will die of something else before.

As we can observe, the natural history of breast cancer does not follow the pre-established theory, nor the intellectual model that corresponds to what theorists have opportunistically imagined in order to fit in with their simplistic view. This study is useful to understand this topic : https://cancer-rose.fr/en/2020/12/17/are-small-breast-cancers-good-because-they-are-small-or-small-because-they-are-good/

The authors come here to this conclusion: due to intrinsically slow growth, many of the small tumors detected excessively by screening have a very good prognosis, which means that they are not expected to become large tumors and are inherently favorable. They are the ones that cause overdiagnosis, which results directly from the activity of screening. They will not develop enough to become dangerous.

In contrast, large tumors, responsible for deaths and most often with immediate poor prognosis, escape unfortunately to mammographic detection, due to too rapid kinetic growth.

A previous similar study:

Sarauj Niraula et al. cohort research remembers us a very important and comprehensive study of Pr. Autier. Mammographic screening: a major issue in medicine

https://www.sciencedirect.com/science/article/pii/S0959804917313850

One chapter in this major analysis deals with the specificity of cancers found through mammographic screening, which are less severe and with better prognosis cancers; they are those "selected" through screening, half of which would be overdiagnostics, meaning needless diagnostics that would never have killed the woman.

Mammography indicates for example a high sensitivity for ductal carcinoma in situ cancers, and a relatively low sensitivity for certain aggressive cancers such as 'triple negative' breast cancer.

Mammography basically does not detect lobular carcinoma in situ or invasive cancers that represent 8-14% of all breast cancers. Lobular carcinomas penetrate the tissues without forming masses, making it impossible to identify them by mammography.

Invasive cancers detected by mammography have the clinical and pathological characteristics of less aggressive tumors compared to interval cancers, i.e. those that progress rapidly between two mammograms, escape detection and have aggressive characteristics.

In addition, after analyzing the characteristics of these tumors and the expansion of the disease at the time of diagnosis, the risk of dying from a screened breast cancer is lower than the risk of dying from an interval cancer.

The authors of this study also reported that the interval cancers were similar to breast cancers diagnosed in the absence of screening.

So, if interval cancers are similar to cancers diagnosed in the absence of any screening, and if cancers screened have on average a better prognosis than interval cancers, it logically follows that a proportion of cancers screened are non-lethal cancers that would never have been symptomatic during a woman's lifetime.

These lesions have the microscopic morphological characteristics of cancer, but would have remained asymptomatic throughout the woman's life if the screening had not occurred.

The authors add: "Cancer overdiagnosis refers to cancer excess in women invited to screen divided by the total number of cancers which would be diagnosed in the absence of screening (on a population of the same profile, with the same age group, without screening)."

"If overdiagnosis is calculated using the number of screened cancers as a denominator, then for 100 screened breast cancers, 30 to 50 will be overdiagnosed."

Our conclusion

Breast cancer is clearly shown to be a very heterogeneous disease; indolent cancers with the probability of better healing outcomes are easily detected by mammography screening, abusively increasing the overall incidence of breast cancer, making believe that there are always more, but it is this mechanism of public health that produces them.

And they also give the illusion that the cure rate is improving because their host will never have been killed by all these cancers.

On the other hand, many of the aggressive and lethal types of breast cancers remain unnoticed or develop in the mammography interval.

Other strategies, particularly a deeper understanding of the natural history of cancer, which includes referring to fundamental studies on cancer growth models, are needed to improve the rate of breast cancer death and overall population mortality.

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Australian study, another factual argument on the uselessness of screening mammography

Assessment of Breast Cancer Mortality Trends Associated With Mammographic Screening and Adjuvant Therapy From 1986 to 2013 in the State of Victoria, Australia

Robert Burton, MD; Christopher Stevenson, PhD

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767514

July 26, 2020

Context

Diagnosis of early breast cancer (EBC) in women by mammographic screening and postsurgical adjuvant endocrine therapy and chemotherapy (termed adjuvant therapy [1] ) began simultaneously in many countries in the 1990s. Subsequent breast cancer mortality declines were variously attributed to mammographic screening and/or adjuvant therapy.

Is population-based mammographic screening or endocrine therapy and chemotherapy (adjuvant therapy) after curative surgery for early or operable breast cancer associated with the decline in breast cancer mortality in Victoria, Australia?

Has the cancer been downstaged thanks to the mammographic screening, explaining the decrease in mortality?

 Objective of study

The study presented here was performed in Victoria state, Australia.

The authors are trying to find the link between the reduction in relative mortality with either adjuvant therapy or with screening, and to determine which of these two events would be associated with the observed reduction in mortality in women with early breast cancer who have been subjected to both options (mammography screening and adjuvant treatment after cancer surgery).

 Methods

This is a cross-sectional analysis [2] on breast cancer mortality study of 76,630 women registered with invasive breast cancer who completed the screening program and received adjuvant therapy. The population consisted of participants in previous population-based breast cancer studies from 1986 to 2013. Data from 4 population surveys on breast cancer treatment were used from 1986 to 1999.

Comparisons were made between the stages of cancer at the time of diagnosis and the use of adjuvant treatment after surgery.

Results

Advanced breast cancer incidence doubled from 1986 to 2013, and crude breast cancer mortality declined by 30% after 1994; by 1999, most women were receiving adjuvant therapy, which may be associated with this decline.

Conclusions

This analysis of cross-sectional studies showed no downstaging of breast cancer by mammographic screening. 

The results indicate that is adjuvant therapy accounted for the observed 30% mortality decline and not the mammogram screening.

Authors suggests that persistence with BreastScreen Victoria may continue to expose Victorian women to unnecessary morbidity and mortality. Given this finding, the authors propose that BreastScreen Victoria  program should be terminated. Continuous measurement of breast cancer stages at diagnosis, all-cause and breast cancer–specific mortality, and adjuvant therapy uptake should be mandatory in monitoring and evaluating mammographic screening programs.

References

1. Treatment that complements a main treatment to prevent the risk of local recurrence or metastases. Chemotherapy, radiotherapy, hormone therapy, immunotherapy may be adjuvant treatments after breast cancer surgery.

2.A cross-sectional analysis is a study which:

-Concerns the population as a whole (as a whole, i.e. it includes all the components of the population, not to be confused with the totality; it is, for the most part only a sample which is studied, but representative of the population as a whole)

-Is performed at a specific point in time (as opposed to longitudinal studies, there is no monitoring of population change over time).

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Manipulation of information provided to women on breast cancer cancer screening by mammography is a topic of interest for research studies

Marc Gourmelon, MD

Cécile Bour, MD

September 2, 2020

At the beginning of July 2020, a research article detailing how to successfully manipulate women in order to increase their participation in breast cancer screening programs by mammography,  was published under the title: 

The Good Outcome of Bad News.
A Field Experiment on Formatting Breast Cancer Screening Invitation Letters [1]. 

This article is published  by Italian authors in a journal which defines itself as follows: 

“The American Journal of Health Economics (AJHE) provides a forum for the in-depth analysis of health care markets and individual health behaviors. The articles appearing in AJHE are authored by scholars from universities, private research organizations, government, and industry. Subjects of interest include competition among private insurers, hospitals, and physicians; impacts of public insurance programs; pharmaceutical innovation and regulation; medical device supply; the rise of obesity and its consequences; the influence and growth of aging populations; and much more. The journal is published for the American Society of Health Economists (ASHEcon), which is a professional, non-profit organization dedicated to promoting excellence in health economics research in the United States. All ASHEcon members receive the journal as part of membership.”[2]

This article is not a scientific medical analysis about the relevance of screening by mammography  for women, but a health economics study, from the point of view of health economics carried out by economists. Screening is an integral part of the "health care market" and women behavior is evaluated, based on the manipulation of the information provided to them.

“We show that giving enhanced loss-framed information about the risks of not having a mammography increases the take-up. This manipulation is most effective among sub-groups with lower baseline take-ups, thereby reducing inequalities in screening.”

OBJECTIVE AND STUDY METHODOLOGY

The goal of this study is to evaluate the impact of the interplay between the "frame” of the invitation letter and the "level" of the information disclosed in it, on the rate of participation in the national breast cancer screening program.

There are four "manipulations" being evaluated, depending on the frame and the level of information. The frame of information refers in this case on how to deliver an information in the form of "gains" from being screened, or rather in the form of a grid of "losses" from not being screened.

The level refers to the quality and completeness of the information.

-The "benefit" of the screening procedure is valued by a high quality information 

-The "benefit" of the screening procedure is valued by a basic information

-The emphasis is placed  on the "loss" of not being screened by using a high quality of information

-The emphasis is placed on the "loss" of not being screened by using basic information.

“To the best of our knowledge, this is the first experimental study assessing how the interplay between the frame of the invitation letter and the information disclosed in it influences the take-up rates for a national breast cancer screening program” explained the authors.

MAIN RESULT

“Results show that the take-up rate in the group that received the letter combining the loss frame with enhanced information on the negative consequences of not taking the mammography is about 2.5 percentage points higher than in the baseline group.”

 According to the authors, “this is a sizeable effect”.

The authors congratulate themselves on these findings showing that that this manipulation “helps to decrease inequalities in screening”,   as it allows for a greater manipulative impact for subjects that, according to them, are “with low average education, with no recent screening experience, and for whom the available observable characteristics would lead us to predict a low likelihood of screening in the absence of any manipulation”.

IDENTIFIED ISSUES

A- THE ETHICAL ISSUE

 It seems to us the major one.

First of all, the aim to increase womens participation, at all costs, is clearly stated. Thus, these researchers claim that « the use of letters sent to women at their houses and the invitation for a free and pre-booked mammography increase take-up rates for breast cancer screening »

« In this respect, the present study aims ...at providing insights on how to design effective invitation letters to promote cancer screening activities. »

The intentions are clearly stated. The authors are well aware that providing the most complete information to women incited to be screened, will reduce their participation in screening:

« Previous studies have analyzed the impact of providing a rich amount of detailed medical information concerning the disease (for instance, as in Bourmaud et al. 2016 and Wardle et al. 2016, by including a booklet in the envelope of the invitation letter) on the take-up rate and generally found negative or zero effect ».

They hypothesize that  « ...invitation letters containing a loss-framed message (meaning « loss »to the woman or even risk if she declines to participate in screening, editor’s note) with enhanced information about the consequences of not taking part in the program are more effective at increasing take-up rates than letters with a gain-framed content or with a restricted informational content ».

Thus, this is about pure and simple manipulation, perfectly claimed since the term itself is used several times in the text, and the authors justify this manipulation as necessary for  « limiting women’s cognitive overload »

We wonder about the authors representation of women.

Cognitive overload is defined as follows: "Cognitive overload corresponds to a mental state in which an individual is engaged in the accomplishment of a task that is extremely demanding for him: he does not have sufficient cognitive resources for the easy implementation of this task. » [3]

If we understand correctly the authors, women would not have the mental state necessary to understand the comprehensive information on breast cancer screening. Isn't this a sexist and paternalistic attitude?

In any case, this runs contrary to the "shared medical decision"  that many medical actors claim.…

B- VALUATION OF THE SCREENING AND NEGATION OF ITS RISKS

Right from the introduction, despite the scientific uncertainty about the interest of screening, which has risen since the 2000s, the doubt about the relevance of breast cancer screening by mammography is swept away.

« Mammography screening programs at population-level are a key component of breast cancer control in many countries. The continuous implementation of these policies over the last decades mirrors the current consensus on the effectiveness of mammography screening. »

The authors are, however, forced to admit that there is « uncertainty about the magnitude of the effects of screening on mortality (see e.g. Welch et al. 2016) and the growing evidence on overdiagnosis » by citing a 2012 study and hurrying to downplay the level of overdiagnosis, which is the major adverse effect.

« However, to the best of our knowledge, the estimated extent of overdiagnosis in Italy is low, as it ranges between 1 and 4.6 percent (see the review by Puliti et al. 2012). These data lead us to consider the phenomenon as negligible for our population of interest ».

The authors deliberately disregard the numerous and more recent studies [4] which no longer demonstrate effectiveness of screening in reducing mortality in women, in reducing the rate of the most severe cancers, or to alleviating the treatment inflicted to them.

In addition to the lack of benefit, multiple adverse effects of screening, such as false alarms leading to over-medicalization of women and over-diagnosis, currently estimated at between 30% and 50% and indicating that one out of three cancers detected or even one out of two cancers detected is an unnecessary detection,  should not be ignored[5][6].

In this respect, here is a link to a recent additional study that we already discussed: this research (a review of cross-sectional studies) showed that mammographic screening did not reduce the stage of cancer, nor did it enable cancers to downgrade from the elevated stage to the early stage cancers. The results strongly suggest that it is the adjuvant therapy and not mammographic screening associated with the decrease in specific breast cancer mortality reported since the initiation of these therapies (1990s).

C –CYNISM AND CONFISCATED INFORMATION


Consequently, under no circumstances should women be properly informed or should the risks of participating in the screening be addressed, as the authors have demonstrated. Otherwise, this would decrease the participation in screening, as these Italian authors have well understood,  on the basis of a French study.

« Bourmaud et al. (2016) assessed the effect of providing a 12-page information leaflet on the take-up rate for breast cancer screening of a randomly selected sample of French women. They found a significant negative effect on the take-up rate. »
Later in the text, the authors intentionally skip over the details on disclosed information: « our baseline invitation letter contains no information on the consequences of screening ». And they add: « We show that a negatively-framed message, which adds “cheap” information in the form of brief and general statements about the consequences of screening to the original invitation letter, is able to enhance take-ups ».

In their conclusion, the Italian authors reach what seems to us to be the very height of cynicism by stating: « In addition, the effect of our proposed manipulation is stronger for subjects identified by the literature as being at higher risk of non-participation, such as those living farther away from the screening sites, the low educated and those with no recent screening experience. »

As a result, the less educated women are, the more effective it is to hide and manipulate information for them.

THE FRENCH PARALLEL

A– INVOLVEMENT OF MEDICAL DOCTORS

The potential influential role of the medical profession is not forgotten: « endorsement of the screening program by general practitioners on the invitation letter increased the overall take-up rate, while a letter of reminder was especially effective at increasing the take-up rate of subjects residing in socio-economically deprived areas »

The promoters of screening in France are also well aware of this, having included the "screening mammography" item in the performance-based remuneration of general practitioners [8].

B – THE LACK OF INFORMATION PROVIDED BY OFFICIAL BODIES

The authors of this Italian study state that « the use of letters sent to women at their houses and the invitation for a free and pre-booked mammography increase take-up rates for breast cancer screening »

It should be noted that this is exactly what is being done in France with the organized breast cancer screening program. The citizens' consultation clearly defined the unacceptable gaps in the information provided to women, and in France we are not outdone to regard patients as unworthy to receive quality medical information due to them[9]. In addition, we examined the lack of this information in the material provided by the INCa[10][11].

IN CONCLUSION

-Denial of the risks of mammography screening for breast cancer.

-Assertion against a large majority of clinical research on the effectiveness of screening.

-The manipulation of the letter of invitation to the screening.

-Sexism and paternalism.

This economic study published in July 2020 by Italian authors, with references to other similar studies, including French ones, leaves us with a deeply bitter taste,  on ethics, on the women representation in academic community or on the promotors behavior  of breast cancer screening through mammography.

It should be noted that the majority of those involved in screening justify the assumed manipulation of women for the sole purpose of raising their involvement in the public health system, which has not only failed to prove effective but is also harmful to women's health.

Références


[1]                              https://www.journals.uchicago.edu/doi/10.1086/708930

[2]                          https://www.journals.uchicago.edu/journals/ajhe/about

[3]                              https://www.universalis.fr/encyclopedie/surcharge-cognitive/

[4]                              https://cancer-rose.fr/category/etudes/

[5]                                 https://cancer-rose.fr/2019/09/06/le-depistage-mammographique-un-enjeu-majeur-en-medecine/

[6]                                 https://cancer-rose.fr/2020/01/28/30-000-cancers-surdiagnostiques-par-an-dans-une-etude-australienne-un-enjeu-de-sante-publique/

[7]                              https://www.oncotarget.com/article/7332/text/

[8]                               https://cancer-rose.fr/2020/04/20/la-nouvelle-rosp-quel-changement-pour-le-medecin-concernant-le-depistage-du-cancer-du-sein/

[9]                                 https://cancer-rose.fr/2016/12/15/nouvelles-du-front-premiere-manche/

[10]                               https://cancer-rose.fr/2017/09/17/analyse-critique-du-nouveau-livret-dinformation-de-linca/

[11]                               https://cancer-rose.fr/2018/02/11/2175-2/

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Cancer regression

June 25, 2020, summary by Cécile Bour, MD

G. Welsch, professor at the Center for Surgery and Public Health Brigham and Women's Hospital proposes an analysis of breast cancer screening by MRI in an educational video, using data from the "DENSE" trial (results published in 2019), with the reservations (see comment at the end of the article) that were expressed after the publication of the results in the NEJM.

What is this trial?

This is a randomized trial, of good quality.

Explanation of the method on the video at 1:12 video.

The researchers divide 40,373 women aged between 50 and 75 years of age, with extremely dense breast tissue and negative results on the initial screening mammogram, into two groups: in the " supplementary MRI" group or in the "screening mammogram only" group; more precisely 8,061 women in the "MRI invitation" group and 32,312 women in the "mammogram only" group.

A control mammogram is then performed for both groups after two years  in order to compare the results on the number of cancers found.

The main finding was the difference between the groups in terms of incidence of interval cancers over a two-year screening period.

Additional MRI screening appears to be associated with fewer interval cancers compared to mammography alone in women with extremely dense breast tissue.

Specifically, the researchers found that the interval cancer rate was 2.5 per 1,000 screenings in 4,783 women in the MRI invitation group compared to 5 per 1,324 women in the mammography alone group.

However, in the analysis of these results, one important element is missing, according to G.Welsch: the exhaustive counting of all cancers in both groups.

The fact that there are more cancers in the screening-MRI group compared to the non-MRI group suggests that there are more detections with MRI. But this finding may also suggest something else, supporting the theory of variable kinetics of breast cancers: all cancers do not have same expression pattern, some of them possibly regress.

Regression of cancers?

We remind that this is a randomized trial. Since women are randomly assigned to one or the other group, it is expected that after two years we should have the same overall cancer rate in both groups.Video at 2:03

Cancers not anticipated by screening in women from the group without MRI would be necessarily expected to express themselves at the end of two years on the mammogram performed for both groups at the end of the study.

What is actually observed?

 - No cancer found at the initial mammogram in either group.

 - Globally more cancers found in the MRI group

- Fewer interval cancers in the MRI group

- At the end of the two-year control mammogram for end of the study, more interval cancers in the non-MRI group, as they were not anticipated by MRI.

 - Fewer mammographic cancers at the end of two years for the MRI group since a fraction is anticipated on MRI.

===> In total, we get an excess of 5.4 cancers found in the MRI group (Video 3:34)

G.Welsch explains: in a randomized trial with two random distribution groups, what is expected is that at the end of the study we will have a similar 'total cancer' rate, since cancers not anticipated by MRI in the non-MRI group are logically detected later on the control mammogram done at the end of two years.

The picture illustrates the group of women screened with additional MRI on the left and the control group without MRI on the right. We see in the red column all the cancers detected by MRI resulting in an excess of detection; the green squares indicate the interval cancers which are more present in the group without MRI as they were not anticipated by this examination; the yellow squares symbolize the cancers seen two years later on the mammogram at the end of the trial which are more numerous in the women without the anticipatory MRI. Nevertheless, a comparison of the 'total-cancers' of the two groups clearly shows an excess of cancers for the group with additional MRI.

Now, what happened to those 5.4 excess cancers not found in the non-MRI group, are they cancers that will appear later?

Or have they disappeared?

In general, the explanation put forward is the hyper-slow growth of these cancers, which do not appear during mammography at 2 years of age, not progressing or very very slow  progressing. This would mean that more than half of the cancers found by MRI are hyper-slow-growing cancers so that they are undetectable on mammography. Reminder at 3/30 of the video: we find in the trial 9.8 cancers in the MRI group, 5.4 excess cancers /9.8 total cancers in the MRI group = 0.5

The alternative explanation exists, and it is the cancerous regression, namely the disappearance of these cancers not found on the mammogram for control after two years. They simply disappear. (Editor's note: this hypothesis also emerges from the 2008 Oslo study, where the group of women screened every two years had a 22% excess of cancers detected over the group of women not screened, the two groups being compared after 6 years with a mammogram performed for each group.)

However, if all cancers were inexorably progressing and were expected to manifest themselves, the same number of cancers should be found at the end of the 6-year observation period in regularly screened women and in the non-screened women, in whom the cancers not detected by previous screenings should then be seen on the mammogram at the end of the study, at the end of 6 years. If this is not the case and there is an excess of cancers in the screened group, it is likely that some cancers that did not occur in the unscreened women have disappeared in the meantime.

Cancer regression is observed for other forms of cancer: kidney cancer (1/4 of cancerous lesions regress) of the thyroid (1/3 of cancerous lesions regress). So why not for breast cancer???

The benefit/risk balance

So let's consider the risk/benefit balance of increased MRI monitoring:

video: 6/08.

Overall, the results tends to suggest that the risks associated with increased MRI surveillance of dense breasts outweigh the benefits.

Good news and bad news

There are  good news when it comes to breast cancer. Since the 90s breast cancer mortality has dropped by 40% (i.e. already before the arrival of national screening campaigns, editor's note).

This is an important reduction, according to G.Welsch who reminds us that this drop in mortality is due to therapeutic advances, and not to screening.

Video: 6:20

The bad news according to him is that screening is the target of a technological weapons race, since the first analog mammography, then mammography, the arrival of 3D (tomosynthesis) and now the advent of MRI, all aimed at finding more cancers. For what benefit?

Conclusion of the author

The challenge is not to find more and more cancers inducing unnecessary over-treatment, but to detect those cancers that are important to find because they are a threat to a patient's life.

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Our study: does organized screening really reduce the surgical treatments of breast cancers?

Revue Medecine , Volume 13, numéro 8, Octobre 2017

https://www.jle.com/fr/revues/med/e-docs/le_depistage_organise_permet_il_reellement_dalleger_le_traitement_chirurgical_des_cancers_du_sein__310529/article.phtml

PDF : Etude mastectomies en France -

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Abstract:

Organized screening for breast cancer is still controversial. According to its supporters, it should enable a decrease of treatments, due to earlier diagnoses. This assumption has never been verified in France. The "Programme de médicalisation des systèmes d'information" (PMSI), is an exhaustive census of the surgical treatments achieved in France. Any change in the number of mastectomies for breast cancer must therefore be found in PMSI.

We searched the PMSI databases and found that no decrease in mastectomies, total or partial, can be reported after the generalization of organized screening.

Keywords: breast cancer; mass screening; mastectomy

Robert Vincent 1, Jean Doubovetzky 2, Annette Lexa 3, Philippe Nicot 4, Cécile Bour 5

1 Hôpitaux Robert Schuman, Département d'information médicale (DIM)- Luxembourg

2 Médecin généraliste, rédacteur senior à la Revue Prescrire, Albi

3 Docteur en toxicologie (Eurotox), Metz

4 Médecin généraliste, expert à la HAS, Panazol

5 Radiologue libéral, présidente de l’Association Cancer Rose, Talange 

Introduction

Organized breast cancer screening was generalized in France in 2004. However, it is still a subject of controversy.

In particular, the postulate stating that organized screening allows earlier diagnosis and detects smaller tumors, leading to less aggressive treatments, has not been evaluated in France.

If this really was the case, in parallel with the generalization of screening, we should see a decline in the heaviest treatments, and in particular of total mastectomies. Since 1997, all surgical operations carried out in France during hospitalization have been recorded as part of the Information Systems Medicalization Program (PMSI) [1]. The aim of our work is to verify whether,  the generalization of organized breast cancer screening in France has been accompanied by a reduction in the number of the most mutilating surgical operations, by studying the annual progression of the number of mastectomies for cancer recorded within the framework of the PMSI.

Materials and methods

The number of mastectomies was estimated from data extracted from the ScanSanté PMSI data recovery platform [2]. The research covered all the territories in France and all types of establishments, both public and private.

The ScanSanté queries were carried out on :

- "Total mastectomies for malignant tumors" (root of GHM 09C04);

- “Subtotal mastectomies for malignant tumors" (root of GHM 09C05) [1] [3].

The number of total mastectomies was lowered by the number of "prophylactic breast ablations".This means that admissions with a main diagnosis Z40.00 were subtracted from admissions classified in the root 09C04.

The PMSI is generally only considered exhaustive from the year 2000 onwards. Data prior to the year 2000 are therefore potentially underestimated and have not been taken into account.

Raw data on the number of mastectomies have been completed by estimating the ratios [annual number of mastectomies/annual incidence of breast cancer]. These ratios could only be calculated for the four years 2000, 2005, 2010 and 2012, for which the incidence of breast cancer in France is available [2].

The number of total mastectomies performed in the last 4 years prior to organized screening (period 2000 to 2003) was compared with the number of total mastectomies performed in the last 4 years with organized screening (period 2013 to 2016).

The trend in the annual number of mastectomies was investigated using a graphical method with linear trend line, completed by a Spearman rank correlation test. For comparisons between 2 periods, confidence intervals were determined by bootstrap resampling with 105 replicates. The significance threshold considered is the usual threshold of 0.05.

All the statistical analyses were carried out using R software version 3.0.2.

Results

As shown in Table 1 and Figure 1, the annual number of total mastectomies for cancer tends to increase over the period 2000 to 2016.

This upward trend is statistically significant (p < 0.0002 on Spearman's rank correlation test).

The comparison of the last 4 years without organized screening (period 2000 to 2003) with the last 4 years with organized screening (period 2013 to 2016) shows that during the period 2013 to 2016, on average 1,615 more total mastectomies were performed each year compared to the period 2000 to 2003 (95% CI: 1010-2280).

Click to enlarge

Table 1 and Graph 2 show that the number of mastectomies of all types (total + partial) is also increasing considerably between 2000 and 2016.

This upward trend is statistically significant (p < 10-7 in Spearman's rank correlation test).

A comparison of the last 4 years without organized screening (period 2000 to 2003) with the last 4 years with organized screening (period 2013 to 2016) shows that during the period 2013 to 2016, on average, 13,389 more mastectomies (all types) were performed each year compared to the period 2000 to 2003 (95% CI: 9,610-17,160).

Table 2 shows the ratios [number of mastectomies / incidence of breast cancer]. These ratios are stable, between 0.38 and 0.41, in the case of total mastectomies.

The data show an increasing trend between 2000 and 2012 for partial mastectomies and mastectomies of all types.

Click to enlarge.

Discussion

The PMSI is the only comprehensive source of information on surgical activity in France. It is mainly used for invoicing hospital stays. However, previous studies have shown that the PMSI can be used for epidemiological analyses, particularly regarding breast cancer [3,4].

If organized screening had been accompanied by a decrease in the number of mastectomies for cancer performed in France, this decrease should be reflected by an equivalent decrease in the number of mastectomies recorded in the PMSI databases. However this is not consistent with the observed results. On the contrary, there is a statistically significant increase in total mastectomies as well as all mastectomies of all types combined.

The stability over time of the ratios between total mastectomy / breast cancer incidence shows that the increase in the number of total mastectomies is parallel to the increase in the number of diagnosed invasive breast cancers. Thus, in 2012, 8 years after the generalization of organized screening, there still were practiced 4 total mastectomies for every 10 new invasive breast cancers, exactly as in 2000, before the generalization of organized screening.

The increasing trend over time in the ratios of partial mastectomies/ breast cancer incidence and ratio of mastectomies of all types / breast cancer incidence suggests that the increase in interventions involving partial mastectomies for cancer is higher than the increase in the incidence of invasive breast cancer.

For example, in 2012, there were nearly 15 procedures involving mastectomy for 10 new invasive breast cancers, compared to less than 13 procedures for 10 new cancers in 2000.

One of the possible explanations could be the over-treatments associated with over-diagnosis. Indeed, according to the authors, in 30% to 52% of cases, screening leads to the discovery of small or slowly progressing cancerous lesions, which would have remained asymptomatic throughout the patient's life. As a precaution, all lesions are treated and their discovery leads to their surgical removal, most often by partial mastectomy [5,6].

It is also possible that partial mastectomies secondarily followed by total mastectomies are being performed in higher number; in other words, it is possible that a certain number of women who were in the past directly treated by total mastectomy are now undergoing a partial mastectomy prior to undergoing secondarily a total mastectomy. However, this mechanism could only play a very small role, since according to the National Health Insurance Fund, in 2012 only 3% of lumpectomies were followed by mastectomy [7].

Hospitalization services are better remunerated for total mastectomies (root 09C04) than for partial mastectomies (root 09C05). It may also be speculated  that there is an over-coding bias in total mastectomies, related to financial motivation. This interpretation is unlikely, for at least two reasons:

- On the one hand, if there were an abusive increase in coding for "total mastectomy" (09C04), it would be done to the detriment of coding for "partial mastectomy" (09C05), which should therefore be decreasing. However, the data available on ScanSanté show that partial mastectomies are on the contrary increasing, and even faster than total mastectomies.

- On the other hand, overcoding would change the balance between the number of total mastectomies recorded in the PMSI and the number of breast cancers. This would result in an increase in the ratios of total mastectomies/ breast cancer incidence, parallel to the increase in total mastectomies. On the contrary, our results show a stability of these ratios.

Our results are consistent with those found in other countries :

- In the United States, in a 2015 study of 16 million women, a 10% increase in screening activity was associated with a nearly 25% increase in lumpectomies and partial mastectomies (RR 1.24; CI 1.15-1.34), without a decrease in total mastectomies [8].

- In the United Kingdom, according to the 2013 Marmot report on breast cancer screening, the frequency of mastectomies is increased by about 20% in the screened population compared to the unscreened population [9].

- For all the randomized controlled trials worldwide that examined this issue in 2013, the Cochrane Collaboration estimates that the number of mastectomies is increased by 20% (RR 1.20; 95% CI 1.08-1.32) and the number of surgical procedures (mastectomies and lumpectomies) is increased by 30% (RR 1.31; 95% CI 1.22-1.42) [10].

Conclusions for practice

PMSI data show that there has been no reduction in surgical treatment of breast cancer in France since the generalization of organized screening.

On the contrary, both the number of total mastectomies and the number of partial mastectomies continue to increase despite current recommendations to favor conservative surgery whenever possible. Whether organized screening is contributing to this increase through over-diagnosis should be investigated.

The authors declare that they have no conflict of interest in relation to the content of this article.

References.

Références.

  1. Manuel des Groupes Homogènes de Malades - Version 2016 de la classification. Bulletin officiel No 2016/5 bis Fascicule spécial.
  2. Binder-Foucard F, Belot A, Delafosse P, Remontet L, Woronoff AS, Bossard N. Estimation nationale de l’incidence et de la mortalité par cancer en France entre 1980 et 2012. Partie 1 – Tumeurs solides. Saint-Maurice (Fra) : Institut de veille sanitaire, 2013. 122 p. (Page 55 du document)
  • Trombert Paviot B, Gomez F, Olive F, Polazzi S, Remontet L, Bossard N et al. Identifying Prevalent Cases of Breast Cancer in the French Case-mix Databases. Med. 2011;50(2):124-30. doi : https://doi.org/10.3414/ME09-01-0064
  • Quantin C, Benzenine E, Hägi M, Auverlot B, Abrahamowicz M, Cottenet J et al. Evaluation de l’intérêt de l’utilisation des données du PMSI pour l’estimation de l’incidence du cancer du sein dans deux départements français. Rev Epidemiol Sante Publique 2010 ; 58 (Suppl. 1) : S14.
  • Jørgensen KJ, Gøtzsche PC. Overdiagnosis in publicly organised mammography screening programmes: systematic review of incidence trends. BmJ. 2009 Jul 9;339:b2587.
  • Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 2012;367:1998-2005.
  • Améliorer la qualité du système de santé et maîtriser les dépenses : proposition de l’Assurance Maladie pour 2015. Rapport au Ministre chargé de la sécurité Sociale et au Parlement sur l’évolution des charges et des produits de l’Assurance maladie au titre de 2015 (loi du 13 août 2014) ; page 62.
  • Harding C, Pompei F, Burmistrov D, Welch HG, Abebe R, Wilson R. Breast Cancer Screening, Incidence, and Mortality Across US Counties. JAMA Intern Med. 2015 Sep;175(9):1483–9.

9- Baum M. Harms from breast cancer screening outweigh benefits if death caused by treatment is included. BMJ 2013 ; 346 : f385. doi : https://doi.org/10.1136/bmj.f385

10- Gøtzsche PC, Jørgensen KJ. Screening for breast cancer with mammography. Cochrane Database of Systematic Reviews 2013 ; 4;(6) : CD001877. doi: https://doi.org/10.1002/14651858.CD001877.pub5

[1] Developed progressively from 1982 onwards, the PMSI aims to describe hospitalizations by classifying them into groups with similar characteristics, the Homogeneous Groups of Patients (HGP). Since 1995, public establishments have been required to provide their data. In 1997, the PMSI was extended to private establishments. It is generally considered that data became quasi-exhaustive from the year 2000 onwards.

[2] The PMSI data are publicly available to all, health care actors and the general public, on a national platform with open access, managed by the Agence technique de l'information sur l'hospitalisation (ATIH). This platform is called ScanSanté and can be consulted at: https://www.scansante.fr/

[3] At the end of a patient's hospitalization, the reason for admission, co-morbidities and procedures performed during the stay are coded to enable their electronic processing. Each hospital stay is then classified in a GHM root, based on the reason for admission and any surgical procedures performed. Thus, the root of GHM 09C04 corresponds, by definition, to hospital stays with an admission reason related to breast cancer and including a total mastectomy surgery. Similarly, the root of GHM 09C05 corresponds, by definition, to hospital stays with an admission reason related to breast cancer and involving a partial mastectomy.

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Main conclusions

Overall, there is as much surgery in 2016 as there were in 2000. In the official recommendations, there should be an increasing tendency to favor conservative surgery whenever possible. It is certain that, despite this declared willingness to favor conservative surgery, the annual number of total mastectomies is not decreasing. What we have also shown is that the number of total mastectomies in relation to the incidence of invasive cancers has not decreased either.

There are two possible explanations:

- either surgery is not more conservative in 2016 than in 2000 (i.e. recommendations favoring conservative surgery whenever possible are not followed; this negates the expected benefit of screening),

- or total mastectomies are performed for non-invasive tumors (over-treatment associated with over-diagnosis) and these additional total mastectomies cause the loss of the benefit of a general trend towards more conservative surgery.

READ MORE :

Explanation of our study

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Mammography screening: a major issue in medicine

Authors: Philippe Autier, Matthieu Boniol *

Abstract, C.Bour, MD

January 3, 2018

*Strathclyde University Institute for Global Public Health at IPRI, European Prevention Research Institute, European Area, Building G, Allée Claude Debussy, 69130 Lyon Ecully, France

*International Prevention Research Institute (iPRI), 95 Cours Lafayette, 69006 Lyon, France

https://www.sciencedirect.com/science/article/pii/S0959804917313850

In this publication to be published in the February issue of the European Journal of Cancer, the authors provide a comprehensive review of mammography screening from several perspectives: effectiveness, criteria for evaluating its effectiveness, economic aspect, over-diagnosis, over-treatment, criticism of the methodology of the studies that founded the first campaigns, natural history of the disease, screening, high-risk women, etc... and they make a comparison with the others screenings that, according to them, are effective in terms of reducing mortality, namely cervical and colon cancer, in order to analyze why screening for breast cancer has ended in the failure that we know today.

A comparison is also presented with the case of neuroblastoma screening, which finished in a similar deadlock to that of breast cancer screening, due to similarities in the epidemiological features of the screening for this cancer.

The highlights

After 20–30 years of mammography screening, the incidence rates of advanced and metastatic breast cancer have remained stable.

Breast cancer mortality rates have not decreased more rapidly in areas where mammography is in place since the late 1980s.

One third to one half of mammography-detected breast cancers would not have been clinical during lifetime (overdiagnosis).

Breast screening randomised trials have adopted distinctive methods that led to exaggerating the efficacy of screening.

The influence mammography screening may have on mortality decreases with the increasing efficiency of cancer therapies.

Two indicators for screening effectiveness

Methods for evaluating the effectiveness of cancer screening are based on :

- monitoring incidence rate adjusted according to the age of advanced cancers, that would be expected to decrease after the introduction of screening.

- mortality rates specific to cancer would be expected to decrease more rapidly in areas where screening is performed than in areas where level of screening is lower but patient management is similar.

However, the accumulation of epidemiological data shows that in populations where mammography screening has been widely practiced for a long time, there has been little or no decrease in the incidence of advanced cancers, and that reduction in breast cancer mortality  in areas with early introduction and high screening penetration is similar to whose in the areas with late introduction and low screening penetration. Reductions in cancer mortality rates in the different randomized trials were expected to be proportional to reductions in advanced cancer rates, which was not the case, and in addition we are faced with the unexpected problem of significant over-diagnosis and consequent over-treatment, as evidenced by the increase in the rate of radical mastectomies seen in many countries. (See 12 studies on the non-reduction of advanced cancers [1].

Parallelism with the history of neuroblastoma

Screening for neuroblastoma in children was abandoned in the early 2000s because these two criteria of effectiveness were not met. In addition, over-diagnosis - the detection of non-evolving occult neuroblastoma that would not have endangered the individual over the course of his or her life - is a major undesirable consequence of screening.

The epidemiological picture of mammography screening closely looks like whose of neuroblastoma screening.

Results of first trials, the studies

Breast cancer screening advocates have favored studies that were consistent with the results of the first trials (New York [2] and the two Swedish counties [3] trials), while minimizing over-diagnosis. These trials had never been contested, but a re-evaluation by the authors of this publication shows major problems (4 mainly) of methodology, which enabled advocates of screening to significantly overestimate the benefit in terms of mortality reduction and minimize over-diagnosis.

So-called IBM studies [4] [5] [6] [7] [8] [9] [10] [11] (based on the incidence of breast cancer mortality) compared breast cancer mortality in screened and unscreened populations over time. These studies based on breast cancer mortality incidence and case-control studies were then used to evaluate the effectiveness of screening. But they are flawed by contradictions.

They had a strong "ecological" bias and did not meet the methodological criteria defined in the CIRC Manual published in 2002 [12]. Adjustments are needed in these studies (on lead time and on the increase in breast cancer incidence), moreover two Norwegian IBM studies which were the most compliant ref 4, 8 with the CIRC criteria found no significant influence of screening mammography on the risk of death from breast cancer.

Two contradictions emerge: how can screening be effective when, in populations where most women have participated in screening mammography for decades, the incidence rates of advanced breast cancer have not decreased at all or only moderately? Screening proponents have nevertheless tried to show that such decreases in advanced cancer rates are indeed observed, but the methodologies are not appropriate. Another contradiction is the impossibility to link the astonishing mortality reductions of 25-31% in breast cancer mortality that have been put forward with the lack of real observed reduction in breast cancer mortality in countries that have rapidly adopted mass screening.

Another unsolved problem is the natural history of cancer. Every small asymptomatic breast cancer detected by screening does not automatically become symptomatic advanced breast cancer. And a serious high-grade cancer is not the result of a small one that was prevented from becoming serious by anticipation. Unfortunately, current evidence indicates that the ability of screening mammography is insufficient to detect these more advanced breast cancers. We do not know the growth patterns of breast cancer and the mechanisms involved in metastatic spread, contrary to a fundamental principle before screening can be implemented, namely that the natural history of the disease, including the development from latent to declared disease, must be well known".

To summarize

The early Swedish trials overestimated the reductions in breast cancer mortality related to screening, partly because of biases in the statistical analyses, some of which were deliberately due to under-reporting of breast cancer in the selected groups. On the other hand, many models assumed that if screening did not take place, the majority of asymptomatic cancers detected by screening would have progressed to symptomatic advanced cancers. The accumulation of demographic data in well-selected populations invalidates the relevance of these initially admitted models, based on a linear evolution of the disease.

The promoters of screening have voluntarily rejected studies that did not show a decline in mortality, such as the Euroscreen Group convened by the the CIRC for to asses the procedure in 2015 [13]. But since then, many major, independent and large-scale studies (from Harding in the USA 2015 [14] [15] or the impact studies by Bleyer and Miller [16] [17] ) have added further evidence of a questionable, minor effectiveness of mammography screening, which in any case does not reflect what was expected.

The example of the Netherlands

 study Autier, The Netherlands

analysis study Netherlands

From 1988 onwards, the national breast cancer screening program in the Netherlands invited women between 50 and 75 years of age to undergo a biennial mammography screening, with a consistently high participation rate of about 80% among women. Despite a high participation in screening for 23 years, the incidence of stage II-IV breast cancer has not improved over time for women aged 50 and over, ranging from 168 per 100,000 in 1989 to 166 per 100,000 in 2012.

The Dutch mammography screening program would have had only a marginal effect on breast cancer mortality.

Similar results are found in other studies (Europe, USA, Australia); furthermore, no association was found between the magnitude of the downward trends in breast cancer mortality and the timing of the implementation of mammography screening in the different states of the United States as evidenced in the Bleyer and Miller impact study ref [16] [17].

According to the authors, population studies using a variety of models would provide convincing evidence that it is rather therapeutic advances that have a favourable influence on breast cancer mortality.

The particularity of the cancers detected during mammography screening, is that less aggressive cancers with better prognosis are selected.

Mammography has a high sensitivity for ductal carcinoma in situ, for example, and a relatively low sensitivity for certain aggressive cancers such as triple negative breast cancer [18] [19]. Mammography practically does not detect in situ or invasive lobular carcinomas, which account for 8-14% of all breast cancers [20] . Lobular carcinomas infiltrate the tissue without forming masses, making them difficult to detect by mammography.

Compared to interval cancers, i.e., those that progress rapidly between mammograms and have aggressive characteristics, invasive cancers detected by mammography have the clinical and pathological characteristics of less aggressive tumors.

Moreover, after examining the features of these tumors and the extent of the disease at the time of diagnosis, the risk of dying from a detected breast cancer is lower than the risk of dying from an interval cancer [21][22][23]. Thus, the fact that a breast cancer has been detected by mammography is in itself a good prognostic factor. Therefore, the method of detection should be considered when estimating a patient's prognosis [24].

“Precursor” lesions

The chronological model of successive stages describes reasonably well the progression from normal tissue to the benign lesion and then to the malignant tumor observed in the majority of colorectal and cervical cancers. It was believed that the model would also be applicable to other cancers, including breast cancer.

However, epidemiological and clinical observations, such as the stable incidence of metastatic (i.e. stage IV) breast cancer in populations that are screened, call into question the validity of this model for describing the natural history of many breast cancers. Rather, these observations are consistent with the hypothesis of a "cancer spectrum", whereby breast cancers consist of a set of malignant lesions that are highly heterogeneous in their ability to invade surrounding tissues and metastasize to distant lymph nodes or organs [25].

Most of these lesions would constitute a reservoir of asymptomatic tumors that would remain indolent or would grow slowly, with rare progression to symptomatic disease. Because of their long detectable sub-clinical period (i.e., the period without clinical signs in the breast), these lesions would represent the main findings of screening mammography and other breast imaging techniques [26].

At the other end of the spectrum, tumors with high metastatic potential would grow rapidly and metastases would already be present in lymph nodes and distant organs when the tumor is detected [27].

Due to the short residence time of rapidly evolving and aggressive cancer, the window of opportunity for its detection before metastatic spread would be very narrow.

Grade, size and stage could reflect the intrinsic malignant potential of a cancer. Since high-grade cancers develop and metastasize rapidly, their size at diagnosis is generally greater than that of low-grade cancers that develop slowly and are not expected to metastasize.

Overdiagnosis

Overdiagnosis of cancer corresponds to the excess of cancers in women invited for screening divided by the total number of cancers that would have been diagnosed in the absence of screening (on a population with the same profile, same age group, without screening).

Over-diagnosis occurs in women attending screening.

If over-diagnosis is calculated using the number of cancers detected at screening as the denominator, then for every 100 breast cancers detected by screening, 30-50 would be over-diagnosed [28] [29].

An interesting observation is that, compared to breast cancers diagnosed in the absence of screening, interval breast cancers are not more deadly and do not have clinicopathological features of more aggressive cancer [30] [31].

If interval cancers are similar to cancers diagnosed in the absence of any screening, and if the cancers detected have a better prognosis on average than interval cancers, it follows logically  that a proportion of cancers detected are non-lethal cancers that would never have been symptomatic during a woman's lifetime.  Under the microscope, these lesions have the morphological features of cancer, but  if screening had not taken place, they would have remained asymptomatic during the woman's lifetime. This phenomenon is called "over-diagnosis", and is first highlighted by the Oslo experience comparing a group of unscreened women to a group of screened women, in which 22% of cancers in excess were reported.

(Editor's note Zahl P-H, Gøtzsche PC, mæhlen J. Natural history of breast cancers detected in the Swedish mammography screening programme: a cohort study. The Lancet Oncology. 2011 Nov;12(12):1118–24.).

The first evaluations, the Canadian one of Miller [32] and the Oslo one [33] considered only invasive cancers alone, without any quantification of in situ cancers. This group, however, is also a major cause of over-diagnosis, especially since it is known that their treatment neither prevents the occurrence of invasive cancers nor reduces their recurrence (see next chapter on CIS).

The sudden drop in incidence in 2002 coincided with the mass discontinuation of hormone replacement therapy after the publication of the Women's Health Initiative trial [34]. The incidence of DCIS in women aged 50 years and older increased from 10 per 100,000 in the 1980s to about 90 per 100,000 in the 2000s. In 2008, the excess incidence was estimated to be 31% of all breast cancers diagnosed in the United States, consisting mainly of DCIS and stage I cancers. [35]

If a large proportion of breast cancers diagnosed in  excess after 1986 were due to advancements in diagnosis, therefore proportional decreases in incidence ratio should have been observed for older women.

Screening by mammography or other imaging modalities preferentially detects these lesions that are not or are mildly aggressive. This is the case for most low-grade DCIS, for instance, but also for atypical epithelial lesions as well. The natural evolution of these lesions is poorly known. However, assuming that cancer develops later, doctors are inclined to treat most of these abnormalities.

CIS (carcinomas in situ)

They represent an over-diagnosis because these lesions are treated despite our limited knowledge of their long-term evolution. Trials and studies show that the greater detection of CIS has not led to a reduction in breast cancer mortality. Before the period of screening, CIS accounted for less than 5% of all breast cancers. In areas where screening mammography is used widely, 15-20% of breast cancers are CIS [36].

Moreover, there is a lack of a real consensus among anatomist-pathologists on the classification of such lesions during biopsies, with a tendency to upgrade them to poorer prognosis categories, for fear of underestimating the disease [37].

Most CIS are non-mandatory precursors of invasive cancer, because the spectacular increase in their detection accompanied by surgical removal was not followed by a proportional decreases in the incidence of invasive cancers [38] [39] .

The long-term consequences of overtreatment can be life-threatening. For example, radiation therapy on these lesions appears to be unable to reduce the risk of death from breast cancer, but is associated with a dose-dependent (10-100% over 20 years) increase in the incidence of major coronary events [40].

Over-diagnosis often has a considerable disruptive effect on the interpretation of clinical results expressed as percentages (instead of raw rates) or as overall survival (instead of mortality rates or staging specific survival), artificially improving these data which in no way reflect the effectiveness of the screening practice.

Overtreatment, mastectomies

In randomized trials, rates of radical mastectomy were highest among women invited for screening. In the Netherlands and the United Kingdom, rates of radical mastectomy increased in the years following the implementation of screening programs. In the United States, a rebound in the rate of radical mastectomies has been observed since 2005. [41] [42][43] [44][45] [46] 

The resurgence of radical mastectomies has been encouraged by the use of preoperative magnetic resonance imaging (MRI) to assess the extent of the cancer and look for malignant lesions in the contralateral breast or multifocal.

MRI has the potential to discover satellite cancer sites, but the clinical outcome of these sites is unknown. Multiple examinations attest to the unfavorable benefit-risk balance of preoperative MRI [47] [48].

Editor's note: see our study on mastectomies in France, published in the October 2017 issue of the Revue Médecine, to be found here :

Study in Médecine/oct 2017

With the analysis here: CR study analysis

The effect of the treatment

A recent study by Prof. Autier suggests that access to effective adjuvant and chemotherapeutic treatments modifies the reduction in the risk of death from breast cancer initially reported by randomized trials[49].

Consequently, with the advent of effective treatments, the necessary number of women needed to be screened to prevent a single death from breast cancer is increasing.

In other words, the ability of the treatments to reduce breast cancer mortality, makes the mortality reduction from screening all the more negligible and inexistent, and even more women will need to be screened to be able to achieve an avoided death that would be prevented by screening rather than by the available treatments.

The imbalance between the effectiveness of screening and over-diagnosis enhances the potential for powerful treatments to reduce breast cancer mortality on their own.

Criticism of the method

A critical review of the literature promptly demonstrates that most studies are based on short-term designs focusing on the ability of different technologies to detect asymptomatic lesions labeled "cancer" after microscopic examination. In addition, many studies have unfortunately considered percentages of lesions by size, or percentages of more favorable grades of the detected cancers, and have reported on statistics of overall survival. These findings are not adequate to evaluate the effectiveness of screening, since we have seen that over-detection is more favorably linked to the lower grades, and artificially increases survival rates by finding lesions that would not have been lethal anyway.

These higher detection rates unfortunately do not translate into fewer advanced breast cancers or fewer breast cancer deaths. The emphasis on detection rates, even in randomized trials, may simply reveal the greater ability of a particular detection method to draw from the reservoir of slowly progressing or progressing tumors, to select those same lesions, according to the adage of "the more you look, the more you find" [50].

The transition from analog to digital mammography has not been accompanied by a decrease in the rate of interval or advanced breast cancers, while false positives, over-diagnosis, and costs have increased, mainly due to increased CIS detection [51].

Priority should be given to studies that can demonstrate that the use of a new screening technique can actually reduce the incidence of interval cancer or advanced cancers, at the cost of acceptable rates for recall and biopsy and limited over-diagnosis.

What is happening elsewhere, public health policies

The Swiss Medical Board has concluded that most of the original evidence is outdated and therefore screening mammography programs should be terminated [52].

The opposite point of view is held by the American College of Radiology, which recommends annual mammography for asymptomatic women from the age of 40 and without limit [53].

Editor's note: we are updating this statement in 2019, as we are now observing across the Atlantic a de-escalation of screening recommendations through the new guidance notes of the American College of Physicians (ACP)[54].

The evaluation of the screening mammography program in Norway rightly concludes that "at the individual level ... each invited woman must weigh information about potential benefits and harms according to her own values, health and life situation to decide whether or not to participate in the program"[55].

The polarization of visions:

In this context of polarized opinions and the pursuit of incentive messages to women, and the weakness of available loyal information, it is difficult to imagine that we can achieve to a consensual information on the harms and benefits of breast cancer screening given to the women and whole society. An alternative might be to inform about divergences between different experts, letting the women make their choice in any case[56] [57].

Personalized screening, prioritized according to risk[58]

- Although attractive, a personalized breast cancer screening strategy encounters major difficulties. First, there is little evidence that more frequent screening (i.e., annually with other imaging of breast techniques) would be more effective than biennial or triennial screening.

- A second difficulty is related to the available data on the factors (or combination of factors) that would identify the asymptomatic women as having an intermediate risk of death from breast cancer. Since screening is supposed to prevent breast cancer death but increases the likelihood of being cancer carrier (over-diagnosis), the risk factors should be those for the risk of breast cancer death, not those for the risk of breast cancer occurrence. Studies to document risk-based screening strategies have generally focused on factors associated with the occurrence of breast cancer and rarely on factors associated with death from breast cancer. Risk factors for breast cancer and risk factors for dying from breast cancer do not necessarily coincide [59].

- Much remains to be learned about genetic determinants and the importance of breast density (related to cancer occurrence and mortality). We also need to learn more about the relationship between this breast density factor and other risk factors such as obesity or atypical breast hyperplasia [60].

Breast imaging technologies such as ultrasound, tomosynthesis and MRI find cancers missed by mammography in dense breasts, and the use of alternative breast imaging techniques is encouraged in women with dense breasts, particularly in the USA. However, there is still no evidence that such an approach would decrease the risk of death from breast cancer, while it certainly increases the risk of false positives, unnecessary biopsies and over-diagnosis. A good option to get around these many problems associated with breast density is to avoid screening mammography before the age of 50, especially since the risk/benefit balance in this age group is uncertain[61].

Currently there are risk calculators that attempt to assess which women would be at risk, including various factors.

 Particular case of women at high risk of breast cancer

Women at high risk of breast cancer, such as women carrying the BRCA1/2 mutation, have a 30 % or greater lifetime risk of developing breast cancer, with an early onset before the age of 50, a high risk of contralateral breast cancer and, depending on the hereditary trait (e.g. BRCA2 mutation), an increased risk for ovarian cancer. They require close monitoring of the breasts: MRI is recommended in these cases [62].

There is no evidence that more frequent mammography screening or screening with other modalities actually reduces the risk of death from breast cancer in women with an intermediate risk of breast cancer (10-29% risk), including women with extremely high breast density,  .

Since 1985, advances in the management of breast cancer patients have resulted in a marked reduction in breast cancer mortality, even in patients with disseminated (stage IV) disease. In contrast, epidemiological data indicate a marginal contribution of mammography screening on the decline in mortality from breast cancer. The more effective the treatments, the less favorable the benefit/risk balance of screening mammography.

Very high-risk women with a BRCA1 or BRCA2 mutation have a 50-85% lifetime risk of breast cancer; these high-risk women represent a context of psychological and medical problems that have nothing in common with women at medium or intermediate risk of breast cancer.

The critical question remains unanswered: to what extent can regular breast surveillance  with mammography and MRI prevent the onset of an advanced cancer and death from breast cancer in high-risk women?

Conducting a randomized trial to evaluate the effectiveness of screening in high-risk women (comparing a group of women who are followed and a group who are not) is obviously ethically indefensible, and many high-risk women will probably not consent to be in the control group of such a trial.

Recent studies indicate rather systematically  that annual surveillance of high-risk women by MRI, with or without other techniques (e.g. mammography and/or ultrasound), avoid to miss interval cancers within a year of screening [63][64][65][66]

These findings suggest that annual MRI screening by experienced radiology teams could be an alternative to more radical options for reducing risks

To conclude

- Evidence shows that in populations where mammography has had high penetration over the past 20-30 years, screening mammography has had little or no influence on the burden of advanced breast cancer and no influence on metastatic breast cancer in women. The authors claim that meta-analyses of randomized trials of breast cancer screening largely overestimated the reductions in breast cancer risk that could be expected from screening mammography.

- Over-diagnosis is a source of considerable harm to women who undergo screening mammography. The medical community's recognition  of the concept of over-diagnosis of cancer has been slow, but  it is no longer acceptable to minimize the burden of it nor its consequences in 2017. According to the authors, probably in 10 years, if we continue in this way, one woman in six will be diagnosed with breast cancer during her lifetime, without any certainty that the risk of death from breast cancer will actually be reduced, but with the certainty that the overall harm induced by screening will only increase.

- While screening mammography has some influence on breast cancer mortality, this influence diminishes, as patient care progresses. This means that the more effective patient care, the more women need to be screened to finally see a breast cancer death prevented by screening.

 - Current evidence indicates that the capacity of screening mammography (and probably other breast imaging technics ) is restricted for the "catch up" of breast cancers before they reach more advanced stages. This essentially reflects our ignorance of the growth patterns of breast cancer and of the mechanisms involved in metastatic spread. This ignorance runs counter to the seventh principle on screening formulated by Wilson and Jungner [67], according to which "the natural history of the disease, including the development from latent to declared disease, should be well understood".

 - According to the authors, since 2016 there has been strong evidence  that improvements in patient care have played a major role in the observed reductions in breast cancer mortality in Europe, Oceania and North America, while the impact of screening mammography has been marginal. Decision-makers struggling to implement affordable and equitable national cancer control plans must be aware of the serious data gaps that are often presented as incontestable to them.

- To justify the perpetuation of screening mammography, some may support the cynical view that all medical activity leads to harm due to over-diagnosis: for example, treating the high blood pressure of a person who would never have died of cardiovascular disease. But breast cancer screening is not about simply taking a pill, but about the threat of life-long damage due to mutilation, over-treatment and psychological distress, with no gain in terms of reduction of the risk of death from breast cancer.

- An increasingly high detection rate indicates little about the ability to prevent interval or advanced cancers; it simply reflects additional over-diagnosis. Prior to the implementation of new breast imaging technologies studies based on the incidence of advanced cancers and the assessment of over-diagnosis will need to be conducted

 -Screening according to the risk level should be researched so that screening recommendations can be tailored to the risk of death from  breast cancer in women.

- Regarding costs: most of the economic evaluations carried out in the 1990s ignored or underestimated the costs due to over-diagnosis, which are estimated to be approximately US$ 4 billion per year in the U.S. [68].

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N Engl J Med 2016; 375: 1438-1447 13 octobre 2016 DOI: 10.1056 / NEJMoa1600249

[30] LH Holmberg, L. Tabar, HO Adami, R. Bergstrom Survival in breast cancer diagnosed between mammographic screening examinations Lancet, 2 (8497) (1986), pp. 27-30

[31] M. Kalager, RM Tamimi, M. Bretthauer, HO Adami Prognosis in women with interval breast cancer: population based observational cohort study BMJ, 345 (2012), article e7536

[32] https://www.bmj.com/content/348/bmj.g366

[33] https://pss17.files.wordpress.com/2009/01/historianatural_invasivosmama.pdf

The natural history of invasive breast cancers detected by screening mammography, Archives of Internal Medicine, 24/11/08 Per-Henrik Zahl, Jan Mæhlen, H. Gilbert Welch

[34] JE Rossouw, GL Anderson, RL Prentice, AZ LaCroix, C. Kooperberg, ML Stefanick, et al.Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial Jama, 288 (3) (2002), pp. 321-333

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[52] N. Biller-Andorno, P. Juni

Abolishing mammography screening programs? A view from the Swiss Medical Board N Engl J Med, 370 (21) (2014), pp. 1965-1967

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Data on reducing breast cancer mortality in women aged 70-74 are mitigated; although data from randomized controlled trials are limited in this age group, there is agreement on screening women at average risk from age 50 to 74. There is no reduction in all-cause mortality among women aged 50 to 69 years. Most guidelines recommend biennial mammography as an acceptable or preferred option for women undergoing screening.

Decreasing the interval exposes women to an increased risk of over-diagnosis. Below and above this age range, the disadvantages outweigh the expected benefit.

There is insufficient evidence of effectiveness for screening by clinical palpation alone or in combination with mammography.

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Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Perception and reality

How women perceive the data from screening, influenced by optimistic  slogans and presentations, versus reality:

When the authors of the report of the Swiss Medical Board (a Swiss medical commission independent from government authorities) evaluated the relevance of the mammographic screening program for breast cancer (see article), (PDF Article) they looked at one data that had been studied in several countries (4), namely how women perceive the benefits of screening according to what has been communicated about it and the information they have received, and who have made their beliefs on the subject.

The authors have presented a comparative table, with data gathered from the perception survey of American women in Part A, and real, objective data from the most probable scenarios, observed from the most convincing and among the most reliable studies in Part B (1-3)

The authors were astonished by the significant discrepancy between women's beliefs about the benefits of screening and reality.

https://boris.unibe.ch/51602/7/Biller-Andorno%20NEnglJMed%202014.pdf

The projected number of women in their fifties who would survive, develop breast cancer and die from other causes while doing regularly screening over 10 years was compared to the expected number of women  who would survive, develop breast cancer or die from other causes, and not doing screening.

71.5% of these interviewed American women estimated that screening mammography reduced by half the risk of dying from breast cancer, and 72.1% believed that at least 80 deaths would be prevented for every 1,000 women invited for screening.

The presentation of mortality risk reduction as a percentage embellishes the data.

A 20% reduction in mortality (a figure found on public institution websites, women committees websites and in the information brochures distributed to women) does not mean that 20 out of every 100 women will die of breast cancer, but that only one less woman will die of it in the best case (and without considering the other, more numerous women screened, who will at the same time suffer from overdiagnosis and false alarms).

The relative risk reduction of 20% corresponds to a comparison between the screened and unscreened groups. If, for example, 5 out of 1000 unscreened women die and 4 out of 1000 screened women die of breast cancer, the relative risk reduction resulting from the comparison of these two groups corresponds to this 20% (5-4/5=0.2), but in absolute terms it is only one woman who is saved. The data that the authors have collected for the Swiss population show also these optimistic expectations in a similar way.

The authors legitimately ask the question, how can women make an informed decision if the benefits of the screening program are overestimated?

We asked ourselves the same question...and tried to answer it (see the brochure on the home page).

RÉFÉRENCES

  1.  

Gotzsche PC, Jorgensen KJ. Screening for breast cancer with mammography. Cochrane Database Syst Rev 2013;6:CD001877-CD001877
Medline

2.

Independent UK Panel on Breast Cancer ScreeningThe benefits and harms of breast cancer screening: an independent review. Lancet 2012;380:1778-1786
CrossRef | Web of Science | Medline

3. 

Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ 2014;348:g366-g366
CrossRef | Web of Science | Medline

4.

Domenighetti G, D'Avanzo B, Egger M, et al. Women's perception of the benefits of mammography screening: population-based survey in four countries. Int J Epidemiol2003;32:816-821
CrossRef | Web of Science | Medline

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Are small breast cancers good because they are small or small because they are good?

The New England Journal of Medicine

Donald R. Lannin, M.D., and Shiyi Wang, M.D., Ph.D.

http://www.nejm.org/doi/full/10.1056/NEJMsr1613680

Summary by Cécile Bour, MD

Presentation, objectives and conclusions of the study

Under this rather provocative title, the authors of this study, Donald Lannin and Shiyi Wang of the Yale Cancer Center (New Haven, Connecticut) use a database from the U.S. Surveillance, Epidemiology, and End Results (SEER) to evaluate the screening.

The study is original in that for the first time, biological data are being used for an epidemiological evaluation, particularly for over-diagnosis.

The study links the biological factors of tumors, their size, and both life expectancy and latency of cancers in order to evaluate overdiagnosis, and to support Welch's thesis that the smallest breast cancers, as often detected by screening, have disproportionately favorable biological characteristics, a very long lead time, and would not compromised women's health or lives if undetected.

Welch quantified over-diagnosis at around 22%.

The authors reached this conclusion:

Many of the small tumors that are excessively detected by screening have a very good prognosis due to their intrinsically slow growth, which means that they are unlikely to become large tumors and are inherently favorable. They are the ones that constitute the over-diagnosis as a direct result of the screening activity. They will not grow enough to be dangerous.

Conversely, large tumors, which are responsible for death and most often have an unfavorable prognosis, are dangerous from the outset. Unfortunately, they escape mammographic detection because their growth kinetics are too rapid.

This theory, that originated from epidemiology a long time ago and which explains why screening does not improve the prognosis of women with breast cancer, is substantiated here.

Procedures, methods, data to be understood

The study concerns only invasive cancers. Lesions are divided into three prognosis groups based on the following biological factors: their grade, the presence of estrogen receptors and progesterone receptors (knowing that tumors with these hormone receptors have a better prognosis).

Twelve combinations are possible based on these three variables, each of these 12 groups having a distinct prognosis.

Four groups of cancers with poor prognosis :

- grade 2, negative receptors

- grade 3, negative receptors

- grade 3, estrogen receptor positive and progesterone receptor negative

- grade 3, estrogen receptor negative and progesterone receptor positive

Three groups of cancers with a good prognosis:

- grade 1, positive receptors

- grade 1, estrogen receptors positive and progesterone receptors negative

- grade 1, estrogen receptors negative and progesterone receptors positive

The other five groups are intermediate prognosis groups.

 The authors investigate the correlation of tumor size and biological features of tumors in relation to cancer-specific survival rates.

A "favorable" tumor is one where the biological features presume a good prognosis and an "unfavorable" tumor if otherwise.

The "mean lead time " that enables the quantification of over-diagnosis is the length of time between when a cancer can be detected by mammography and when it would have become clinically apparent without early screening by mammography (adjustment to the age being made).

The fraction of women with a life expectancy less than the lead time represented the percent of overdiagnosis.

(This means that these women will die from causes other than their breast cancer, which would have been unnecessarily detected because it did not endanger them).

Study results 

I-Biological characteristics of tumors as a function of their size:

The percentages of favorable, intermediate, or unfavorable tumors for each tumor size are examined for women over 40 years of age and for women under 40 years of age.

For women aged 40 and over :

For tumors 1cm and less: 38.2% are "favorable" tumors.

Among the lesions of 1cm and less, only 14.1% are "unfavorable" tumors. On the other hand, among tumors larger than 5 cm, 35.8% are "unfavorable" tumors.

Results for women under 40 years of age:

The  favorable tumors  were only about half as common and the unfavorable tumors were much more common, for each tumor size examined.

II-Study of specific survival as a function of both biological characteristics and tumor size.

Classification into small tumors for those between 0.1 and 2 cm = T1; and into large tumors for those between 2.1 and 5 cm = T2.

The diagram below shows that both tumor size and biological factors influence the prognosis, but that large tumors with a favorable biological features had a better prognosis than small tumors with an unfavorable biological features.

This means that the difference in survival is less dependent on size than on biological factors, while larger size will be more critical when the biological factors are already unfavorable.

III-Evaluation of over-diagnosis according to the lead time

The approach finds a close link between the over-diagnosis rate and the lead time, by identifying the average lead time most in line with a given frequency of over-diagnosis.

It is important to remember that the lead time is the period of time between the time when cancer could be detected if a mammogram was performed and the time when clinical signs appear if a mammogram is not performed.

When life expectancy is known (estimated according to several factors including age), and when one of the two data, overdiagnosis rate or lead time, is known, it is possible to estimate the one of these two data that is unknown, and this for each of the 12 biological groups listed above.

The lead time, according to all models, is longer for tumors with favorable than unfavorable factors.

Thus, the percentage of overdiagnosis could be estimated at 53% for favorable tumors, 44% for intermediate tumors, 3% for unfavorable ones; in fact there is no evidence that unfavorable tumors do not progress, the small overdiagnosis observed in the unfavorable group is due to deaths occurring in these patients from unrelated causes before the lead time, which is short for these forms.

We find the figure proposed by Welch of 22% over-diagnosis overall, again concerning only invasive forms (not the cancers in situ).

IV-Tumor size may be an indirect indicator of good or poor biological features

If all tumors were progressing we would expect a steady state to be reached in which there would be a similar distribution of tumor biological features across size categories.

There would be favorable and unfavorable forms in similar rates in each size category.

Instead, these data provide fairly direct evidence that many small tumors with favorable biological features do not progress to large tumors over the lifetime of the patient.

Furthermore, the data imply that large tumors do not arise equally from all small tumors but preferentially develop from a distinct subpopulation of small tumors with unfavorable biological features.

The figure below shows the distribution of tumors of the three different prognostic values according to tumor size; on the x-axis the number of patients, on the y-axis the tumor size. The colors correspond to a prognostic value.

The upper part corresponds to women under 40 years of age and the lower part for women over 40 years of age.

There are generally more tumors with good prognosis in the small tumor size category and vice-versa.

Click to enlarge

Reminder of the conclusions, in detail

- Both data: tumor size and biological features impact the prognosis, but a large tumor with favorable biological features is likely to have a better prognosis than a small lesion with unfavorable features. Furthermore, tumor size is more decisive for the prognosis in the category of tumors with unfavorable biological features.

- Many small tumors with favorable biological factors do not progress to a large size during the patient's lifetime. Large tumors do not arise from the small ones, but from a subpopulation of small lesions with pejorative biological factors from the outset. The higher incidence of favorable tumors in women aged 40 and over suggests that these tumors are precisely and preferentially detected by systematic mammography, and that this explains the obviously very favorable survival rates for this detected age group.

- The authors' estimate of over-diagnosis by all biological groups combined is similar to Welch's estimate of 22%, and indicates that the lead time for the most favorable cancers is 19 years (between 10 and 20 years), compared to 2 years or less for unfavorable cancers.

- Lead time: due to a very long lead time in the favorable tumor group, mammography is necessarily very effective for these tumors with a very good prognosis, long time latent, which find themselves over-represented among small tumors. A considerable number of these tumors would never manifest themselves during a woman's lifetime. And those of these less aggressive tumors that are likely to grow, keep this excellent prognosis. Thus their detection by mammography is of little interest but leads to a perception of efficiency and exaggerated survival.

In the most favorable group, which certainly contains the largest proportion of over-diagnosed cancers (grade 1, positive receptors and size < 2cm), the 10-year survival rate is 97%. The proportion of over-diagnosis can be estimated to be at least 50%. (In fact, the smaller the tumor in this group, the greater the likelihood of over-diagnosis. It is therefore not surprising to see these very good survival figures highlighted in  communication on screening, Editor’s note).

- Still in this very favorable group, over-diagnosis predominates in older women compared to younger women. Indeed, because of this very long lead time of 15 to 20 years, many of these cancers could have been diagnosed only around the age of 70, but are now detected around 50 to 60 years because of screening. And a large proportion of these non-aggressive and indolent lesions detected by screening in these 70-year-olds may never have been detected during a person's lifetime in the absence of mammography.

- For tumors with unfavorable biological features, the prognosis is considerably better if the detection is early (less than 2cm), unfortunately this is very rarely the case due to their short lead time, so they are often diagnosed late and few of these unfavorable tumors are found in the small tumor group because of their rapid growth.

 Early detection is not a universal benefit

In sum

====>>>> Low-grade  and high-grade malignancies tumors result from different molecular mechanisms; a low-grade tumor almost never dédifferentiates into a high-grade tumor. It seems to be arguable that the biological features of a tumor represent a constant natural factor.

=====>>>> The biggest problem resulting from the over-diagnosis of small, favorable lesions, over-represented in tumors detected by screening, is the over-treatment and anxiety that these unnecessary diagnoses cause.

There is a need to educate physicians, patients, and the general public that some cancers are indolent.

Editor's note: The partial indicators that are the five-year survival and the increase in the proportion of cancers detected at an "early" stage are not relevant criteria for judging the effectiveness of existing diagnostic and therapeutic practices. Once again, only mortality is a relevant indicator.

N.B. :

Sparano, J.A, Gray R et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. The New England Journal of Medicine. 2015;373(21):2005-14. https://www.nejm.org/doi/full/10.1056/NEJMoa1510764

The majority of cancers are diagnosed at an early stage.

However, diagnosing increasingly smaller cancers was not accompanied by any decrease in breast cancer mortality until the 1990s. The prognosis of a cancer varies more according to its molecular characteristics than to its size, whether it is larger or smaller than 2 cm.

Extract from the study :

"In multivariate analysis including age ...., tumor size (2.1 to 5.0 cm vs. ≤ 2 cm in the largest dimension), histological grade (high vs. intermediate vs. low) and type of operation ... only histological grade showed a significant correlation with rate of recurrence."

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Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

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

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.