Heart disease is the biggest killer of breast cancer survivors

Summary by Cécile Bour, MD

 January 12, 2020

Causes of Death After Breast Cancer Diagnosis: A US Population-Based Analysis

original article Cancer journal

Medscape

The longer  women are followed up after being diagnosed with breast cancer, the more likely it is that a cause of death unrelated to the original cancer would be found. The most common cause of death is heart disease, according to the authors of the study published at the end of 2019 in the journal "Cancer".

The study is based on a population of more than 750,000 American women diagnosed with breast cancer over the past 15 years since the beginning of the century.

The proportion of deaths from non-cancerous causes increased from about 28% in the first year after diagnosis to just over 60% among women who lived for more than 10 years after their breast cancer diagnosis.

These women, having survived their cancer longer, had a significantly increased risk of heart disease and Alzheimer's disease compared to general population.

Results according to monitoring

  • For deaths within 1 to 5 years after diagnosis, breast cancer itself is the responsible cause in the most frequent cases.
  • Among women who died 5-10 years after diagnosis of breast cancer, breast cancer was the cause of death in 38.2%, followed by other cancers in 13.4%, and non-cancerous causes in 48.4%. Heart disease was the most common non-cancer cause of death (15.7%), followed by cerebrovascular disease (stroke) and chronic obstructive pulmonary disease (3.9%) and Alzheimer's disease (3.4%).
  •  In a more distant follow-up, the cardiovascular cause prevails.

Evoked causes

As discussed above, deaths from heart disease and stroke are leading causes of death unrelated to cancer during the post-diagnosis follow-up periods.

But other important causes of death unrelated to breast cancer include chronic liver disease, sepsis, infectious and parasitic diseases. Suicide must also be considered, as it is a significantly higher cause of death than in the general population in all women but particularly among young women.

The high rates of death from heart disease are probably related to the toxicity of chemotherapy (especially anthracyclines) and radiation therapy (especially left breast).

Hypotheses

According to Dr. Sonbol, co-author of the article,

1°Some women could be cured of breast cancer and then die of other intervening causes.

2°For other women breast cancer, e.g. metastatic cancer, may have been transformed into a chronic disease, it may be under control through systematic therapy, and then other causes contribute to death.

Conclusion

According to the authors, these findings provide considerable insight into how patients treated for their breast cancer should receive warnings about future health risks.

Hospital physicians who follow up women that have had breast cancer must work closely with general practitioners to ensure optimal long-term follow-up and prevent various pathologies that may occur during the lifetime of these patients after their treatment.

EDITOR'S NOTE

We would add that overdiagnosis, in this context, must become a major concern, all the more so since it throws healthy women into an illness they should not have known about, and exposes them to these other, potentially serious pathologies which are also likely to seriously impact their lives and lead to death.

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Effect of a mammography screening decision aid for women 75 years of age and older

April 23, 2020

Randomized clinical trial by "cluster" (cluster)

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2764100

 Authors: Mara A. Schonberg, MD, MPH; Christine E. Kistler, MD, MASc; Adlin Pinheiro, MA et al.

A cluster randomization trial is a trial in which subjects are randomized not individually but by randomization unit or groups of subjects, known as "clusters".

Here 546 women aged 75 to 89 years, who received a decision aid on mammography screening prior to a health care visit with their practitioner, constitute the randomization unit.

Purpose of the study :

To investigate how the use of a screening decision aid for women 75 years of age and older affects their decision to participate in mammography screening.

Study Results

Providing these women with a mammography screening decision aid prior to their medical visit helps them make informed decisions and leads to fewer women undergoing mammography screening.

Study Conclusion

Therefore a decision support tool can help reduce overscreening.

Our analysis

Cécile Bour, MD

Such a study could be of interest on younger age groups, although an assessment of what concerned women perceive and the impact of the lack of balanced information has already been carried out [1].

How do women perceive the benefits of screening according to what has been conveyed about it, and according to the information they have received, and which has forged their convictions on the subject?
This is the question posed in this study by Domenighetti et al, according to which the table below was drawn up by Nikola Biller-Andorno, a bio-ethics researcher who collaborated on the work of the Swiss Medical Board. [2] [3]

In this comparative table we can find, in part A, data from Domineghetti's American Women's Perception Survey, and in part B, actual data from the most likely scenarios, found from the most convincing and reliable studies. [4]1-3)

The authors (Biller-Andorno et al.) were stunned by the significant discrepancy between women's beliefs about the benefits of screening and the reality, and legitimately asked the question: how could women make an informed decision if the benefits of the procedure were overestimated?

See our article with the detailed results of this work here: https://cancer-rose.fr/en/2020/12/18/perception-and-reality-2/

For the moment, the decision-making tool for women requested by the citizen consultation is completely absent in France, since 2016 when the consultation took place.

There is indeed a question of establishing one " in the French way ", which will hardly be possible given the deficient epidemiological data in our country [5].

Recently in JAMA a viewpoint was published on recommendations for shared decision making with the patient [6].

Unfortunately at the moment it seems that the shared decision is more a medical " dream " than a reality.

Indeed, recommendations from learned societies always have more weight than the values and experiences of the patient, and are sometimes imposed in the media and on patients with great virulence and authoritarianism, as we saw in 2019 with the abusive campaign of the French national college of obstetricians and gynecologists (CNGOF)[7], advocating the extension of screening to the elderly, without any national or international recommendation. The Council of the Order, which we had alerted, did not react ,[8] even though it regularly calls to order those who violate the communication of verified medical notions, as is currently the case in the Covid context.

To conclude

There is still an enormous amount of work to be done so that the values and reality of each patient's life, including her age, can guide the practice of every physician. There is also a long way to go, to ensure that physicians have the practical means to contribute to shared decision making, so that women, both older and younger age groups, finally have access to real tools made on a correct and independent scientific basis.

The development of such tools implies admitting the possibility of women's refusal to participate in screening, as the performance of mammography screening has proven over the decades and in the course of modern studies to be increasingly disappointing.

The real problem is that neither health authorities nor politicians are prepared to accept the possibility of women refusing to be screened for political and ideological reasons, thus depriving them until now of true autonomy in health.

References

[1] 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

https://www.ncbi.nlm.nih.gov/pubmed/14559757

[2] https://www.nejm.org/doi/10.1056/NEJMp1401875

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

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

  • 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/
  • 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/

[5] https://cancer-rose.fr/2020/01/22/faisabilite-dun-outil-daide-a-la-decision-sur-le-depistage-du-cancer-du-sein-a-la-francaise-selon-les-criteres-ipdas/

[6] https://cancer-rose.fr/2020/03/14/recommandations-pour-une-prise-de-decision-partagee-avec-le-patient/

[7] https://cancer-rose.fr/2019/04/07/la-campagne-pour-le-depistage-de-la-femme-agee-par-le-college-national-des-gynecologues-et-obstetriciens-de-france-cngof/

[8] https://cancer-rose.fr/2019/05/02/lettre-au-conseil-national-de-lordre-des-medecins-concernant-la-campagne-du-cngof/

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.


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High risk of breast cancer and mammography, in practice

JANUARY 18, 2021

(We have addressed this specific topic in two articles, below is a practical summary at the request of one of our readers. [i] [ii])

The first problem is to define a woman who is at high potential risk of developing breast cancer during her lifetime. And what is a "family at risk".
A family history alone, even a direct one, does not constitute the proof of being a person "at risk", contrary to what is often presented as a scarecrow to women.
We receive plenty of testimonials from young women who are unnecessarily alarmed and above all incited to unnecessary and dangerous over-medicalization.

What about the search for genetic mutations in women? When should it be done? 

This is the question that the independent French medical journal Prescrire addressed, Volume 36 N°388/February 2016.

Genetic mutations in the BCRA1 and BCRA2 genes are autosomal dominant, and women with these mutations are at higher but earlier risk of breast and ovarian cancer than the general population.

-The median age of onset is 40 years and the cumulative risk of cancer at age 70 is 51% to 75% for the BRCA1 mutation, 
-The median age is 43 years and the estimated cumulative risk is 33% to 55% for the BRCA2 mutation.

The journal Prescrire proposes the following criteria as significant backgrounds for proposing an onco-genetic consultation:

-Three people from the same branch, with breast cancer before the age of 70,

-Two people in the same branch, with cancer before the age of 50

-A person who has had ovarian cancer

-A person with breast cancer with a diagnosis before the age of 40, or a bilateral form, the first one before the age of 50, or a hormone receptor negative cancer that occurred before the age of 60.

Eisinger Score

The Eisinger score is a decision aid for requesting an onco-genetic consultation.(Click below to download) :

Several situations can arise in families with multiple cases of breast cancer:

A- Mutation identified in a woman in the family, presenting a breast cancer.

This search for genetic mutation brings valuable information to the women in the family: women who are carriers have a higher risk, women in the same family who do not have it, end up with the risk of the general population.

If a woman in the family decides to do a mutation search on the BCRA1 or BCRA2 genes because of a loaded genealogy, and finds herself carrying a deleterious mutation on these genes, then her risk of developing breast cancer appears to be high, and this risk is also very high for relatives.

B- No mutation found in women with breast cancer.

Either there is really no mutation and the patient has developed a form of cancer without a genetic cause, or there is a mutation, but it may be due to an unidentified genetic cause.

Therefore, there will be uncertainty for the women in her family regarding the hereditary nature or not of this cancer, the risk of the familial nature of this cancer is not as high as in the case of an identified mutation such as BRCA but probably slightly higher than in the general population.

Uncertainty makes it necessary to analyze genealogy, which also has its share of uncertainties and imprecisions…

C- The person with breast cancer has not done any genetic research.

For the women among the relatives, this gives useless information: either the ill person may have had a mutation that was not researched, or she is free of a mutation but the mutation possibly exists in the family members.

All overall, the following points should be kept in mind:

  • Either the person presents a family case carrying a mutation but she is free of any mutation herself, her risk will be close to that of the general population. 
  • Or the person has the mutation and can be estimated to have a higher risk of breast cancer than the general population.
  • But for other women there are still uncertainties about their family's risk of breast cancer:

-In women whose family members have had breast cancer but without a mutation found in only one of the family cases,
-In women with a personal genetic research of a mutation that is negative, with a genealogy presenting several cases of breast cancer, but without research done on the ill persons.

Proposals of conduct to be followed, different options depending on the situation

Who are the individuals with the highest theoretical risk?

-Woman with a case of breast cancer in a first-degree relative (mother, sister, daughter) before the age of 40.

-Two women with breast cancer in the family of first or second degree.

-Male relative with breast cancer in the family of the first or second degree

-First or second degree female relative with ovarian cancer.

Summary according to the Prescrire dossier published in the Revue Prescrire May 2016/Tome 36 N°391-p.355 to p.361

Here is a table summarizing the proposed courses of action according to the presence of mutation or not, and proposals for complementary imaging (downloadable table, click below):

TABLE

EXISTING RECOMMENDATIONS IN FRANCE

1°In 2014, the French National Authority for Health (Haute Autorité de Santé) issued recommendations that are still in force:

https://www.has-sante.fr/upload/docs/application/pdf/2014-05/depistage_du_cancer_du_sein_chez_les_femmes_a_haut_risque_synthese_vf.pdf

2° The recommendations of the National Cancer Institute, click (table p.10 of the doc)

As you will read, early and annual mammography is recommended, ignoring the greater risk of radiation-induced cancer, which can occur, depending on mutations, as early as the first mammogram. iii] [iv]

For these women at particular risk, recommendations are made without any objective data on the impact of different screening strategies, on overall mortality data, breast cancer mortality, mastectomies, treatment effects, over-diagnosis and false alarms for this at-risk population. In absence of data, these women and their caregivers are unsure of what to do and are struggling empirically.

While assessments are conducted on the general population, it is equally important to do them in these special populations, but they are not available.

General cautions

A thorough discussion should be undertaken with the patient because the knowledge of this high risk will condition for her, in addition to an important psychological burden:

-Permanent anxiety

-Numerous false alarms (false positives)

-Over-diagnosis is highly probable but not evaluated since no studies have been carried out to quantify it.

To quote the May 2016 issue of the journal Prescrire: "To ensure that screening has a favorable benefit-risk balance, it is not enough to determine the most effective detection method: earlier diagnosis does not always change the burden of treatment for patients, nor necessarily the prognosis of the disease".

"It is also necessary to establish the conditions where this translates into tangible clinical benefits for the people screened. It is also important to measure the undesirable effects to which all screening exposes people: over-diagnosis and over-treatment, sources of serious undesirable effects sometimes; iatrogenicity of the tests; false positives causing anxiety and useless tests; medicalization of the healthy person's existence. »

And further on, on the ethical aspect:

"Ethics. The magnitude of the risk of breast cancer in these higher-risk women compared to the general population does not make it unethical to conduct randomized clinical trials, on the contrary. Clinical trials comparing the effects of various screening strategies on clinical criteria such as total mortality, breast cancer specific mortality, frequency of breast amputations, frequency of cytotoxic treatments, would provide the answers that are lacking, instead of leaving women and caregivers without solid evidence for these important decisions". 

According to the journal Prescrire, a U.S. evaluation reports 125 cases of radiation-induced breast cancer per 100,000 women between 40 and 74 years of age screened by mammography every year, 16 of which are fatal. And for high-risk women, it has been shown that breast cancer was twice as frequent in women exposed to x-ray examinations before the age of 30 than in those not exposed.

Other complementary exams

Other exams than mammography, each having its limits, and an adapted follow-up can be proposed.


MRI

This exam has a higher sensitivity compared to mammography and is less radiating.

MRI + Mammography:
84% of cancers found

MRI alone:
75% of cancers found

Mammography alone:
32% of cancers found

These proportions are almost identical for women at high risk, but here the problem is the same, we do not know the proportion of overdiagnosis. It is not known whether there is a gain in survival for these women who are followed in this way, or whether, on the contrary, they are exposed to more overdiagnosis and invasive treatments.

The long-term effects of Gadolinium injected annually are also unknown. The assessment of this potential risk is all the more necessary as these women will be integrated into heavy surveillance protocols, with multiple repeated MRI scans.

This product has possible side effects during injection and some cases of allergic reactions have been described.

Ultrasound:


this examination increases overdiagnosis and exposes to false positives and multiplies unnecessary biopsies.

Clinical examination by a professional:


The authors of the Prescrire dossier did not find any study evaluating the performance of breast self-examination.

But according to all the studies examined by the authors, it seems that at least half of the cancers discovered by an imaging examination were not diagnosed by the clinical examination carried out at the same time. It is not known if a delay in clinical diagnosis would be life threatening, as this has not been evaluated.

References

[i] https://cancer-rose.fr/2016/11/20/observations-femmes-a-risques/

[ii] https://cancer-rose.fr/2016/11/20/depistage-et-risque-familial-eleve-de-cancer-du-sein/

[iii] https://cancer-rose.fr/en/2020/12/15/radiotoxicity-and-breast-cancer-screening-caution-caution-caution/

[iv] https://its.aviesan.fr/getlibrarypublicfile.php/cd704e89988a4e3bcf2e1217566876cf/inserm/_/collection_library/201800012/0001/J1-098ITS-2017.foray.lyon.ITMO.TS..21.nov.2017.pdf.pdf

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.

Additional MRI screening for women with extremely dense breast tissue

https://www.nejm.org/doi/full/10.1056/NEJMoa1903986
Bakker, M. F.; de Lange, S. V.; Pijnappel, R. M.; Mann, R. M.; Peeters, P. H. M. and all, Supplemental MRI screening for women with extremely dense breast tissue. N Engl J Med. 2019;381(22):2091–2102 , DOI: 10.1056/NEJMoa1903986

Synthesis Cécile Bour November 28, 2019

Background

Extremely dense breast tissue is believed to be a risk factor for breast cancer, a factor that is especially limiting for cancer detection by mammography.

The aim is to test whether the use of MRI would reduce the occurrence of interval cancers, i.e. cancers appearing between two mammograms, the previous mammogram having been considered normal.

Method

This is a randomized controlled trial (study subjects randomly assigned to either group), multicentre (conducted in two or more centers with the same protocol and a coordinator responsible for processing all data and analyzing the results).

It is carried out by van Gils and his colleagues in the "DENSE" trial group.

The researchers divided 40,373 women between 50 and 75 years of age with extremely dense breast tissue and negative screening mammogram results, into two groups: either the "additional MRI" group or the "screening mammogram only" group; specifically 8,061 women in the "MRI-invitation" group and 32,312 women in the "mammogram-only" group.

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

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

The researchers stated that “Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting,but supplemental screening is not recommended in American guidelines. “

Although complementary imaging increases the rate of cancer detection in women with dense breasts, the question that remains is whether it improves health outcomes. Read about it: https://jamanetwork.com/journals/jama/article-abstract/2733521

Conclusion of the study

Additional MRI screening appears to be associated with fewer interval cancers compared to mammography alone in women with extremely dense breast tissue and normal mammography results. It appears that for dense breasts, the risk of interval cancers is reduced by half in women with negative mammograms and MRI screening.

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-only group.

Overall, 59% of women in the MRI group really attended this additional screening. Of the 20 interval cancers diagnosed in the group that was invited for MRI, 4 were diagnosed for women receiving MRI, and 16 were diagnosed for those who did not receive MRI.

Limitations of the study

  • False positives : Supplemental MRI scans were associated with a cancer detection rate of 16.5 per 1,000 screens and resulted in a false positive rate of 8.0% (79.8 per 1,000 screens). Among women who had a breast biopsy based on an MRI indication, 26.3% had breast cancer and 73.7% did not.
  • Sample not large enough.  To examine the effect of MRI screening on breast cancer specific mortality or overall mortality, the study would require a larger sample size and a longer observation period.

The lower rate of interval cancers observed in MRI participants may have an effect on mortality, but it would also be necessary to see a reduction in the number of advanced cancers in order to demonstrate a benefit on mortality reduction, which has not yet been demonstrated for mammography screening alone.

Reservations expressed 

In an accompanying editorial, Dan L. Longo, Associate Editor of the New England Journal of Medicine, and Professor. of Medicine at Harvard Medical School, (Boston), praised the high quality data from this unprecedented randomized trial: « It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening ».

But the problem of over-diagnosis and the usefulness of additional screening in asymptomatic women, in whom lesions will be detected and be treated, without any evidence of survival or reduction in mortality, continues to be raised.

Dan Longo writes :

« But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival. »

« The ultimate test of the value of MRI screening in women with extremely dense breast tissue will be whether its use improves survival — an answer that we will not have for a very long time. In the meantime, we now have a trial showing that MRI screening can lead to a lower rate of interval cancers. The cost is that 74% of the biopsies that are subsequently performed will not lead to a cancer diagnosis, and we do not know whether the cancers that were detected needed to be found or treated. »

« So the dilemma remains. Women with dense breasts and a negative mammogram who undergo MRI have a very low risk of having breast cancer (16.5 per 1000 screenings in this trial) and an increased risk of a false positive scan. The findings of this trial are likely to reinforce the idea that MRI screening is important in women with dense breast tissue. But will we be putting these women at increased risk of procedures without contributing to their eventual survival? »

In addition, another study :

The concern about additional MRI screening is addressed in another controlled study of MRI screening for contralateral breast cancer patients in the United States. (Wang SY, Long JB, Killelea BK, et al. Preoperative breast magnetic resonance imaging and contralateral breast cancer occurrence among older women with breast cancer. J Clin Oncol 2016;34:321-8.)

Although the incidence of invasive breast cancer in the contralateral breast after the screening period was lower with MRI screening than without screening, the overall incidence of breast cancer in the MRI group was twice as high as in the no MRI group, with no change in the incidence of advanced cancer throughout the five-year follow-up period. However, it is the incidence of advanced breast cancer that tells us whether or not screening is effective.

The researchers concluded :

“An increased synchronous contralateral breast cancer detection rate, attributable to MRI, was not offset by a decrease of subsequent contralateral breast cancer occurrence among older women with early-stage breast cancer, suggesting that preoperative MRI in women with breast cancer may lead to overdiagnosis.”

References

Bakker, M. F.; de Lange, S. V.; Pijnappel, R. M.; Mann, R. M.; Peeters, P. H. M. and all, Supplemental MRI screening for women with extremely dense breast tissue. N Engl J Med. 2019;381(22):2091–2102 , DOI: 10.1056/NEJMoa1903986

Longo, D.L, Detecting Breast Cancer in Women with Dense Breasts-Editorial, N Engl J Med 2019; 381:2169-2170 DOI: 10.1056/NEJMe1912943

Wang SY, Long JB, Killelea BK, et al. Preoperative breast magnetic resonance imaging and contralateral breast cancer occurence among older women with breast cancer. J Clin Oncol 2016;34:321-8.

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.

Digital mammography not more effective in reducing the most serious cancers, according to Australian meta-analysis

by Cécile Bour, MD, June 28, 2020

https://academic.oup.com/jnci/article/doi/10.1093/jnci/djaa080/5859630

This is a meta-analysis of 24 studies of more than 16 million screening mammograms (10,968,843 film and 5,614,900 digital mammograms) by Australian researchers, which reported the following results :

With digital mammography is observed :

  • A statistically significant increase in recalls and false positives; bearing in mind that false positives can generate considerable anxiety in women who are misidentified as having breast cancer. After the transition to digital mammography, which began around the year 2000, a recall increase rate of 6.96 per 1,000 screens was  reported.
  •  No impact on the rates of interval cancers, these cancers not being anticipated by screening because they are often very rapid and progressive and appear between two screening mammograms, despite a previous negative mammogram. Their rate is not lowered by digital technology.
  •  A modest but statistically significant increase in the cancer detection rate, however this improved detection rate is largely due to a higher detection of carcinoma in situ, the great majority of which are of unnecessary detection, with little difference in the detection of invasive cancers.

 Precisions and some reminders

1° Transition from analog to digital

Initially, mammography was analogical, i.e. using films that had to be developed. The radiological signal, to make it simple, is  transformed into a 'visual' signal, which involves technical uncertainties that can alter the quality of the film to be interpreted (film artifacts, quality and fragility of the films, problems with developing baths, etc.). With the digital process, used in screening since 2008, sensors retrieve the image, store it in memory, there is no transformation of the signal and the image is projected in real time on the computer screen (or console). The diffusion of the signal is limited to the maximum ('photon counting' technique) to keep only the useful information. This technology has been acclaimed for its better detection rate compared to the analog system, especially in case of dense breasts, and for its lower irradiation.

This last aspect is certainly not negligible, but should be relativized, since radio-biologists have made us understand the mechanisms of radio-toxicity, which is much less dose-dependent than subject-dependent. See: https://cancer-rose.fr/en/2020/12/15/radiotoxicity-and-breast-cancer-screening-caution-caution-caution/

2° The impact of digital in terms of benefits

 In 2010, questions were already being raised about the real impact for women in terms of mortality reduction, because the interest of screening is to detect the cancers that endanger the most women's lives, and thus reduce mortality, a fact that is difficult to prove with breast cancer screening (reduction in breast cancer mortality since the 1990s, thanks to therapeutic advances, a reduction well before the advent of screening campaigns).

However, an increase in detection rate ranging from 20 to 28% with the digital technique (in fact according to the Australian study, there is 25% more detection for carcinoma in situ and only 4% more for invasive carcinoma), this represents only one additional cancer detected thanks to this new technique per 1000 women, and it does not mean that one more life is saved.

Screening performance is measured by mortality and not by the detection rate. The problem is that it preferentially detects a cancer that will be little or not life-threatening, and that would have been detected by analog mammography one year later anyway, or even in the absence of any screening by the appearance of a clinical symptom, without changing the therapeutic result. More cancers that would never have manifested themselves are also detected. The problem of overdetection by preferential detection of cancers with little or no evolution thus causing overdiagnosis, has already been raised.

3° The problem of over-detection of carcinoma in situ (CIS)

Below is a reminder of what we explained about in situ carcinoma of the breast: https://cancer-rose.fr/en/2020/12/30/a-blog-for-women-with-dcis-ductal-carcinoma-in-situ/

In situ carcinoma of the breast is defined by the proliferation of cancer cells within a galactophoric duct without the cells protruding beyond the wall of the duct to invade the rest of the breast.

It is essentially a mammographic finding, as 90% of women diagnosed with DCIS had microcalcifications on mammography.

The vast majority of these lesions do not threaten women's lives if they are not detected, their prognosis is very good, the 10-year survival rate, a parameter widely used by health authorities, is over 95%. There is the ductal form and the lobular form considered rather as a risk factor for breast cancer.

CIS contributes to overdiagnosis. Tests and studies show that the increasing detection of CISs has not contributed to the reduction of breast cancer mortality. Before the introduction of screening, CIS accounted for less than 5% of all breast cancers, rising to 15-20% in all countries where screening campaigns exist. They are not counted in the incidence figures (rate of new cases) given by the National Cancer Institute, as they are considered separately and not as "true" cancers.

In addition, there is a lack of real consensus among pathologists for the classification of these lesions in the analysis of the biopsies they receive, with a tendency to outclass them in poorer prognostic categories, for fear of underestimating a "disease".

Most CIS are considered as non-mandatory precursor lesions to invasive cancer; paradoxically, the dramatic increase in their detection followed by their surgical ablation has not been followed by proportional decreases in the incidence of invasive cancers.

The major problem is that these particular breast cancer entities are treated with the same severity as breast cancer.

In November 2016, a study carried out by University of Toronto reported  the following results:

- Their treatment makes no difference in women's survival.
- Women with CIS are heavily treated (sometimes by bilateral mastectomy) and have the same likelihood of dying from breast cancer as women in the general population.
- Treating CIS does not decrease their recurrence.
- Preventing recurrence by radiation therapy or mastectomy would also not reduce the risk of mortality from breast cancer.

Similarly, our study of mastectomies in France showed a steady increase in surgical procedures, our first hypothesis being the overtreatment of lesions that are not invasive cancers, but so-called pre-cancerous lesions and CIS [3] [4].

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 increase (10-100% over 20 years) in the rate of major coronary events. [5]

In several countries, clinical trials are being conducted to test a simple active surveillance, especially for low-grade CIS, rather than aggressive treatment:

- COMET(US)
- LORIS(UK)
- LORD(EU)

For Philippe Autier [6], from the International Prevention Research Institute (IPRI), the problem is undoubtedly inherent to routine mammography, in particular digital mammography, which is too efficient for the detection of small calcifications; these are the most frequent radiological sign of these forms, and mammogaphy has an excellent sensitivity for the detection of these microcalcifications.

You will find in our media library several clinical cases of carcinomas in situ, abusively called carcinomas.

Conclusion of authors of Australian meta-analysis

The increase in cancer detection after the switch to digital mammography did not result in a reduction in interval cancer rates. Recall rates were increased.

These results suggest that the transition from film to digital mammography, primarily motivated by reasons of better technological performance, did not result in health benefits for screened women.

This analysis reinforces the need to carefully evaluate the effects of future technological changes, such as tomosynthesis [1] [2], to ensure that the new technologies lead to better health outcomes, beyond the gains in technical performance alone.

[1] Read : https://cancer-rose.fr/2019/11/28/avis-de-la-haute-autorite-de-sante-sur-la-performance-de-la-mammographie-par-tomosynthese-dans-le-depistage-organise/[2] Read also  : https://cancer-rose.fr/2019/03/09/association-de-la-tomosynthese-versus-mammographie-numerique-dans-la-detection-des-cancers/

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.

Overscreening of older adults

August 4, 2020,
Summary, Cécile Bour, MD

Judith Garber, political scientist at the Lown Institute [1] had already published an interesting article on the opportunity to reduce screening during the Covid period and during lockdown [2].

This time she synthesizes in a publication of the Lown Institute the result of a study published in Jama on overscreening of older adults.

Background

In very old age, people are less likely to live long enough to benefit from the advantages of screening, but they are much more exposed to the risks of treatments that will follow the discovery of a lesion that would not have had the time to endanger their lives if it had not been detected. This is why the recommendations, whether American or European, set age limits beyond which screening will not only be useless but potentially harmful.

Judith Garber reminds us the figures of excessive screening in elderly people in a study conducted in 2014 among older patients at very high risk of mortality: 37.5% were screened for breast cancer, 30% were screened for cervical cancer and 40% were screened for colorectal cancer.

The study is published in the JAMA by researchers at the Penn State College of Medicine

Researchers analyzed the data set of more than 175,000 participants and measured the proportion of adults above the recommended age who reported being screened for colorectal cancer (age cutoff of 75 years), cervical cancer screening (age cutoff of 65 years) and breast cancer mammography screening (age cutoff 74 years). 

The results are as follows:

  •  45% of survey respondents reported having had a colorectal, cervical or breast cancer screening, even though they had exceeded the recommended age for screening set by the USPSTF [3]. 
  • Overscreening was most common for breast cancer, with 74% of women over 74 years of age having had a mammogram. 
  • Cervical cancer had the lowest rate of overscreening, with 45.8% of women over 65 years of age,
  • Yet 32% of women being overscreened despite a previous hysterectomy. 
  • Even people with a high mortality risk were no less screened than those with a longer life expectancy.

For breast cancer, there were disparities: women living in metropolitan areas, with good quality health care and in good or excellent health, were more frequently overscreened than women living in rural areas, without an usual source of care and poorer reported health status. (Editor's note: it should be noted that this fact was also reported in a previous study in the state of Sao Paulo in Brazil. [4] )

Higher levels of education were associated with higher rates of overscreening among women.

What are the reasons for overscreening of older adults and outside of recommendations?

According to the authors of the Penn State College of Medicine study, overscreening for women may be related to residing in urban areas, because women have easier access to screening facilities than women living in rural areas, and are offered more screening, whether or not it is appropriate.

Another hypothesis is that clinicians in rural areas have longer and more trusting relationships with patients, so that they have time to explain to patients why screening is no longer recommended after a certain age. 

Judith Garber brings up the interesting theory, which the authors did not raise, that the greater availability of medical facilities in cities, the fact that there are more technological offerings and more competition for patients in urban areas, encourage overuse of the system by medical insurance beneficiaries, and thus unnecessary screening, as a March 2020 study also suggests.

Researchers at the Penn State College Institute are calling for additional research on causes to reduce this persistent trend.

References

1] The Lown Institute (USA Massachusetts) is a non-profit organization, “a think tank generating bold ideas for a just and caring system for health“

[2] https://cancer-rose.fr/en/2020/12/15/reduction-in-the-number-of-cancer-screenings-during-the-covid-19-period-what-are-the-expected-consequences/

3] an independent U.S. organization of primary care and prevention experts that systematically reviews evidence of effectiveness and develops recommendations. 

4] https://bmjopen.bmj.com/content/7/8/e016395

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.

Objective information and less acceptance of screening by women

Marc Gourmelon, MD, Cécile Bour, MD

September 8, 2020

A French study in 2016 showed that when women are given slightly more objective information about breast cancer screening by mammography, they are less likely to attend it.

https://www.oncotarget.com/article/7332/text/ : "Decision aid on breast cancer screening reduces attendance rate: results of a large-scale, randomized, controlled study by the DECIDEO group"

Background and methods

This study was conducted in 2016 by Aurélie BOURMAUD who was working at the time for the Cancer Institute of Loire Lucien Neuwirth 1408, Saint Priest en Jarez, France, very invested in screening as shown by her support for the events of Pink October [1].

She is now an Associate Professor in public health and currently works at the clinical epidemiology unit of the Robert Debré Hospital (Paris) and at the University Paris Diderot. Her research themes are prevention, patient education, complex intervention and patient care pathways.

The summary of his study indicates the following:

“The aim of this study was to assess the impact of a decision aid leaflet on the participation of women invited to participate in a national breast cancer screening program. This Randomized, multicentre, controlled trial. »

« 16 000 women were randomized and 15 844 included in the modified intention-to-treat analysis. »

« This large-scale study demonstrates that the decision aid reduced the participation rate. The decision aid activate the decision making process of women toward non-attendance to screening. These results show the importance of promoting informed patient choices, especially when those choices cannot be anticipated. »

In introduction is explained :

« Benefits in terms of mortality reduction are not clearly documented. It has been suggested that prevention campaigns should change from persuasive approaches to approaches based on information and women’s decision empowerment. »

In order to carry out this study, a decision support tool, DECIDEO, was distributed to the participants (Outil DECIDEO, in two languages starting on page 7).

« A decision aid, known as the DECIDEO leaflet, was developed following international guidelines for the ‘provision of information and the construction of decision aid tools ».

The hypothesis of this study was as follows:

« Our hypothesis was that this decision aid would increase informed choice in the intervention group. We estimated the effect of this written decision aid on informed choice, by measuring the participation rate of a population-based breast cancer screening. »

This 2016 study was brought to our attention because it is cited by Italian authors who demonstrated that manipulating the message to women likely to get screened by mammography, increases their participation in screening. We had recently analyzed this study (Italian study analysis).

The Italian study shows that information on the risks of screening reduces women's participation in breast screening, which is a real problem for the Italian authors. They therefore suggest manipulating the information given to women by selectively presenting the negative effects (according to them) of not getting screened.

What are the results of the 2016 study by A.Bourmaud et al.?

“The overall participation rate at 12 months (Table 2), was significantly higher in the control group: 42.13% versus 40.25% in the decision aid group (p = 0.02).”

This clearly means that women participating in the decision support group were less likely to be screened than women in the control group.

In other words, when women are given information about screening, they attend less the screening. This finding is critical.

“This study is the first to compare a decision aid to real life: the control group consisted of women aged 50 to 74, receiving the usual information about screening. Our results are however in accordance with previous trials in this field suggesting a decreased attendance as results of the implementation of a decision aid on cancer screening”.

“Our results demonstrate that a decision aid, designed following specific guidelines, sent with a formal invitation to attend breast cancer screening, resulted in a lower attendance rate and a decrease in the delay of attendance for the women who did participate.”

This confirms what the recent Italian study showed: in order to increase participation in breast cancer screening by mammography, the information must be manipulated in the sense of less disclosure of the true risk/benefit balance of screening.

Discussion and analysis

A-Analysis of the tool

According to the authors themselves, the DECIDEO tool has some shortcomings, and not the slightest:

 "Another limitation (of the study, editor's note) is that recent data on over-diagnosis and over-treatment have not been implemented in the decision aid. »

These elements to be informed are however capital among the risks of screening.

The tool's figures (starting on page 8) are not referenced anywhere, and, as stated in the introduction, once again in the authors' own words: "The benefits in terms of mortality reduction are not clearly documented".

However, what women want to know first and foremost when they undergo a medical procedure is whether it can guarantee them less death from the disease and whether the procedure has no major side effects.

Overdiagnosis and overtreatment being the two major adverse effects of screening, there is clearly a form of manipulation by not communicating to women these two fundamental and essential data for their health and well-being.

Furthermore, it is noteworthy that contrary to what is implied by the references cited in the study (reference 26 on IPDAS criteria), this tool distributed to participants in the study does not meet IPDAS criteria in any way.

The IPDAS criteria are very specific requirements that the tool must meet to guarantee a high quality of information.[2]

The mention of overdiagnosis and overtreatment is therefore an absolute must.

In this respect, we were already concerned about the shortcomings in the completeness and quality of the information provided by the National Cancer Institute itself, whose mission it is, however, to do it [3].

B-the ethical problem

In this study, as in the Italian one, the authors have a question that does not miss to surprise:

"the DECIDEO leaflet discouraged older women, as well as those with a low mean household income, from attending the national breast cancer screening program. “

Women with a lower educational level could have had difficulty in understanding the decision aid. Those two phenomena could partly explain the effect of the DECIDEO leaflet on those specific populations, additional studies being needed to confirm this hypothesis.

This hypothesis put forward by the authors, seems to come straight from their lack of knowledge of the social environment of modest women to which, it seems to us, "social class beliefs " are added.

Indeed, there is an aspect that is not at all addressed nor only mentioned by the authors, but that any "field" doctor understands very quickly, provided that he offers an attentive ear to the most socially and economically deprived patients. Low-income women, and even populations with a low socio-economic level in general, do not have such prohibitive problems of understanding that the authors of the DECIDEO group imply that they do, if indeed efforts are made to make medical information available to them.

On the other hand, these populations fear the disease much more than others. In fact, falling ill makes them even poorer and more ostracized; women who have low-paying jobs panic about losing this often thankless job and being deprived of an income that is indispensable to the family. The jobs of these women often require physical commitment (household, home work, labour); they know that they will no longer have the professional skills required of them after certain treatments, and they fear being further discredited as " ill " at the expense of society.  Further studies could demonstrate this, but simply by questioning these economically weak people, the diagnosis appears obvious to explain their lesser compliance with screening recommendations, of all kinds, moreover.

The actual questioning of the need to provide honest information that might decrease participation seems unethical to us, since the obligation to provide fair and complete information is stated in the law [4].

« In this large, randomized, clinical trial we observed that the DECIDEO decision aid resulted in decreased breast cancer screening attendance although it accelerated the decision to attend, for those women who did attend. These results suggest that this leaflet have accomplished its main purpose which was to inform the decision-making process. 

We believe that our results highlight the dilemma between the goals of population health initiatives and individual choices.”

Conclusion

This study went unnoticed.

And for reason, it proves that the more exhaustive the information given to women about breast cancer screening by mammography, the less they participate in the organized screening program set up and promoted by official structures.

And we are surprised that the DECIDEO form, far from meeting the IPDAS standards of exhaustive information on screening, achieves such results in terms of reduction in recourse to screening.

The more women are informed, the less incentive campaigns such as the Pink October campaign can reach them.

Screening uptake does not have strong evidence of an effect on mortality reduction, as stated at the outset in the introduction :

“Benefits in terms of mortality reduction are not clearly documented [10-13]. It has been suggested that prevention campaigns should change from persuasive approaches to approaches based on information and women’s decision empowerment ”

We must then stop trying at all costs to persuade women to get screened. We have to stop manipulating at such a point the so-called decision support tools. Instead, we must inform women, so they can make an informed decision.

This represents nothing less than the conclusions of the consultation on screening mammography in 2015 [5].

In the end, one rather amusing thing to note is that even with a biased decision support tool, such as DECIDEO is, women are very difficult to fool and send to a screening test to which, despite the misleading and pink incentives, they do not massively comply…

It therefore seems obvious to us that, as requested by the 2015 citizens' consultation, and in accordance with the ever-increasing scientific evidence on the ineffectiveness of mammography screening, this organized breast cancer screening by mammography has to be stopped in France.

Read also our previous article on the manipulation of women, as a scientific topic.

References

[1]https://www.icloire.fr/wordpress/icln-octobrerose2018/

[2]https://cancer-rose.fr/2020/01/22/faisabilite-dun-outil-daide-a-la-decision-sur-le-depistage-du-cancer-du-sein-a-la-francaise-selon-les-criteres-ipdas/

[3]https://cancer-rose.fr/en/2020/12/31/david-versus-goliath-which-is-better-at-informing-women-cancer-rose-or-national-institute-of-cancer-inca-in-france/

[4] Law on the obligation to provide information in the French public health code:
https://www.legifrance.gouv.fr/affichCode.do?idSectionTA=LEGISCTA000006196409&cidTexte=LEGITEXT000006072665&dateTexte=20180522

[5]https://cancer-rose.fr/en/2020/12/14/final-report-of-the-citizen-consultation-report-of-the-steering-committee/

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.

Scaling back in health care: more shared decision making and thoughtful consideration of recommendations

Identify recommendations for stopping or reducing unnecessary routine primary care

Summary by Cécile Bour, MD, September 15, 2020

September 14, 2020 "Identifying Recommendations for Stopping or Scaling Back Unnecessary Routine Services in Primary Care".

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2770724

A study by Eve A. Kerr, MD, MPH; Mandi L. Klamerus, MPH; Adam A. Markovitz, BS; et al.

Eve A. Kerr is a Research Professor of Internal Medicine at the University of Michigan School of Medicine. She is an elected member of the American Society of Clinical Investigation and the Association of American Physicians, a Fellow of the American College of Physicians and a member and responsible for measures of Choosing Wisdom International. 

The concept of Less is More[1][2] medicine emerged in North America in 2010. It is an invitation to practice medicine with an awareness of the potential dangers of over-medicalization, challenging the principle that more medicine means better care.

In response, several medical societies around the world have launched campaigns focusing on choice and appropriateness of care (Choosing wisely [3]) and calling for discussion with patients about the usefulness of medical tests, treatments and procedures.

As the rate of discoveries in therapeutics slowed in the late 1980s, the focus shifted from the search for further innovation to a more reasonable application of existing knowledge. Evidence-based medicine (EBM) was born and is the current driving force for achieving a better level of general practice.

What is EBM?

The EBM is based on a tripod:

1) external experience, basically scientific studies

2) Internal experience: what we learn from our professional practice

3) patient preferences and values.

Among these criteria, guidelines, or recommendations, serve as standards to facilitate medical practice.

Guidelines are a kind of... ways developed to help clinicians and patients make better decisions together, in a spirit of sharing perspectives, all in the best interests of the patient. 

But...

The guidelines, as the authors describe, generally act in the cumulative sense of 'more is better'. The solution proposed by the authors is that the guidelines should be reshaped in the sense of de-escalation, in order to achieve 'less is more'.

The problem often pointed out is that the guideline is the result of a more or less valid consensus reached among several experts. Uncertainties about the health processes that are analyzed by the experts are hardly mentioned and often replaced by the opinion of the expert(s). The independence of the experts can also be a subject of discussion...

Recommendations that drive decisions for patients and clinicians may unintentionally discourage real sharing in decision making, and encourage compliance with the guideline, or may result in rejection and less compliance, depending on the patient's values.

Another challenge is the need to re-evaluate the guideline over time as new knowledge about the risk-benefit balance becomes available.

In addition, we are continually witnessing an encouragement to do rather more tests and treatments, an incentive that is societal, administrative and financial at the same time, by remunerating doctors when including patients in screening procedures.

What does Kerr's study say, and what is its purpose?

The conclusion is that a large part of health care involves the agreed and routine use of medical processes as part of the treatment of chronic disease or as part of what is referred to as 'prevention'. It is the latter that interests us.

The authors argue that it is essential to stop these processes and health services when the evidence on their relevance changes, or if the benefits no longer outweigh the risks as is the case with screening. 

 Yet currently most guidelines focus on escalation of care and procedures, and provide few explicit recommendations for reducing or even stopping treatment and screening tests.

The objective of the Choose Wisely group is to develop a systematic, transparent and consistent approach to identifying, specifying and validating recommendations for deintensification in routine adult primary care [4].

A targeted review of existing guidelines and recommendations was conducted to identify and prioritize potential indications of deintensification. 

Validity of these recommendations is examined according to several items: high-quality evidence that deintensification is likely to improve patient outcomes, evidence that intense testing and/or treatment could cause harm in some patients, absence of evidence on the benefit of continued or repeated intense treatment or testing, and evidence that deintensification is consistent with high-quality care.

Finally, in this study, a total of 178 opportunities to deintensify primary care services were identified, 37 of which were validated as high-priority deintensification recommendations. To date, this is the first study to develop a model for identifying, specifying and validating deintensification recommendations that can be implemented and monitored in clinical practice.

Concerning screening, what are these recommendations for deintensification (de-escalation?)

There is no great revolution in this area except that in the additional recommendations given by Choosing Wisely, clinicians are no longer supposed to recommend screening for breast, colorectal, prostate or lung cancer without considering life expectancy (no screening if life expectancy is less than 10 years) and without considering the risks of screening: overdiagnosis and overtreatment.

This is in contrast to the USPSTF and American College of Physicians' guidelines that urge screening with a strong recommendation for women aged 50-74 years, and the American Cancer Society's recommendations for screening as young as 45 years, all of these bodies not considering information on overdiagnosis or overtreatment in the recommended age groups.

For prostate cancer screening, its non-recommendation is recalled by the Choosing Wisely group, which is asking for at least a shared decision aid for men who would like to be screened.

Conclusion

The guidelines for deintensification proposed by Choosing Wisely, although modest on screening, can initiate this necessary change that will enable health care professionals to reverse the trend of 'more care'.

But the evolution towards sharing medical decision making with patients cannot take place, in our opinion, without active assistance through decision support tools, and without the willingness of official health authorities to support practitioners.

Public health education is also needed. Between financial incentives (ROSP: remuneration of doctors on public health objectives in France) to physicians and societal messages to screen more and more (general public TV programs such as "naked stars" [5] and Pink October campaigns in France), there is for the moment only a very timid effort to achieve this informed sharing, too little academic training in this sense (despite local initiatives in medical schools), and certainly too little official and media support to make it clear that it is in the best interests of patients to review our practices towards a deintesification of routine care.

References 

[1] https://www.revmed.ch/RMS/2013/RMS-381/Less-is-more

[2] https://cancer-rose.fr/en/2020/12/15/less-is-more-medicine/

[3] http://www.lessismoremedicine.com/blog/tag/choosing+wisely

[4] https://www.irdes.fr/documentation/syntheses/soins-de-sante-primaires.pdf Primary care includes : - prevention, screening, diagnosis, treatment and follow-up of patients; - dispensing and administration of drugs, medical products and devices, as well as pharmaceutical counselling; - orientation in the health care system and the medico-social sector; - health education.

[5]https://cancer-rose.fr/2020/02/06/ah-mais-quelle-aubaine-ce-cancer/

 

 

 

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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.

Hormone Replacement Therapy (HRT) and Breast Cancer

Synthesis by Cécile Bour, MD, 

December 29, 2020

The debate on the question of the link between HRT and breast cancer is long-standing, dating back to 2002 when an American study suggested an over-risk of cancer in patients on HRT. This first study resulted in great controversy. This WHI (Women Health Initiative) trial is a large randomized American study whose objective is to evaluate the risks and benefits of different dietary and medical strategies that can reduce the incidence of cardiovascular disease, breast cancer, colorectal cancer and fractures in postmenopausal women.

Planned to last more than 8 years, the trial was prematurely stopped in the first half of 2002 after a little more than 5 years, as the risks were deemed to outweigh the benefits, in particular due to the appearance of unfavorable and unexpected cardiovascular effects of HRT.

Indeed, the study confirmed a vertebral and femoral anti-fracture effect, a beneficial effect on the decrease of colon cancer rate, but found an increase in cerebrovascular accidents, myocardial infarction, phlebitis and pulmonary embolism, and breast cancer.

The results were contested in France on the basis that the products used in the study were orally administered and normodosed equine estrogens (whereas in France were used transdermally or orally estradiol), and medroxyprogesterone acetate which was not used in France. Great relief therefore when JAMA[1], in 2017, came back on these first rather frightening results and contested this excess mortality in the WHI study, the French gynecologists then considering HRT globally as a "good thing if the treatment is not standardized but personalized"[2].

However, in medicine, nothing is ever set in stone, and in 2003, another study, an English one[3] conducted from 1996 to 2001 including more than a million menopausal women between 50 and 64 years old, showed an over-risk of breast cancer under HRT, even with treatments commonly used in Europe. The result of the study was that the risk of developing breast cancer as well as the risk of cancer-related death was greater in treated women than in untreated women, and greater in women treated with combined estrogen-progestin therapy than in women receiving estrogen therapy alone. This English study examined many of the treatments used in Europe, both for the types of estrogen-progestin and for their means and routes of administration.

The controversy was such that the systematic prescription of HRT was drastically slowed down in 2004. And it is true that a decrease in the incidence of this cancer was observed around 2004, when HRT was stopped being prescribed on a large scale and for long periods of time. [4]

A 2019 study – an over-risk of cancer confirmed under HRT treatment

This is a review of 58 epidemiological studies on the subject of the association between HRT and breast cancer, mostly observational, involving more than 100,000 women in total. Published in 2019 in The Lancet [5], this review demonstrates an increased risk of breast cancer in women undergoing hormonal treatment for the effects of menopause. While this excess risk decreases well after stopping treatment, it persists for at least ten years.

The study is innovative in that it quantifies the risk for each type of treatment.

For example, a fifty-year-old woman who has been on HRT combining estrogen and progesterone continuously for 5 years has a risk of developing breast cancer within 20 years of starting treatment of 8.3%. The risk would be only 6.3% for women of the same age who have had no treatment.

The risk of developing breast cancer after 20 years would be 7.7% for women who have been treated with estrogen and progesterone but intermittently, and 6.8% for those treated with estrogen alone, according to the researchers.

What should be learned essentially from the study?

  • All hormonal treatments for menopause are associated with increased risk, with the exception of estrogen gels for local application.
  • The risk would also increase with the duration of treatment, the use of HRT for 10 years would result in an excess risk of breast cancer about twice as high as the risk of a 5-year treatment alone.
  • Conversely, using HRT for less than a year would result in a low risk.

Adapt according to the need

Currently the practice aims to individualize prescriptions, carefully considering the risks and benefits of treatment for each woman and taking into account whether or not to use HRT, depending on the woman's climacteric disorders (Climacteric refers to the years of hormonal change experienced by the woman before and after menopause).

The recommendation of the High Authority of Health (HAS-France)

In 2004 the French High Authority for Health (HAS) issued a recommendation[6] that is still in force: HRT should be prescribed for a short period of time. The HAS specifies that there is no need to prescribe additional or specific radiological examinations for women treated with HRT, but the HAS does request that all women treated be systematically included in the screening program. The following is recommended  [7]:

  •  In case of hormone replacement therapy or menopause hormone treatment in progress :

In case of prescription before the age of 50 and in the absence of sufficient data to determine the benefit-risk balance of mammography, no specific radiological monitoring is recommended.
In case of prescription after the age of 50, no specific radiological monitoring is recommended. The woman should be encouraged to participate in the national organized screening program.

Therefore, in the case of prescribing HRT, the prescribing physician cannot, at the risk of legal action, manage the treatment without recommending the systematic screening of his patient for breast cancer[8].

References

[1] https://jamanetwork.com/journals/jama/article-abstract/2653735

[2] https://www.lequotidiendumedecin.fr/actus-medicales/recherche-science/thm-letude-whi-montre-finalement-une-absence-de-surmortalite

[3] https://www.ansm.sante.fr/S-informer/Communiques-Communiques-Points-presse/Traitement-hormonal-substitutif-et-risque-de-cancer-du-sein

[4] Page 6 of the document: " STATUS AND KNOWLEDGE REPORT / GUIDELINE FILES".

FEBRUARY 2015

HORMONE TREATMENTS/MENOPAUSE AND RISKS OF CANCERS

Document written and coordinated by the Prevention Department, Public Health and Care Unit (PSPS)-INCa. "Although this hypothesis needs to be further explored, the decrease in breast cancer incidence has also been described in other countries where the drop in the prescription of THMs (hormonal treatment for menopause) has been spectacular, such as in Canada, Germany, the United States, Belgium and Australia".

[5] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31709-X/fulltext

[6] https://www.has-sante.fr/jcms/c_1754596/fr/traitements-hormonaux-de-la-menopause

[7] https://www.has-sante.fr/jcms/c_1741170/fr/depistage-du-cancer-du-sein-en-france-identification-des-femmes-a-haut-risque-et-modalites-de-depistage#toc_1_2

[8] https://cancer-rose.fr/2020/03/02/depistage-et-paradoxe-lors-de-lusage-de-certains-medicaments/

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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.

DIABETES AND CANCER

By Dr. C. Bour, January 5, 2021

The link between diabetes and cancer in general and diabetes and breast cancer in particular is well known, as shown in a 2012 meta-analysis [1].

This meta-analysis revealed a significant increase in the risk of breast cancer in women with diabetes compared to non-diabetic women. However, the association between diabetes and breast cancer risk appeared to be limited to postmenopausal women. Type 1 diabetes and diabetes in premenopausal women were not associated with a significant increase in breast cancer risk.

People with type 2 diabetes have a higher risk of developing cancers of the breast, pancreas, liver, kidney, endometrium and colon. 
While patients with type 1 diabetes are more likely to develop cervical and stomach cancers.

Several studies have also shown that patients with diabetes and cancer have a poorer prognosis than those without diabetes. Diabetes and hyperglycemia are associated with higher infection rates, shorter remission periods and shorter median survival times, as well as higher mortality rates[2].

Several mechanisms might explain why type 2 diabetes could increase the risk of cancer are being implicated: hyperinsulinemia, hyperglycemia and inflammation. The increase in blood glucose levels is believed to have carcinogenic effects by causing DNA damage.

Particular case of breast cancer

The meta-analysis discussed at the beginning of this article was conducted using a random effects model to study the association between diabetes and breast cancer risk [3].

The risk of breast cancer in women with type 2 diabetes is increased by 27%, a figure that decreases to 16% after adjusting for BMI. Obesity is an aggravating factor as shown in other studies.  

No increase in risk has been observed in women in pre-menopausal age or with type 1 diabetes.

In addition to the over-risk of cancer in the diabetic patient, what about the management of the patient with both diabetes AND cancer? [4] [5]

The management of the diabetic patient requires treatment not only by hygienic and dietetic measures but also by a finely tuned medication protocol that may include insulin and one or more oral agents.

Chemotherapy and analgesics can affect glucose homeostasis[6] and insulin sensitivity; drug interactions can interfere with the patient's tolerance to diabetes drugs; decreased appetite, nausea, vomiting and weight loss resulting from both disease and cancer treatment can cause imbalances in blood glucose levels.

Chemotherapeutic agents

Several chemotherapies are known to cause or exacerbate these adverse conditions. For example, cisplatin is known to cause kidney failure, and anthracyclines can cause cardiotoxicity. Cisplatin, paclitaxel and vincristine may be neurotoxic. Unfortunately, many of these side effects may remain permanent.

For cancer treatment to be effective, at least 85% of the chemotherapy dose must usually be administered. Patients with diabetes should be carefully monitored before the start and during chemotherapy. Treatment decisions should be based on the patient's clinical picture, but always be aware that any change in dose, or alteration in the timing of administration, or substitution of another chemotherapeutic agent may compromise results by reducing the response rate to treatment.

Corticosteroids

They represent an important part of treatment in cancer pathologies and are widely used to improve nausea and vomiting associated with chemotherapy, as well as to suppress neurological symptoms when the cancer has metastasized to the spine or brain. And they cause significant hyperglycemia within hours after administration. 

The treatment of hyperglycemia resulting from glucocorticoids then depends on the type of diabetes, the severity of the hyperglycemia levels, the dose and the duration of therapy. Administering steroids in multiple doses throughout the day instead of a single bolus dose, or administering the entire daily dose of steroids intravenously over 24 hours, can help control hyperglycemia.

Patients with pre-existing diabetes can be maintained on oral hypoglycemic agents and closely monitored. However, these medications are generally unsuitable for managing hyperglycemia in this setting and insulin is used.

Patients using insulin prior to glucocorticoid therapy will typically require both basal and preprandial insulin. These patients may require two to three times their usual insulin dose. Insulin is the preferred drug for the management of steroid-induced or steroid-exacerbated hyperglycemia in patients with known diabetes.

Patients with type 1 diabetes will need to adjust their dose. Type 2 patients who are already taking oral agents at baseline will add insulin, but only during this period when their blood glucose levels are high.

Several studies of cancers as disparate as small cell lung cancer and breast cancer have found an association between poorly controlled hyperglycemia and poor outcomes in these patients with both diabetes and cancer. Hyperglycemia also increases the risk of infection.

In patients with active cancer, the management of hyperglycemia focuses on the prevention of long-term complications to avoid acute and sub-acute outcomes, such as dehydration due to polyuria, infection, catabolic weight loss, hyperosmolar non-ketotic states and diabetic ketoacidosis [7].

Analgesics

Analgesics can cause constipation that affects patients in two ways. It can make them want to not eat, but also, by slowing down intestinal motility, narcotics may delay the absorption of nutrients. This can lead to a mismatch between the administration of insulin and the absorption of glucose. The patient faces the risk of hypoglycemia.

Statins and chemotherapy [8]

Statins and chemotherapeutic agents are metabolized by the same enzymes in the liver. 

If the liver enzymes are all captured by statin therapy, this may result in less elimination of chemotherapy. Some research suggests that it also works the other way around. If you give a statin to a patient on chemo and then stop the statin, he or she will eliminate the chemotherapy drug much more quickly. 

In general, therefore, there is a reluctance to start statin therapy in someone just starting chemotherapy because of possible hepatotoxicity," says Lavis [9] . If patients are already on statins, it is important to be aware of their effects and monitor them carefully. 

It is appropriate to target therapeutic interventions according to the patient's prognosis. If the prognosis is poor, we should be less demanding about the goals and not overburden the patient's treatment based on excessive expectations.

Prognosis and comfort

Prognosis, longevity and quality of life are important considerations in setting blood glucose targets. A pragmatic approach to the management of hyperglycemia in these patients is necessary.

The interest of a very strict glycemic control is to try to prevent complications in 10, 15, 20 years. 

But in a person with a poor prognosis or a life expectancy of only a few years, one must be more concerned about comfort and quality of life in the remaining years.

The goal would then be to avoid the effects of acute hyperglycemia, such as dehydration and ketoacidosis.

Conclusion

There is strong epidemiological evidence that diabetic diseases are associated with an accumulated risk of several cancers. There is also growing evidence that the degree of hyperglycemia and the treatment modalities for hyperglycemia influence cancer risk. 

The risk of breast cancer in women with type 2 diabetes is increased and obesity is an aggravating factor. On the other hand, there is no over-risk observed in women in pre-menopausal age or with type 1 diabetes.

The management of blood glucose levels in patients with diabetes and cancer can pose a significant clinical challenge. As there is no clear evidence that tight glucose control improves cancer outcomes, hyperglycemia must be managed pragmatically to ensure that the patient remains asymptomatic and at low risk of acute decompensation. 

Proactive management of glucocorticoid-induced hyperglycemia can help reduce large fluctuations in glucose levels. 

Read also :

https://www.healthline.com/diabetesmine/living-with-cancer-and-diabetes#1

References

[1] Diabetes and breast cancer risk: a meta-analysis  British Journal of Cancer (2012) 107, 1608–1617 https://pubmed.ncbi.nlm.nih.gov/22996614/

P Boyle M Boniol A Koechlin .....and P Autier1/Prevention Research Institute, 95 cours Lafayette, 69006 Lyon, France

[2] Clinical Challenges in Caring for Patients With Diabetes and Cancer
Helen M. Psarakis, RN, APRN-Diabetes Spectrum Volume 19, Number 3, 2006

https://spectrum.diabetesjournals.org/content/19/3/157

[3] https://pubmed.ncbi.nlm.nih.gov/22996614/

[4] https://endocrinenews.endocrine.org/july-2014-double-jeopardy/

[5] Clinical Challenges in Caring for Patients With Diabetes and Cancer-Helen M. Psarakis, RN, APRN-Diabetes Spectrum Volume 19, Number 3, 2006

https://spectrum.diabetesjournals.org/content/19/3/157

[6]  Phenomenon by which a key factor is regulated to persist around a beneficial value for the body.

[7] https://www.cancernetwork.com/view/diabetes-management-cancer-patients

[8] https://endocrinenews.endocrine.org/july-2014-double-jeopardy/

[9] Victor Lavis, MD, professeur au Département de néoplasie endocrinienne et des troubles hormonaux à l'Université du Texas MD Anderson Cancer Center à Houston.( https://endocrinenews.endocrine.org/july-2014-double-jeopardy/)

 

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