Translation and synthesis by Cancer Rose, February 10, 2024

Journal article on atypia and new recommendations

Free opinion, Dr C.Bour, radiologist

Related article on 'in situ'

Atypia detected at breast cancer screening and subsequent development of cancer: observational analysis of the prospective Sloane atypia cohort in England.

BMJ 2024; 384 doi: https://doi.org/10.1136/bmj-2023-077039 (Published February 01, 2024) https://doi.org/10.1136/bmj-2023-077039

Karoline Freeman, senior research fellow (Warwick Screening, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK) ; David Jenkinson, senior research fellow (Screening Quality Assurance Service, NHS England, Birmingham, UK),Karen Clements, breast cancer research manager (Screening Quality Assurance Service, NHS England, Birmingham, UK),  Matthew G Wallis, consultant radiologist,  Sarah E Pinder, professor of breast pathology,   Elena Provenzano, lead consultant breast pathologist,  Hilary Stobart, patient representative, Nigel Stallard, professor of medical statistics,  Olive Kearins, national lead breast screening, Nisha Sharma, consultant breast radiologist,  Abeer Shaaban, consultant pathologist, Cliona Clare Kirwan, consultant oncoplastic breast surgeon, Bridget Hilton, national audit project senior QA officer, Alastair M Thompson, section chief breast surgery, Sian Taylor-Phillips, professor of population health on behalf of the Sloane Project Steering Group.

WHAT IS AN ATYPIA?

This term covers what are also known as "borderline lesions", which are on the increase as a result of screening and the multiplication of breast biopsies.

They constitute a fringe of breast abnormalities between strictly benign and strictly malignant lesions, and the boundaries between the two are often blurred, frequently leading the pathologist to "upgrade" his report for fear of undertreatment. These lesions are a major source of the problem of over-treatment generated by systematic breast cancer screening.

Frontier lesions are varied, bearing different names depending on their characterization under the microscope, and are classified in the table below, according to the risk of breast cancer attributed to them. The second table lists the therapeutic proposals currently in place.

ISSUES AND BACKGROUND

These borderline lesions raise a number of problems.

First of all, for the pathologist, their diagnostic identification requires a high level of experience, an infallible technique, and a solid knowledge of the classification criteria to ensure that the result of the histological analysis is reproducible and identical if read by another pathologist, which is not always guaranteed....

Then, for the patient, treatment is based on what has been identified in the guided biopsy specimen. But the different entities found in a sample are sometimes intertwined, and the boundaries unclear; in a focal point of atypia, there may be a micro-focal of in situ, making classification decisions very difficult and leading to more extensive treatment. And very often, most of these lesions, which were thought to lead de facto to breast cancer, are surgically excised, as illustrated in figure 1 of the article on the study we're about to discuss (Click on the image).

This is a study of a cohort of 3,238 women diagnosed with epithelial atypia, known as the English 'Sloane' cohort. This cohort is linked to the English Cancer Registry and the Mortality and Birth Information System, to obtain information on subsequent breast cancers and mortality.

The aim of the study was to compare the number and type of breast cancers developed after atypia screening with the 11.3 cancers estimated to be found subsequently by screening per 1000 women over a three-year screening cycle, in the UK.
More specifically: The aim is to find out whether women with atypia have an increased risk of developing more cancers, and if so, which atypia are more predisposing to cancer.
To this end, data from this cohort were collected on radiology, histopathology, surgery and radiotherapy forms, in order to provide robust and generalizable evidence on atypia behavior.
The occurrence of subsequent cancers was compared by comparing women in the 'Sloane Atypia' project database with data from the National Cancer Registry, and mortality information was added. The main follow-up criteria are the number and type of invasive breast cancers detected one, three and six years after the diagnosis of atypia, by type of atypia, age and year of diagnosis.

CURRENT FINDINGS ON ATYPIA

The authors first observe:
“There was a fourfold increase in detection of atypia after the introduction of digital mammography between 2010 (n=119) and 2015 (n=502).”

This can be seen very clearly in the detailed graphs below, compiled in figure 3 of the article. (Click on the image)

Overall, this surge in over-detections was easily observed when we switched to digital mammography around 2010, which is much more sensitive to the detection of microcalcifications in particular. Microcalcifications are one of the three main radiological signs that we look for on mammograms, which may indicate the presence of cancer including : masses, architectural distortions and microcalcifications, which the digital process detects particularly well.

The explanations put forward for the excess detection of these lesions are as follows:
“We propose that the gradual introduction of digital mammography in England since 2010, which identifies more microcalcifications could explain a large proportion of the increase in atypia from 2012 and might be the reason why lower rates of subsequent invasive cancers were detected in women with atypia from 2012 onwards.
The remaining increase in atypia incidence might be because of a shift in atypia definitions and pathologists refining their diagnostic criteria, particularly the diagnosis and terminology of columnar cell lesions.”

“Another factor possibly relating to the increase in atypia could be the increased size of the biopsy needle that might have been used in recent years, increasing the probability of finding atypia and decreasing the probability of misclassifying atypia as DCIS.”

STUDY RESULTS

The analysis focused on the following key questions:

1.         How many women develop cancer after a diagnosis of atypia, and when?
2.         What type of cancer occurs?
3.         How many cancers are not detected when atypia is diagnosed?
4.         Does the risk of developing cancer depend on the type of atypia?
5.         How does this compare with women screened without the diagnosis of atypia?

The results are as follows:

"-The number of cancers after diagnosis of atypia (at 3 and 6 years) was low, and these cancers were similar to those in the general screening population, with similar homolateral and contralateral risk.
-Few cancers were missed when atypia was diagnosed, and VAE (minimally invasive vacuum-assisted excision) did not result in more missed cancers than surgical management.
-The number of cancers did not differ significantly by type of atypia, breast density or age, after adjustment for year of diagnosis.
-The number of cancers after 3.5 years following diagnosis of atypia was equal to the number of cancers in the general screening population.
-Cancer risk in recent years has been lower than historical risk, probably due to the introduction of digital mammography which identifies more microcalcifications, a change in atypia nomenclature and refinement of diagnostic criteria by pathologists, as well as an increase in biopsy needle size.

To summarize: "Women with more recently detected atypia had lower rates of subsequent cancers detected within three years" and "the grade, size and lymph node involvement of subsequent invasive cancers were similar to those of cancers detected in the general screening population, with equal numbers of homolateral and contralateral cancers."

The analyses confirmed that, in the short term, many atypical lesions may represent risk factors rather than true precursors to invasive cancer, and concluded that annual mammography for 5 years after the diagnosis of atypia may not benefit women under the current English NHS breastcancer screening program. In addition, recent changes to mammography and biopsy techniques appear to identify cases of atypia that are more likely to represent overdiagnosis."

CONCLUSION

The authors conclude as follows:

"It appears that few cancers were unrecognized at the time of diagnosis of atypia, and that non-surgical management proved as safe as surgical excision of atypia in this cohort."
“The characteristics of cancers detected after atypia were similar to cancers detected in the general screening population and no subgroup was identified that was at increased risk of developing invasive cancer. Therefore, the reporting of atypia at screening could contribute to the problem of overdiagnosis in breast cancer screening.”

And so they suggest:

“Many epithelial atypia diagnoses might represent risk factors rather than precursor lesions for invasive cancer “
"Annual mammography in the short term after atypia diagnosis might not be beneficial and should be reviewed."

IMPLICATIONS FOR CLINICAL PRACTICE

Recommendations for the follow-up of these lesions are likely to require substantial change.
The authors write:

"The results suggest that an additional annual mammogram for the first three years following a diagnosis of epithelial atypia may not be necessary in addition to the standard UK screening practice offered to all women (i.e. once every three years).
The number of women diagnosed with atypia who developed cancer in the first three years was low."

Guidelines in the UK, Europe and America generally recommend excision of atypia by biopsy or surgical biopsy-exeresis, followed by close imaging surveillance.
Based on what this study adds in terms of knowledge about these lesions, the authors, in a second publication which we shall see, suggest a modification of the recommendations.

The additional insights that the Sloane cohort study provides are:
"- Breast cancer diagnosis within three years of atypia was low, particularly in more recent years (since 2012), and may contribute to increased overdiagnosis in breast cancer screening.
- More frequent mammography for five years after the diagnosis of atypia may not be beneficial in quality-assured breast cancer screening programs that include universal use of digital mammography and vacuum-assisted excision of indeterminate lesions; these surveillance protocols should be reviewed.
- Surgical removal of atypia has not been shown to be necessary to avoid missed cancers; suction-assisted excision appears to be as safe as surgical excision in the management of atypia."

Recommendations based on these new data should be considered.

Evidence-informed recommendations on managing breast screening atypia: perspectives from an expert panel consensus meeting reviewing results from the Sloane atypia project

British Journal of Radiology, Volume 97, Issue 1154, February 2024, Pages 324–330, https://doi.org/10.1093/bjr/tqad053

Karoline Freeman, PhD,  Alice Mansbridge, BSc,  Hilary Stobart, MSc,  Karen Clements, BSc, Matthew G Wallis, MBChB,  Sarah E Pinder, MBChB,  Olive Kearins, MSc, Abeer M Shaaban, MBBCh, MSc, PhD,  Cliona C Kirwan, MBBS, BSc, PhD, Louise S Wilkinson, BMBCh,  Sharon Webb, MPH,  Emma O’Sullivan, BSc, Jacquie Jenkins, MSc,  Suzanne Wright, PhD,  Kathryn Taylor, DCR, MSc, Claire Bailey, BNurs,  Chris Holcombe, MD,  Lynda Wyld, BMedSci, MBChB, PhD, Kim Edwards, MBBCh, DMRD,  David J Jenkinson, PhD,  Nisha Sharma, MRCP, Elena Provenzano, MB BS, PhD,  Bridget Hilton, BSc,  Nigel Stallard, PhD, Alastair M Thompson, BSc, MBChB, MD, Sian Taylor-Phillips, PhD on behalf of the Sloane Project Steering Group

A half-day consensus meeting was held, attended by 11 clinical experts, a representative of the Independent Cancer Patients Voice, six NHS England representatives, and two researchers, to discuss the results of the Sloane Atypia analysis, mentioned above, and to re-consider existing guidelines and actions.

Until now, explain the authors, “The guidelines were based around existing evidence on upgrade rates to cancer on excision and long-term cancer risk. However, no evidence on the effectiveness of short-term regular surveillance mammography was available and the guidelines included a comment that this should be amended as “more data and national guidance become available.”

Which is now the case.

REVISED RECOMMENDATIONS FOR WOMEN IN THE UNITED KINGDOM

The group decided by a majority of 17/19 (89.5%, one person left the group) on the current evidence, that annual surveillance mammography for the first five years is not beneficial for women with atypia, regardless of the type of atypia or the woman's age.

The group recommended that women with screen detected atypia should be offered routine 3-yearly screening (as is done for the population of women aged 50-70 in the UK), with a clear message that thorough investigation has shown that they do not have cancer and therefore management should be the same as for those without cancer.

SITUATION IN FRANCE

We very much hope that French recommendations will also wisely evolve towards de-escalation of follow-up.

For the time being, this is what is recommended by the Institut National du Cancer and the Haute Autorité de Santé:

In addition to reducing the annual mammography follow-up scheduled for 10 years in France (up to now, only 5 years in the UK), and the associated risks (radiation, over-diagnosis), it would also reduce the anxiety associated with this excessive follow-up, and free these women from the "high-risk woman" label.
The 2019 HAS recommendations concerning "specific screening modalities for high-risk women" are based on the 2014 recommendation, with the bibliography including a framework note dating back to 2011; we can't say that the sources are very recent.

It's high time to modernize all this, and, of course, to provide women with clear information on the escalating overdiagnosis and overtreatment that occur as a result of screening itself, as requested by the 2016 citizens' consultation, which has so far gone carefully ignored.

Reflexion of a radiologist

February 11, 2024, Dr Cécile Bour, Radiologist

After reading recent publications on carcinomas in situ and so-called "borderline" lesions of the breast, representing a useless over-detection of screening because they have no impact on women's lives, I'd like to make a few personal observations. They are based on my own practice and the findings I've been able to accumulate, having followed this screening closely from its genesis and generalization in 2004 as a young radiologist, all the way to the present day, at an age when my career is coming to an end.

It's important to remember, over and over again, that the main aim of screening is not to find as many lesions as possible, or to find as many things as possible, but to achieve three types of benefit:
- to reduce mortality from the disease,
- to reduce the number of advanced forms of breast cancer,
- to ease the burden of treatment, by reducing the need for total mastectomies and other major treatments.

The effect on breast cancer mortality is unproven (according to various hypotheses and meta-analyses, it would be necessary, broadly speaking, to monitor 700 to 2,500 women for fourteen to 20 years to find a single death avoided). In parallel:
- Excess diagnoses, called overdiagnoses, according to the most pessimistic assessments reach 30 to 50%.
- Interval cancers, despite all efforts at early detection, which are the most harmful and aggressive, still account for a third of all cancer cases.
-aggressive treatments are on the increase. (Approximately 30 to 35% more chemotherapy and radiotherapy. Surgical procedures are not decreasing at all, on the contrary).

From the 1990s onwards, as screening became more widespread, there was a surge in the number of ductal cancers in situ.
This spectacular increase in the number of in situ cancers diagnosed was reported as early as 1996 by Virginia Ernster, an epidemiologist at the University of California, San Francisco (Ernster VL, Barclay J et al. Incidence of and treatment for ductal carcinoma in situ of the breast. JAMA. 1996 Mar 27;275(12):913-8. )

Atypical lesions and borderline lesions were already highlighted by Nielsen in a meta-analysis of autopsy studies, based on 13 studies from 10 different countries, over 6 decades (1948 to 2010), including 2363 autopsies with 99 cases of so-called "incidentalomas" ("incidental findings"), precancerous lesions, cancers in situ and atypical hyperplasia, but few invasive cancers.

Two studies also shed light on these lesions and the fact that their presence in the breast is frequent, without impacting women's lives: the Nashville, Tennessee study (Page Dl, Dupont WD et al. Continued local recurrence of carcinoma 15-25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy. Cancer. 1995 Oct 1;76(7):1197-200. ), and the Bologna study in Italy (Eusebi V, Feudale E, Foschini MP et al. Long-term follow-up of in situ carcinoma of the breast. Seminars in Diagnostic Pathology. 1989;6(2):165-173. )
They report cases of women for whom the diagnosis of carcinoma in situ was made ten to twenty years late. When the biopsies were first read, in the 1950s for one study and in 1960 for the other, the lesions were classified as benign.
The women had therefore not been treated.
But after a more recent re-reading of these same biopsies, it turned out that these women were in fact carriers of in situ cancer.
How did these cancers, which had escaped the vigilance of doctors, evolve? Ten years later, 25% of the Tennessee women who were still alive had invasive cancer, and twenty years later, 11% of the Italian women had invasive cancer. In other words, 75% and 89% respectively of these women with carcinoma in situ had NOT developed invasive cancer.

Of course, you could argue that it's a pity for the majority of women with in situ cancer to be treated unnecessarily to save the small minority with DCIS who will develop invasive cancer. But it's an acceptable harm all in all.
If this were indeed the case and if the treatment of DCIS were beneficial, we would see a reduction in the most serious forms of cancer among women screened, and a drastic drop in breast cancer mortality. But this is not happening.
A very recent study shows that screening does not prolong life.
The Toronto study shows that treating ductal cancer in situ does not reduce breast cancer mortality, and preventing recurrence by radiotherapy or mastectomy does not reduce breast cancer mortality either.

The diagnosis of in situ cancer by screening has a profound impact on the quality of life of women who, uninformed of the potential dangers to which screening exposes them, continue to undergo aggressive treatment and the profound fear of disease without any proven benefit.

Where are we now?

We're trying to "catch up". We've gone wrong, we've promised women the impossible, and since this Titanic of screening can't go backwards, we're trying to throw it a few lifelines by attempting, as best we can, to limit the damage and advocate therapeutic de-escalation.
But we are cynical enough to do this "in agreement with the patient", giving her the opportunity to make her "own decision".

So, yes, it's all very well and very modern to make a shared decision, and we're all in favor of it, who could be against ?
But in the end, after decades of terrorizing women that they might get breast cancer if we relaxed the pressure even a little, after telling them that every minute counts, that we mustn't leave even the smallest degraded cell in a breast, now we're putting the brakes on to reduce our abusive treatments. And we're putting all the weight of the decision, which women will always feel is fraught with consequences, on their shoulders. The questions "Did I do the right thing?" will hang over her like a sword of Damocles for the rest of her life, from exam to exam.

The therapeutic de-escalation we're calling for, will do nothing to relieve women of mortal anguish. We've just loosely shifted the burden of responsibility from the doctor to the woman. Instead of having the courage, all of us, to tell women that screening campaigns were introduced too quickly, too early, without sufficient proof, that we were on the wrong track, that we screwed up, that there's no real loss of chance in not going for screening, that we can do without it, that in the end, the further we go, the more we tinker, the more we change our "therapeutic cuisine" without getting to the end of the killer cancer, the only one we needed to curb, which screening has completely failed to do.

I believe it is incredibly cynical to place all of the responsibility on the shoulders of women.

Related article: Changing the narrative on ductal carcinoma in situ and breast cancer risk

We've often talked about the particular case of carcinoma in situ (DCIS), considered a non-cancer, or "stage 0" cancer, to the extent that it is not counted in the figures for new cases of breast cancer in the statistics of institutes monitoring disease epidemiology, nor by the French National Cancer Institute.

Some scientists think it should be " renamed ", and no longer referred to as " carcinoma ". It is currently considered more as a non-obligatory risk factor for subsequent breast cancer.
We need to change the narrative on this particular entity, and re-consider the risk it exposes women to of invasive cancer, and thereby also change follow-up attitudes and therapeutic recommendations.
In short, we need to take the same steps as for atypia, in any case to move towards a de-escalation of treatment, and a less frightening vision for women of their " disease " condition.

This is what emerges from this October 2023 publication, which we translate below, and which gives the results of a research project, called PRECISION. The aim of this research project is to find out how low-risk DCIS differs from higher-risk DCIS, to help women better adapt treatments and avoid over-treatment.

The article:

Article written by Bethan Warman, with thanks to Esther Lips, Marjanka Schmidt, Jelle Wesseling and Hilary Stobart for their input.

In 2015, Cancer Grand Challenges set the Lethal versus Non-lethal Cancers challenge with the aim of finding ways to distinguish between lethal cancers that need treating and non-lethal cancers that don’t. Since 2017, the PRECISION team, led by Professor Jelle Wesseling of The Netherlands Cancer Institute (NKI), has been addressing this challenge in ductal carcinoma in situ (DCIS).

DCIS is the presence of abnormal cells within the breast milk ducts. By definition, these abnormal cells are non-invasive, but in a small number of cases they can develop into ipsilateral (same breast) invasive breast cancer. 
Despite the chances of progression to breast cancer being low, DCIS is often referred to as early breast cancer and therefore treated as such. Part of PRECISION’s efforts has been to refine this narrative. 

In a new multinational study of over 47,000 women with DCIS from the Netherlands, UK and US, published in the British Medical Journal, the team reported that the 10-year cumulative incidence of ipsilateral invasive breast cancer after DCIS was 3.2%. 
“I think our most important finding is that invasive ipsilateral cancer after DCIS is really a rare event and so it's even more important that we find out who are the women that are at risk. DCIS itself is not life threatening, and we don't want to treat all women intensively, unnecessarily,” says Professor Marjanka Schmidt of the NKI, co-investigator in PRECISION and lead author of the paper.

The finding was part of a study that set out to determine the association of DCIS size and margin status with the risk of developing ipsilateral invasive breast cancer. These two clinical factors are often used in the clinic to stratify the risk of DCIS lesions and determine the course of treatment. 
Currently, treatment is generally recommended for all women with DCIS and may include surgery, radiation and hormone therapy. Doctors may use the grade of DCIS to help decide on the best treatment approach. 
But in most cases, women will have undergone treatment for DCIS that would have not progressed to cancer. To reduce the burden of overtreatment, there is an urgent need to find ways to distinguish the cases of DCIS that are at high risk of developing into invasive breast cancer from those that are at low risk. 

The team combined data from four patient cohorts – one from the Netherlands, one from the UK and two from the US – comprising 47,695 women diagnosed with DCIS between 1999 and 2017 who had received either breast conserving surgery or mastectomy, often followed by radiotherapy or hormone treatment, or both.

They found only a weak association between DCIS size and margin status and the risk of subsequent invasive breast cancer in the same breast, concluding that clinical features such as these were limited in discriminating between low- and high-risk DCIS.
“We concluded that these associations are not large enough to, in clinical practice, drive the decisions around who we should treat and who we should not treat,” says Marjanka. 

The study is the largest of its kind to date to explore the value of prognostic risk factors after DCIS, made possible by the international collaborations established between the research groups in PRECISION and the large-scale funding of the Cancer Grand Challenges initiative. 
“By combining and comparing the multiple patient cohorts, we saw that the risk of subsequent invasive breast cancer in the same breast is very similar for the UK, US and the Netherlands, and other clinical variables are actually very comparable too. Although the cohorts have been collected in a different way and the treatments are somewhat different between countries, the actual risks amongst women are very similar,” adds Dr Esther Lips of the NKI, PRECISION co-investigator and senior author on the paper.

Emphasising the need for the Lethal versus Non-lethal Cancers challenge

The vision for the Lethal versus Non-lethal Cancers challenge was to be able to identify changes that distinguish a non-lethal from a potentially lethal tumour and then determining how these changes can be detected accurately. 
This work from the PRECISION team really emphasises the need of solving this challenge in DCIS, and raises important considerations for the clinical management of DCIS.
“Everything we knew about DCIS in daily practice prior to PRECISION was largely based on relatively small, often biased series that could not yield the impact to inform guidelines in the clinic,” says Jelle.
“While we want to preserve the excellent treatment outcomes for women with high-risk DCIS, we need to know exactly which women are at high risk. And I think this paper shows that some key clinically used factors, such as size and margin status, are in fact not really indicative of the risk. Even though it makes a slight difference, it doesn't have clinical utility.”

Alongside the team’s research, the collaborative work of the PRECISION team has sparked important conversations across national borders amongst researchers, patient advocates and clinicians around defining DCIS and raising awareness about breast cancer risk. 
Understanding the risk is particularly important for women with DCIS who face the decision of whether or not to pursue treatment. “Women need much more information about their individual future risks before they make treatment decisions, but the dilemma is that clinicians and scientists still can’t safely distinguish which DCIS will progress and which will not,” says Hilary Stobart, a patient advocate on the team. 
“The international PRECISION team is working hard to resolve this dilemma by working together to find a combination of biomarkers which will safely distinguish those women who have DCIS which needs treating and those who do not. This large ‘real-world’ international study is an important step towards that goal, so that women and their clinicians will be able to make informed treatment decisions and potentially avoid overtreatment. It has been a great privilege to be a patient advocate working with the PRECISION team.”

The findings underline the need for new prognostic markers, and PRECISION has been exploring several avenues with the aim of finding biological markers that can be used as tools to assess breast cancer risk following a DCIS diagnosis.
The PRECISION team is funded by Cancer Research UK and the KWF Dutch Cancer Society. 
“In a multidisciplinary team, PRECISION tries to identify risk factors to predict whether a woman with DCIS needs treatment or not. Being able to tailor treatments to an individual’s risk, with the aim to prevent overtreatment, fits very well with KWF’s main goals to stimulate better treatment for every type of cancer and to aim for a better quality of life for patients,” says Carla van Gils, director of the KWF Dutch Cancer Society.

Read the full paper in the British Medical Journal.