Carcinoma in situ, the problem of its overdiagnosis in screening mammography

Cécile Bour, MD

October 21, 2020

What is carcinoma in situ?

Carcinoma in situ (CIS) of the breast is defined by the proliferation of cancer cells within a milk duct without the cells spreading beyond the wall of the duct into the rest of the breast.

It is either strict ductal, developing in the milk excretory duct (ductal carcinoma in situ or DCIS), or in the lobule, the excretory unit around the duct (lobular carcinoma in situ or LCIS).

We have synthesized the main information in a summary for quick reading here: https://cancer-rose.fr/en/2020/11/30/what-is-a-ductal-carcinoma-in-situ-dcis/

In the media library you will also find some examples of images:

A very interesting blog by Donna Pinto is dedicated to DCIS with a lot of very practical and useful information: https://dcis411.com/

Ductal carcinoma in situ (DCIS) was rarely diagnosed before the introduction of breast screening, and now it accounts for 20-25% of all breast cancers, with this increase being directly correlated to over-detection by national routine breast cancer screening programs. 

Yet most DCIS lesions remain indolent. 

The problem

Despite being a pre-invasive or even non-invasive lesion, and although the natural evolution of this intra-ductal process is unknown, DCIS is still considered the early, non-obligatory form of (stage 0) breast cancer. The fear of not being able to distinguish between harmless lesions and potentially invasive forms, leads to over-treatment of this condition in many patients.

Therefore the classical patient management, and also in France, is to treat all DCIS lesions with a treatment that includes either mastectomy or breast conservative surgery supplemented by radiotherapy. 

The Marmot report in the United Kingdom (screening assessment report, 2012), recognized the burden of excessive treatment on women's well-being[1]. 

As a matter of fact, women with DCIS are labeled as "cancer patients", with concomitant anxiety despite the fact that most DCIS lesions are unlikely to ever progress to invasive breast cancer. ... The inflicted treatment (surgery followed or not by  radiotherapy) is therefore excessive for some, and very likely for many women, having a strong negative impact on their quality of life.

This particular form of cancer, that some call "pre-cancer" or " false cancer",  and some even consider as a non-cancer and only as a risk marker for breast cancer, greatly contributes to overdiagnosis, i.e. the discovery of abnormalities that, if they had remained unknown, would never have endangered the woman's life or health.

The problem with DCIS is that it is very easily revealed by mammography because of its association with calcifications, which are easily detected by mammography.

The data

The number of women diagnosed with DCIS in recent decades follows largely the introduction of  breast cancer mass screening, and is growing in parallel with the participation in screening[2] [3] [4] [5] [6].

The European standardised rate (i.e. the age-adjusted rate for the European population) of in situ lesions has quadrupled from 4.90 per 100,000 women in 1989 (representing 4.5% of all registered breast cancer diagnoses) to 20.68 per 100,000 women in 2011 (representing 12.8% of all registered breast cancer diagnoses[7] ). Of all reported in situ breast lesions, 80% are DCIS [8] [9].

Nevertheless, the incidence of breast cancer mortality has not decreased with the detection and treatment of DCIS, indicating that the management of DCIS does not reduce specific mortality from breast cancer.

A review of autopsies in women of all ages revealed a median prevalence (existing cases) of 8.9% (range 0-14.7%).  For women over 40 years of age, this prevalence was 7-39% [10], whereas breast cancer is diagnosed in only 1% of women in the same age group [11]. 

This means that these lesions are present more frequently than they are diagnosed in women in the living population, and that a large number of women carry undetected DCIS that would never become symptomatic, since more of them are found in women who have died from other causes than in the living population at the same time.

Classical lobular carcinoma in situ (LCIS), on the other hand, confers a risk of 1-2% per year of developing into invasive disease[12] [13].

What is also known, is that the stage of carcinoma in situ detected, is not a good and reliable indicator of the risk of progression of this lesion [14] [15].

In addition, patients diagnosed with DCIS have an excellent breast cancer specific survival rate, of approximately 98% after 10 years of follow-up [16] [17] [18] [19] and a normal life expectancy. If low-grade DCIS (considered a low-risk lesion) progresses to invasive breast cancer, it will often be a slow-growing, early-detectable, lower-stage invasive disease with an excellent prognosis.

However, despite this excellent prognosis and normal life expectancy, women diagnosed with DCIS suffer from stress and anxiety [20].  Studies report that most women with DCIS (and early breast cancer) have little knowledge about their condition and have misperceptions about the risk of disease progression, and this misperception is associated with significant psychological distress [21] [22] [23] [24] [25] [26].

In view of all these elements, it is considered that the current management of DCIS involves excessive treatment.

The problem of overtreatment

Currently, a conservative breast treatment for DCIS is frequently recommended. A mastectomy is advised if the DCIS is too large to allow breast conservation. Radiotherapy is often combined, which has been proven effective in reducing the risk of local recurrence.

However, it is also known that treating ductal carcinoma in situ does not reduce breast cancer mortality; also preventing recurrence by radiotherapy or mastectomy has also been shown not to reduce the risk of breast cancer mortality. Treatment would also not extend either breast cancer-specific survival or overall survival [27].

Due to the side effects of hormone therapy and ambiguous clinical trial results, postmenopausal women with DCIS are rarely treated with endocrine therapy in many countries. 

Some leads

Given the disappointing results of DCIS management in terms of reduction of invasive cancers, considering the absence of impact on survival, the implementation of treatments that were ultimately too severe for the results observed, and the major psychological impact, several countries have undertaken clinical trials aimed at testing a simple active surveillance, particularly for low grade CIS, rather than aggressive treatment.

Three clinical trials have randomized patients with low risk DCIS into two groups, one group under active surveillance versus one group receiving standard therapy. 

- COMET(US) [28] [29]
- LORIS(UK) [30]
- LORD(EU) [31]

A research program (PRECISION) has been initiated, encompassing these 3 international trials. https://www.dcisprecision.org/wp-content/uploads/2020/08/DCIS-Nieuwsbrief-Final_140820.pdf

CONCLUSION

There is an uncertainty regarding the manner in which DCIS develops, and there is a lack of global consensus on the best way to manage this lesion in an optimal manner. 

A better understanding of the biology of DCIS and the natural course of the disease is needed to help patients and health care professionals make more informed treatment decisions, to reduce the current over-treatment of DCIS that results in physical and emotional harm to patients and unnecessary costs to society. 

There is even an urgent need to reframe patients' perceptions of risk.

Initiatives and trials will hopefully contribute to better knowledge and informed decision-making between patients and clinicians.

Read also: https://www.nature.com/articles/s41416-019-0478-6

References

[1] Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet 380, P1778–P1786 (2012).

[2] Bleyer, A. & Welch, H. G. Effect of three decades of screening mammography on breast-cancer incidence. N. Engl. J. Med.367, 1998–2005 (2012).

[3] Bluekens, A. M., Holland, R., Karssemeijer, N., Broeders, M. J. & den Heeten, G. J. Comparison of digital screening mammography and screen-film mammography in the early detection of clinically relevant cancers: a multicenter study.Radiology 265, 707–714 (2012).

[4] Ernster, V. L., Ballard-Barbash, R., Barlow, W. E., Zheng, Y., Weaver, D. L., Cutter, G. et al. Detection of ductal carcinoma in situ in women undergoing screening mammography. J. Natl. Cancer Inst. 94, 1546–1554 (2002).

[5] Esserman, L. J., Thompson, I. M. Jr. & Reid, B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement.JAMA 310, 797–798 (2013).

[6] Kuerer, H. M., Albarracin, C. T., Yang, W. T., Cardiff, R. D., Brewster, A. M., Symmans, W. F. et al. Ductal carcinoma in situ: state of the science and roadmap to advance the field. J. Clin. Oncol. 27, 279–288 (2009).

[7] https://www.nature.com/articles/s41416-019-0478-6

[8] Kuerer, H. M., Albarracin, C. T., Yang, W. T., Cardiff, R. D., Brewster, A. M., Symmans, W. F. et al. Ductal carcinoma in situ: state of the science and roadmap to advance the field. J. Clin. Oncol. 27, 279–288 (2009).

[9] Siziopikou, K. P. Ductal carcinoma in situ of the breast: current concepts and future directions. Arch. Pathol. Lab. Med.137, 462–466 (2013).

[10] Welch, H. G. & Black, W. C. Using autopsy series to estimate the disease ‘reservoir’ for ductal carcinoma in situ of the breast: https://www.acpjournals.org/doi/10.7326/0003-4819-127-11-199712010-00014

[11] Siziopikou, K. P. Ductal carcinoma in situ of the breast: current concepts and future directions. Arch. Pathol. Lab. Med. 137, 462–466 (2013).

[12] Lakhani, S. R., Audretsch, W., Cleton-Jensen, A. M., Cutuli, B., Ellis, I., Eusebi, V. et al. The management of lobular carcinoma in situ (LCIS). Is LCIS the same as ductal carcinoma in situ (DCIS)? Eur. J. Cancer 42, 2205–2211 (2006).

[13] Ottesen, G. L., Graversen, H. P., Blichert-Toft, M., Christensen, I. J. & Andersen, J. A. Carcinoma in situ of the female breast. 10 year follow-up results of a prospective nationwide study. Breast Cancer Res. Treat. 62, 197–210 (2000).

[14] Elshof, L. E., Schaapveld, M., Schmidt, M. K., Rutgers, E. J., van Leeuwen, F. E. & Wesseling, J. Subsequent risk of ipsilateral and contralateral invasive breast cancer after treatment for ductal carcinoma in situ: incidence and the effect of radiotherapy in a population-based cohort of 10,090 women.Breast Cancer Res. Treat. 159, 553–563 (2016).

[15] Bijker, N., Peterse, J. L., Duchateau, L., Julien, J. P., Fentiman, I. S., Duval, C. et al. Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J. Clin. Oncol.19, 2263–2271 (2001).

[16] Worni, M., Akushevich, I., Greenup, R., Sarma, D., Ryser, M. D., Myers, E. R. et al. Trends in treatment patterns and outcomes for ductal carcinoma in situ. J. Natl. Cancer Inst.107, djv263 (2015).

[17] Morrow, M. & Katz, S. J. Addressing overtreatment in DCIS: what should physicians do now? J. Natl. Cancer Inst. 107, djv290 (2015).

[18] Fisher, E. R., Dignam, J., Tan-Chiu, E., Costantino, J., Fisher, B., Paik, S. et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 86, 429–438 (1999).

[19] Elshof, L. E., Schmidt, M. K., Rutgers, E. J. T., van Leeuwen, F. E., Wesseling, J. & Schaapveld, M. Cause-specific mortality in a population-based cohort of 9799 women treated for ductal carcinoma in situ. Ann. Surg. 267, 952–958 (2017).

[20] Ganz, P. A. Quality-of-life issues in patients with ductal carcinoma in situ. J. Natl. Cancer Inst. Monogr. 2010, 218–222 (2010).[21] Hawley, S. T., Janz, N. K., Griffith, K. A., Jagsi, R., Friese, C. R., Kurian, A. W. et al. Recurrence risk perception and quality of life following treatment of breast cancer. Breast Cancer Res. Treat. 161, 557–565 (2017).

[22] Ruddy, K. J., Meyer, M. E., Giobbie-Hurder, A., Emmons, K. M., Weeks, J. C., Winer, E. P. et al. Long-term risk perceptions of women with ductal carcinoma in situ. Oncologist18, 362–368 (2013).

[23] Liu, Y., Pérez, M., Schootman, M., Aft, R. L., Gillanders, W. E., Ellis, M. J. et al. A longitudinal study of factors associated with perceived risk of recurrence in women with ductal carcinoma in situ and early-stage invasive breast cancer. Breast Cancer Res. Treat. 124, 835–844 (2010).

[24] van Gestel, Y. R. B. M., Voogd, A. C., Vingerhoets, A. J. J. M., Mols, F., Nieuwenhuijzen, G. A. P., van Driel, O. J. R. et al. A comparison of quality of life, disease impact and risk perception in women with invasive breast cancer and ductal carcinoma in situ. Eur. J. Cancer 43, 549–556 (2007).

[25] Partridge, A., Adloff, K., Blood, E., Dees, E. C., Kaelin, C., Golshan, M. et al. Risk perceptions and psychosocial outcomes of women with ductal carcinoma in situ: longitudinal results from a cohort study. J. Natl. Cancer Inst. 100, 243–251 (2008).

[26] Davey, C., White, V., Warne, C., Kitchen, P., Villanueva, E. & Erbas, B. Understanding a ductal carcinoma in situ diagnosis: patient views and surgeon descriptions. Eur. J. Cancer Care 20, 776–784 (2011).

[27] https://jamanetwork.com/journals/jamaoncology/fullarticle/2427491

[28] Comparison of operative versus medical endocrine therapy for low risk DCIS: the COMET Trial. http://www.pcori.org/research-results/2016/comparison-operative-versus-medical-endocrine-therapy-low-risk-dcis-comet.

[29] Hwang, E. S., Hyslop, T., Lynch, T., Frank, E., Pinto, D., Basila, D. et al. The COMET (Comparison of Operative to Monitoring and Endocrine Therapy) Trial: a phase III randomized trial for low-risk ductal carcinoma in situ (DCIS). BMJ Open 9, e026797 (2019).

[30] Francis, A., Thomas, J., Fallowfield, L., Wallis, M., Bartlett, J. M., Brookes, C. et al. Addressing overtreatment of screen detected DCIS; the LORIS trial. Eur. J. Cancer 51, 2296–2303 (2015).

[31] Elshof, L. E., Tryfonidis, K., Slaets, L., van Leeuwen-Stok, A. E., Skinner, V. P., Dif, N. et al. Feasibility of a prospective, randomised, open-label, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ - The LORD study. Eur. J. Cancer 51, 1497–1510 (2015).

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