There is much debate about the necessity of treating women with ductal carcinoma in situ (DCIS) with surgery or radiotherapy.1,2 It is disconcerting to many that patients with DCIS are treated in the same way as are women with early-stage invasive breast cancer. Many patients with DCIS have bilateral mastectomies.2 Much effort is being expended to identify women at sufficiently low risk who might avoid surgery and/or radiotherapy.3-9
Steven A. Narod, MD
In a recent paper from the UK, Mannu et al followed women with DCIS for breast cancer mortality.10 They found the 20-year mortality rate to be surprisingly high—4.4% for women with screen-detected DCIS and 6.1% for women with DCIS that was not screen-detected. Moreover, the breast cancer mortality rate differed little by surgical approach; those treated with mastectomy had similar mortality rates as those treated with lumpectomy, despite having many fewer invasive recurrences. Among 22,753 women with nonscreen-detected DCIS, the 25-year breast cancer mortality rates were 6.5% with mastectomy, 8.6% with lumpectomy and radiotherapy, and 7.8% with lumpectomy without radiotherapy. We reported similar results in our study of patients with DCIS in the Surveillance, Epidemiology, and End Results registry,11 although our breast cancer mortality rate at 20 years was lower (3.3%).
Few women experience a local invasive recurrence after mastectomy. Radiotherapy reduces the risk of local recurrence but not the risk of death.12 From this, we concluded that the deaths from breast cancer after DCIS are not a consequence of local invasive recurrence, but they are from latent metastases present at the time of diagnosis.13 The time from diagnosis to death could be as long as 25 years. There were 908 patients with DCIS who died of breast cancer in the UK study and 517 who died of breast cancer in the U.S. study. Could these deaths have been prevented?
The deaths from breast cancer after DCIS are not a consequence of local invasive recurrence, but they are from latent metastases present at the time of diagnosis.— Steven A. Narod, MD
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Understanding the Role of Adjuvant Chemotherapy for DCIS
To date, much of our focus on DCIS treatment research is to find a subgroup of patients with a sufficiently low risk of recurrence to avoid radiotherapy.3-9 De-escalation is a laudable goal, but it won’t save lives, and I think we should also try harder to identify those who will ultimately die of invasive cancer. If we could identify those patients with DCIS at the outset who had a 12% or higher risk of dying of breast cancer, would it be reasonable to consider chemotherapy upfront?
(One thing that puzzles me is why patients who have had a lumpectomy do not do better than patients who have had a mastectomy. How often do patients with DCIS receive adjuvant chemotherapy at the time of local recurrence? One presumes chemotherapy would be an effective treatment of invasive cancer after DCIS, and local recurrence provides a window of opportunity to offer life-saving systemic therapy. Women who have a mastectomy and die of DCIS usually first present with distant, rather than local, recurrence, and at that point, chemotherapy is not considered curative.)
Clarifying the Goals of DCIS Treatment
Many women with DCIS in the United States report confusion about their chances of developing an invasive breast cancer or metastatic cancer and the options available to them to avoid these unwanted outcomes.14 Consider the goals of treatment of DCIS. The primary goal is to prevent invasive cancer. Secondary goals are to prevent contralateral cancer, distant recurrence, and death from breast cancer. The risk of an invasive in-breast recurrence after DCIS is the same as the risk of an invasive in-breast recurrence after invasive breast cancer.
The risk of contralateral invasive breast cancer is the same after DCIS as it is after invasive breast cancer.— Steven A. Narod, MD
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In the Banting database at Women’s College Hospital, the 15-year risk of invasive local recurrence after DCIS was 15.6%; after stage 1 breast cancer, it was 15.3%, and after stage 2 breast cancer, it was 15.9%.15 The benefit of radiotherapy on reducing ipsilateral invasive breast cancer is the same for patients with DCIS and with stage 1or 2 breast cancer.15 In the Banting database, the 15-year risk of ipsilateral invasive recurrence was 14% for patients with DCIS who received radiotherapy and 29% for patients with DCIS who did not receive radiotherapy—a difference of 15%.15 The risk of contralateral invasive breast cancer is the same after DCIS as it is after invasive breast cancer.16
We have learned from these studies and from the NSABP trials17 that mastectomy and radiotherapy prevent local recurrences, but not breast cancer mortality, for both women with DCIS and invasive cancer. It appears the net benefit of mastectomy or radiotherapy or bilateral mastectomy is the same for women with DCIS as it is for those with early-stage invasive cancer. So, is it not reasonable that local treatment should be the same?
Identifying Those at Higher Risk of Mortality
If we wish to reduce death from breast cancer after DCIS, we must consider giving systemic therapy, either at the time of DCIS or at the time of local invasive recurrence. There may be a survival benefit from tamoxifen, but as far as I know, mortality is not an endpoint in the current tamoxifen trials. And we should not forget that tamoxifen chemoprevention reduces the risk of cancer, but we have not yet seen a benefit on cancer mortality.18
We cannot generalize that the predictors of recurrence are also predictors of mortality.— Steven A. Narod, MD
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We all agree the average risk of death after DCIS is too low (3%–6%) to warrant chemotherapy, but what if we could identify a subgroup of patients with DCIS for whom the risk was much higher (say 12%)? One could argue that chemotherapy would then be warranted.
Mannu et al made an important step toward this goal by identifying a higher risk of mortality in nonscreen-detected cases of DCIS than in screen-detected cases. Other risk factors for mortality include young age at diagnosis, Black race, multifocality, microinvasion, and tumor size > 25 mm.19-21 The risk factors for invasive recurrence may differ from those for mortality, and we cannot generalize that the predictors of local recurrence are also predictors of mortality. Among young Black women, the risk of dying of DCIS approaches 10%.11 In the Mannu et al study, the 25-year risk of breast cancer death was 7.6% for patients diagnosed before age 45. I don’t think we should take the word “cancer” out of DCIS just yet.22
Closing Thoughts
Several genomic tests are being used to estimate the risk of local recurrence after DCIS with the goal of avoiding radiotherapy (de-escalation).4-8 But conversely, does a high score contribute sufficient information that they might benefit from systemic therapy early on? If we could predict with a high degree of certainty which women with DCIS had a high risk of dying of breast cancer—say 12% or higher—I think we would be in a position to consider escalation of treatment. Hopefully, we could then show that finding DCIS does save lives.
I don’t think we should take the word ‘cancer’ out of DCIS just yet.— Steven A. Narod, MD
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Dr. Narod is a Tier 1 Canada Research Chair in Breast Cancer and Director of the Familial Breast Cancer Research Unit at Women’s College Hospital; Professor at the Dalla Lana School of Public Health at the University of Toronto; and a senior scientist at Women’s College Research Institute.
DISCLOSURE: Dr. Narod served as a consultant for PreludeDx.
1. Hewitt K, Esserman LJ: Reframing DCIS as an opportunity for cancer prevention. The ASCO Post. March 10, 2024. Available at https://ascopost.com/news/february-2024/reframing-dcis-as-an-opportunity-for-cancer-prevention/. Accessed March 18, 2024.
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3. Toss M, Miligy I, Thompson AM, et al: Current trials to reduce surgical intervention in ductal carcinoma in situ of the breast: Critical review. Breast 35:151-156, 2017.
4. Vicini FA, Mann GB, Shah C, et al: A novel biosignature identifies patients with DCIS with high risk of local recurrence after breast conserving surgery and radiation therapy. Int J Radiat Oncol Biol Phys 115:93-102, 2023.
5. Manders JB, Kuerer HM, Smith BD, et al: Clinical utility of the 12-Gene DCIS Score assay: Impact on radiotherapy recommendations for patients with ductal carcinoma in situ. Ann Surg Oncol 24:660-668, 2017.
6. Rakovitch E, Parpia S, Koch A, et al: DUCHESS: An evaluation of the ductal carcinoma in situ score for decisions on radiotherapy in patients with low/intermediate-risk DCIS. Breast Cancer Res Treat 188:133-139, 2021.
7. Hahn E, Rodin D, Sutradhar R, et al: Can molecular biomarkers help reduce the overtreatment of DCIS? Curr Oncol 30:5795-5806, 2023.
8. Lin CY, Mooney K, Choy W, et al: Will oncotype DX DCIS testing guide therapy? A single-institution correlation of oncotype DX DCIS results with histopathologic findings and clinical management decisions. Mod Pathol 31:562-568, 2018.
9. Hwang ES, Hyslop T, Lynch T, et al: The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: A phase III randomised controlled clinical trial for low-risk ductal carcinoma in situ. BMJ Open 9:e026797, 2019.
10. Mannu GS, Wang Z, Dodwell D, et al: Invasive breast cancer and breast cancer death after non-screen detected ductal carcinoma in situ from 1990 to 2018 in England: Population-based cohort study. BMJ 384:e075498, 2024.
11. Narod SA, Iqbal J, Giannakeas V, et al: Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol 1:888-896, 2015.
12. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Correa C, McGale P, et al: Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr 2010:162-177, 2010.
13. Narod SA, Sopik V: Is invasion a necessary step for metastases in breast cancer? Breast Cancer Res Treat 169:9-23, 2018.
14. Rosenberg SM, Gierisch JM, Revette AC, et al: ‘Is it cancer or not?’ A qualitative exploration of survivor concerns surrounding the diagnosis and treatment of ductal carcinoma in situ. Cancer 128:1676-1683, 2022.
15. Sopik V, Nofech-Mozes S, Sun P, et al: The relationship between local recurrence and death in early-stage breast cancer. Breast Cancer Res Treat 155:175-185, 2016.
16. Giannakeas V, Lim DW, Narod SA: The risk of contralateral breast cancer: A SEER-based analysis. Br J Cancer 125:601-610, 2021.
18. Sopik V, Narod SA: Overdiagnosis in breast cancer chemoprevention trials. Curr Oncol 22:e6-e10, 2015.
19. Wärnberg F, Bergh J, Zack M, et al: Risk factors for subsequent invasive breast cancer and breast cancer death after ductal carcinoma in situ: A population-based case-control study in Sweden. Cancer Epidemiol Biomarkers Prev 10:495-499, 2001.
20. Wadsten C, Garmo H, Fredriksson I, et al: Risk of death from breast cancer after treatment for ductal carcinoma in situ. Br J Surg 104:1506-1513, 2017.
21. Sopik V, Sun P, Narod SA: Impact of microinvasion on breast cancer mortality in women with ductal carcinoma in situ. Breast Cancer Res Treat 167:787-795, 2018.
22. Esserman L, Eggener S: Not everything we call cancer should be called cancer. The New York Times. August 30, 2023. Available at https://www.nytimes.com/2023/08/30/opinion/cancer-breast-prostate-treatment.html. Accessed March 18, 2024.
