Ductal Carcinoma in Situ and Relevant Endpoints for Omission of Standard Treatments: Are We There Yet?


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Meena S. Moran, MD

These data should be used as a starting point to begin discussions on what risk of relapse is considered too high to recommend observation only after surgical excision and what risk might be considered too low to warrant adding radiation treatment.

—Meena S. Moran, MD

The optimal management strategy for ductal carcinoma in situ has become increasingly controversial with respect to potential overdiagnosis and overtreatment. Much of the controversy for ductal carcinoma in situ stems from its exceptional breast cancer–specific survival, which approaches close to 100% irrespective of local treatment choice. With an absence of data to demonstrate that any of our current treatment modalities for ductal carcinoma in situ directly affects survival, it is easy to argue that we may be overtreating and should consider modifying our treatment strategies.

Remaining Challenges

Although most treating physicians agree that there is significant variability in the natural history of ductal carcinoma in situ, with a proportion likely remaining clinically insignificant in the absence of any treatments, precisely how to consistently identify this indolent subset remains the challenge. We have yet to scientifically establish and reliably demonstrate any subgroups of patients for whom radiation therapy has not been beneficial in decreasing invasive in-breast recurrences.1 And because invasive recurrences are associated with decreased survival,2,3 careful selection when omitting radiation therapy is warranted.

Furthermore, the optimal clinical endpoint(s) for ductal carcinoma in situ is not agreed upon. Should we adhere to survival outcomes such as breast cancer–specific survival, for which no local treatment modality (mastectomy or local excision, with or without radiation or hormone therapy) appears to have comparative benefit over another? Alternatively, should we be measuring all in-breast recurrences, since any recurrence, irrespective of whether it is invasive or in situ, is generally meaningful for the patient, provoking anxiety and mandating additional surgery? Or should we only be measuring invasive recurrences, which theoretically have the potential to metastasize and ultimately affect survival?

In-Breast Recurrences

If all in-breast local relapses in ductal carcinoma in situ are estimated by annual risk of recurrence, it is estimated that approximately 1% to 2+% will recur per year with breast-conserving surgery alone. The addition of radiation therapy generally results in a ≥ 50% relative risk reduction for both invasive and noninvasive recurrences, diminishing the overall in-breast recurrence risk to < 1% per year.1 Five years of hormone therapy in estrogen receptor–positive patients results in an additional 30% relative risk reduction, thus bringing the annual risk of in-breast recurrence to < 0.7%+/year.2

Generally speaking, radiation oncologists will use ≤ 1% per year as a rule of thumb threshold for an acceptable upper limit of in-breast recurrences with breast radiation therapy. For example, based on disease estimates from the long-term follow-up of the four randomized ductal carcinoma in situ radiation trials, the 15-year in-breast recurrence with local excision alone across the whole spectrum of ductal carcinoma in situ ranged from 20% to 30+%.2-5 With adjuvant radiation therapy, the event rate is reduced to 10% to 15%, and with hormone therapy, a relapse rate of well under 10% is achieved at 15 years.2,5 These numbers may be an overrepresentation of the breast events experienced by these patients with ductal carcinoma in situ today, given the advances in screening/earlier detection and improvements in pathology procedures.

Nevertheless, using the estimates described above, one can roughly anticipate in-breast recurrence rates with local excision alone (without radiation) for “low-risk” patients, despite the variation in the definition of “low-risk” across studies that have prospectively attempted to omit radiation.

The only prospective, randomized study is the RTOG 98-04, which randomized mammographically detected grade I/II ductal carcinoma in situ measuring < 2.5 cm with margins > 3 mm to whole-breast radiation vs observation after local excision. Of the enrolled patients, 62% received tamoxifen. Despite being statistically underpowered because of poor accrual, with only one-third of the projected enrollment (target N = 1,800, final N = 636), the initial report at 7 years of follow-up demonstrated a significantly greater risk of in-breast recurrences for patients who did not receive radiation therapy (7% vs ≤ 1%, P < .001). The authors concluded that radiation significantly reduced the number of in-breast events despite the low-risk characteristics and limited numbers of patients and that longer follow-up was needed because of the protracted clinical course of ductal carcinoma in situ.6

Another prospective, single-arm study enrolled patients with “low risk” ductal carcinoma in situ to receive wide local excision alone (the WEA study). Their definition of “low-risk” was mammographically detected lesions measuring < 2.5 cm with ≥ 10 mm margins and predominantly grade I/II. Tamoxifen was not delivered. This trial also closed early, after accrual of 158 patients, because of the extraordinarily high number of in-breast events that met the protocol’s stopping rules.

At 5 years, the initial cumulative incidence of in-breast recurrence was 12%, with an annual recurrence rate of 2.4% per year,7 which was more recently updated to a 10-year cumulative incidence of 15.6%. The authors concluded that with longer follow-up, the risk of local relapse increases over time and remains substantial for favorable ductal carcinoma in situ treated with widely excised margins without radiation therapy.8

Lastly, ECOG 5194 was a prospective observational study of two separate cohorts of “low-risk” patients treated with local excision alone. The protocol mandated margins of ≥ 3 mm in all patients and required sequential sectioning and complete embedding of each specimen, which are not routine practice in many institutions. Each group was distinguished by its grade and size, with group 2 defined as high grade, smaller (≤ 1 cm) tumors and group 1 as low/intermediate grade, larger (≤ 2.5 cm) ductal carcinoma in situ. The original report of 5-year in-breast recurrences of 15.3% in group 2 and 6.1% in group 1 led the authors to conclude that the recurrence rate in group 2 was too high to consider surgery alone, but it was reasonable to consider omitting radiation for patients with pathologic characteristics of group 1.9

Starting Point to Discussions

Consequently, the most recent 12-year results of ECOG 5194—reported by Solin et al and summarized in this issue of The ASCO Post—are not surprising.10 In-breast recurrences steadily increased over time in both cohorts of “low-risk” patient. The 12-year rate of in-breast recurrence was 24.6% in group 2 and 14.4% in group 1, of which, as expected, approximately 50% were invasive (13.4% and 7.5%, respectively). Consistent with other data, this update clearly exhibits the late but ongoing risk of recurrence in patients with ductal carcinoma in situ. Since risk of in-breast relapses increased without plateau over the 12-year follow-up period for these seemingly low-risk patients, the authors concluded that these data should be used as a starting point to begin discussions on what risk of relapse is considered too high to recommend observation (no radiation) after surgical excision and what risk might be considered too low to warrant adding radiation treatment.

Collectively, these data suggest that the longer a patient is followed, the higher the overall (absolute) risk for in-breast recurrence. The current methods being employed to stratify patients with ductal carcinoma in situ into a “low-risk” category, whether clinical-pathologic criteria or genomic testing, are not truly identifying those with indolent disease. Although they may be separating the large spectrum of ductal carcinoma in situ into a smaller group in which the absolute risk of in-breast relapse is lower, a significant proportion of these patients will develop in-breast (and invasive) recurrences—which can be reduced with radiation therapy. Which brings us to the question: How low must risk for in-breast recurrence be to be considered low enough?  Potentially, a combination of clinical-pathologic features and genomic analysis will allow for accurate identification of a subset within this low-risk group with truly inconsequential disease.

Major Advances in Radiation Therapy

Lastly, with regard to the omission of radiation therapy, it is important to note that our subspecialty, too, has undergone major advances over the years. Relative to the patients treated in the original ductal carcinoma in situ randomized trials that established the benefits of radiation therapy with breast conservation, major advances in treatment planning and delivery of radiation therapy have resulted in significantly diminished side effects. There are now level 1 data demonstrating that three-dimensional and intensity-modulated radiation therapy techniques deliver a significantly more homogeneous dose, which consequently results in both decreased acute and long-term toxicities for breast treatment compared with two-dimensional techniques.11,12

Additionally, technologic advances such as the use of deep inspiration breath hold, respiratory gating, and prone positioning have helped to eliminate heart and lung exposure significantly.13 And finally, techniques that deliver treatment in a shorter amount of time, such as accelerated hypofractionated radiation and accelerated partial-breast irradiation, are being utilized to increase patient convenience.14

Hence, who is to say that 5 years of hormonal therapy (which diminishes only invasive [but not in situ] recurrences and is effective in reducing in-breast relapses only in hormone receptor–positive patients, has its own potential for serious side effects, and is predictably associated with a high noncompliance rate15), would be more appealing than a course of radiation as adjuvant treatment? Even for patients with indolent disease, the selection of the most tolerable treatment and the thresholds for “what is too low” to warrant treatment or “what is too high” to omit treatment is subjective to the individual patient.

Future Direction

An alternative strategy has been proposed to manage patients with clinically indolent ductal carcinoma in situ with no treatment after biopsy alone. As such, two prospective, randomized trials are currently examining no treatment for “low-risk” ductal carcinoma in situ as their experimental arm.16,17 In these studies, asymptomatic, mammographically screen-detected, low- or intermediate-grade ductal carcinoma in situ with calcifications will be observed after biopsy alone compared with the treatment arm of surgery with or without radiation and with or without  hormonal therapy.

In addition to reporting breast recurrence outcomes as their primary endpoints, these studies will importantly also include patient-reported outcomes such as anxiety, coping, and quality-of-life measures for treatment vs no treatment.17 Incorporating patient-centered endpoints into future studies of treatment omission for ductal carcinoma in situ will allow for better incorporation of these scientific data into clinical practice by providing data supporting that psychological well-being and quality-of-life measures are noninferior (not affected) when treatment is omitted for ductal carcinoma in situ.

Thus, ductal carcinoma in situ remains a complex disease entity. Until we are able to reliably distinguish lesions of true malignant potential (warranting aggressive treatment) from those of no consequence (possibly warranting less than standard therapy), we, as treating physicians, will need to incorporate multiple factors beyond risk stratification alone in our discussions. An individual patient’s risk of relapse can be roughly estimated using clinical nomograms,18 historic data,1 or more-contemporary studies of low-risk patients.6,10 But ultimately, this risk estimation must be placed in context with the patient’s comorbidities, anticipated longevity, preferences among various management options, and relative anxiety levels pertaining to recurrence vs treatment—since such decisions can be anticipated to be more likely to impact these patients’ quality-of-life measures than breast cancer–related survival outcomes. ■

Disclosure: Dr. Moran reported no potential conflicts of interest.

References

1. Early Breast Cancer Trialists’ Collaborative Group, 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.

2. Wapnir IL, Dignam JJ, Fisher B, et al: Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst 103:478-488, 2011.

3. Donker M, Litière S, Werutsky G, et al: Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-Year recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized phase III trial. J Clin Oncol 31:4054-4059, 2013.

4. Wärnberg F, Garmo H, Emdin S, et al: Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: 20 Years follow-up in the randomized SweDCIS trial. J Clin Oncol 32:3613-3618, 2014.

5. Cuzick J, Sestak I, Pinder SE, et al: Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: Long-term results from the UK/ANZ DCIS trial. Lancet Oncol 12:21-29, 2011.

6. McCormick B, Winter K, Hudis C, et al: RTOG 9804: A prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol 33:709-715, 2015.

7. Wong JS, Kaelin CM, Troyan SL, et al: Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol 24:1031-1036, 2006.

8. Wong JS, Chen YH, Gadd MA, et al: Eight-year update of a prospective study of wide excision alone for small low- or intermediate-grade ductal carcinoma in situ (DCIS). Breast Cancer Res Treat 143:343-350, 2014.

9. Hughes LL, Wang M, Page DL, et al: Local excision alone without irradiation for ductal carcinoma in situ of the breast: A trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27:5319-5324, 2009.

10. Solin LJ, Gray R, Hughes LL, et al: Surgical excision without radiation for ductal carcinoma in situ of the breast: 12-Year results from the ECOG-ACRIN E5194 study. J Clin Oncol 33:3938-3944, 2015.

11. Donovan E, Bleakley N, Denholm E, et al: Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol 82:254-264, 2007.

12. Pignol JP, Olivotto I, Rakovitch E, et al: A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol 26:2085-2092, 2008.

13. Moran MS, Haffty BG: Radiation techniques and toxicities for locally advanced breast cancer. Semin Radiat Oncol 19:244-255, 2009.

14. Rowe B, Moran MS: Accelerated partial breast irradiation and hypofractionated whole breast radiation. US Oncol Hematol 7:31-37, 2011.

15. Livaudais JC, Hwang ES, Karliner L, et al: Adjuvant hormonal therapy use among women with ductal carcinoma in situ. J Womens Health (Larchmt) 21:35-42, 2012.

16. Elshof LE, Tryfonidis K, Slaets L, 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.

17. Francis A, Thomas J, Fallowfield L, et al: Addressing overtreatment of screen detected DCIS. The LORIS trial. Eur J Cancer 51:2296-2303, 2015.

18. Rudloff U, Jacks LM, Goldberg JI, et al: Nomogram for predicting the risk of local recurrence after breast-conserving surgery for ductal carcinoma in situ. J Clin Oncol 28:3762-3769, 2010.

Dr. Moran is Professor of Therapeutic Radiology at Yale University School of Medicine, New Haven, Connecticut.


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