Ductal Carcinoma In Situ of the Breast: ‘Making the Punishment Fit the Crime’

Many oncologists were heartened by the study recently published in the Journal of the National Cancer Institute showing the ability of the “Ductal Carcinoma in Situ (DCIS) Score” (based on the Oncotype DX breast cancer assay) to help predict the risk of invasive breast cancer in patients with newly diagnosed DCIS. This enthusiastic response, despite the acknowledged limitations of the study, may, as much as anything, be evidence of the difficulty of making treatment decisions for this patient population, and the urgency of the need for truly effective tools.

Contention about the best management of DCIS begins with its common inclusion with invasive breast cancer as “early breast cancer.”[1] Because DCIS is a common but not an obligate precursor of invasive breast cancer, this conflation leads to what is termed “overdiagnosis of breast cancer.”[1] Indeed, DCIS is far more common than invasive breast cancer, being found in 15% of medicolegal autopsies of women 20 to 54 years of age.[2] Because it lacks the ability to invade or metastasize, it is not a true carcinoma until-and if-it later becomes invasive. Invasive breast carcinomas progress to lethality, albeit at various rates, unless controlled, or unless intercurrent disease ends life before they do. DCIS, on the other hand, poses no threat of lethality beyond its risk of progression to an invasive cancer over time.

However detected, DCIS can only be diagnosed as in situ or invasive breast cancer after excision and histopathologic examination. Some patients present with such extensive DCIS that it may already contain areas of invasion, and mastectomy may be felt necessary to control the process in a person with years of expected survival.

Individual clinicians and tumor boards struggle with several questions in advising the most appropriate treatment for localized DCIS:

(1) How widely should it be excised?

(2) Should the breast be irradiated?

(3) Should adjuvant hormonal therapy be recommended?

The question of margin of excision has been much debated. It has been demonstrated that having a pathologically clear margin is not equivalent to having no residual DCIS in the breast. The minimum margin for DCIS appears to be at least 2 mm, greater than that shown to be necessary for breast-conserving therapy that includes irradiation for invasive cancer.[3,4] The surgical margin targeted is a balance between the ideal of taking nearly 1 cm to make certain that 2 mm of microscopic margin is clear, and the desire to minimize the volume resected in order to avoid diminishing the cosmetic appearance of the breast, the preservation of which is a goal of breast-conserving therapy.

The question of irradiation after excision of DCIS to clear margins is far more complex. Several randomized studies have been subjected to meta-analysis, demonstrating that the relative reduction in risk of recurrence by irradiation is more than 50% (28% vs 13% at 10 years; P < .00001).[5] The benefit is clear, although the off-setting cost makes the decision more complex. Over time, some early breast edema may be replaced by fibrosis and shrinkage of the breast or later swelling. The cosmetic loss comes later rather than initially. Patients are also exposed to very small increased risks of lung and esophageal carcinoma, sarcoma of the chest wall, and vascular damage. This would be a small price to pay to control a cancer, but what of controlling a precancerous change? Seventy percent of these lesions would be controlled without the irradiation. If irradiation has been delivered and a new area of DCIS arises in the breast, mastectomy is recommended for control, but if irradiation has been avoided, it can be used as breast-conserving therapy with excision of the new/recurrent lesion.

Breast irradiation is not the only adjuvant available. For estrogen receptor–positive DCIS, the addition of tamoxifen reduces the risk by half again,[6] or in postmenopausal women, an aromatase inhibitor may be used,[7] although more definitive data on the latter topic await the results of the National Surgical Adjuvant Breast and Bowel Project B-35 study and the IBIS II trial from the United Kingdom.

However, while the addition of irradiation or hormone therapy reduces the risk of recurrence, neither of these adjuvants has had an effect on survival.

To make the punishment fit the crime, you would want the decision of whether or not to use adjuvants to be informed by the degree of risk that the DCIS would recur. An intergroup trial (Eastern Cooperative Oncology Group [ECOG] 5194) was sponsored by the National Cancer Institute to examine surgery without radiation in selected patients. It now has 10 years of follow-up. The study was limited to small areas of DCIS, < 2.5-cm diameter lesions of low or intermediate grade, or 1-cm or smaller lesions of high grade. At 5 years, the high-grade lesions had a 15% rate of in-breast recurrence, and the lower-grade lesions a 6% rate in the absence of irradiation. As a comparison, in the 3,723 women in the Early Breast Cancer Trialists’ Collaborative Group meta-analysis of trials of DCIS excised and randomized to radiation or not, patients in the irradiated arms had a 7.6% recurrence rate at 5 years; however, the average woman in this meta-analysis had larger foci of DCIS.

What factors can predict for an increased risk of recurrence, or more importantly, the risk of an invasive breast cancer occurring? Young patient age, size of the DCIS, grade of the DCIS, and margin size have all been shown to be prognostic factors. These have been combined in attempts to predict freedom from recurrence, or a high risk of recurrence. The Van Nuys Prognostic Index was one of the first such attempts.[8] More recently, a nomogram was published by Memorial Sloan-Kettering Cancer Center.[9] The MD Anderson Cancer Center evaluated this nomogram in their patient population[10] and concluded that “our current ability to accurately predict recurrence on the basis of clinical parameters alone is limited.” This conclusion was challenged by the originators of the nomogram.[11]

Ideally, one would choose patients at a higher risk of recurrence, especially those at higher risk of developing an invasive breast cancer, and target adjuvant therapy to these patients to reduce this risk. A multigene expression assay was developed by the group that had developed the Oncotype DX breast cancer assay. The clinical material available from ECOG 5194 was made available to these researchers to see if they could use the “DCIS Score” to select those patients at higher risk who might best be advised to have irradiation and hormonal therapy in addition to excision. They sorted 75% of the patients into a low-risk group with only a 3.7% chance of developing an invasive breast cancer in 10 years, vs 12.2% for an intermediate group and 19.2% for a high-risk group. In terms of any in-breast event, 75% of the patients had a 10.6% risk at 10 years, with the intermediate-risk and high-risk groups comprising the other 25%, at a 26% to 27% risk.[11] The patients eligible for this study had relatively small volumes of DCIS, and further studies are awaited, but as with other multigene assays that are entering clinical use, it appears more predictive than standard clinical parameters.[12]

Careful review of the risks of DCIS balanced against the risks of therapies designed to lower the chance of recurrence will allow patients to make informed choices, keeping in mind the fact that none of the choices is associated with a survival outcome that is inferior to the others.

Financial Disclosure:Dr. Wood has received travel funding from Genomic Health Inc to serve on a think tank on the DCIS Score, and he has received travel funding and an honorarium to speak at an Oncotest-Teva meeting in Israel.

References:

REFERENCES

1. Bleyer A, Welch HG. Effect of three decades of screening mammography on breast cancer incidence. N Engl J Med. 2012;367:1998-2005.

2. Nielsen M, Thomsen JL, Primdahl S, et al. Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. Brit J Cancer. 1987;56:814-9.

3. Dunne C, Burke JP, Morrow M, Kell MR. Effect of margin status on local recurrence after breast conservation and radiation therapy for ductal carcinoma in situ. J Clin Oncol. 2009;27:1615-20.

4. Revesz E, Khan SA. What are safe margins of resection for invasive and in situ breast cancer? Oncology. 2011;25:890-895.

5. Early Breast Cancer Trialists’ Collaborative Group. NCI Monograph. 2010;41:162-77.

6. Allred DC, Anderson SJ, Paik S, et al. Adjuvant tamoxifen reduces subsequent breast cancer in women with estrogen receptor-positive ductal carcinoma in situ: a study based on NSABP Protocol B-24. J Clin Oncol. 2012;30:353-4.

7. Gross PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364:2381-91.

8. Silverstein MJ. The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast. Am J Surg. 2003;186:337-42.

9. 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. 2010;28:3762-9.

10. Yi M, Meric-Bernstam F, Kuerer HM, et al. Evaluation of a breast cancer nomogram for predicting risk of ipsilateral breast tumor recurrences in patients with ductal carcinoma in situ after local excision. J Clin Oncol. 2012;30:600-7.

11. Solin LJ, Gray R, Baehner FL, et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2013 May 5. [Epub ahead of print]

12. Badve SS, Gray RJ, Baehner FL, et al. Correlation between the DCIS Score and traditional clinicopathological features in the prospectively designed E5194 clinical validation study. J Clin Oncol. 2012;30(Suppl):A1005.