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Management of DCIS—A Work in Progress

Management of DCIS—A Work in Progress

Improved screening practices have lead to a dramatic increase in the diagnosis of ductal carcinoma in situ (DCIS) over the past 40 years. At present, it accounts for about 30% of newly diagnosed breast cancers.[1] Our current understanding of the natural history of DCIS indicates that it is an immediate, nonobligate precursor of invasive cancer. DCIS is confined to the breast parenchyma, but if it progresses to invasive breast cancer, the potential exists for the development of distant metastasis and subsequent death. The primary goal of treating DCIS is thus to prevent the development of invasive cancer. Treatment of DCIS is successful for most women; however, the disease can recur, and half of all local recurrences present as invasive breast cancer. At present, we still have a limited understanding of which cases of DCIS will ultimately progress to invasion and which cases will be resistant to therapy. Therefore, tailored management of DCIS is still a work in progress.

Key Studies of DCIS Treatment

The current treatment recommendations for DCIS are based on the findings from four prospective randomized studies conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP B17 and NSABP B24), the European Organisation for Research and Treatment of Cancer (EORTC), and DCIS trialists in the United Kingdom, Australia, and New Zealand (UK/ANZ).[2-5] NSABP B17 compared lumpectomy alone to lumpectomy and whole-breast radiation in women diagnosed with DCIS who had negative surgical margins. The addition of radiation reduced the risk of both noninvasive and invasive recurrence by 50%. NSABP B24 compared lumpectomy and whole-breast radiation to lumpectomy, whole-breast radiation, and tamoxifen; it found that the addition of tamoxifen further reduced the incidence of invasive in-breast recurrence by 44%. The incidence of contralateral invasive breast cancer was also reduced by 52%.[6] In the two NSABP studies, negative surgical margins were not required and some women received a radiation boost to the lumpectomy cavity in addition to the whole-breast radiation. The two other studies found that radiation reduced recurrence by an amount similar to that seen in the NSABP studies; however, no benefit was seen with the addition of tamoxifen, and none of the studies demonstrated a survival benefit from the addition of radiation.[7] In these original studies, the effects of histologic grade, margin width, and hormone receptor status on risk of recurrence were not evaluated.

An update of the two NSABP studies was recently published by Wapnir et al. The goal of the update was to evaluate long-term invasive ipsilateral in-breast recurrence outcomes in the two studies. The update confirmed previous findings: mortality from DCIS is low regardless of treatment, and recurrence risk is highest in patients who do not receive radiation therapy or tamoxifen.[6]

Prognostic Factors and Treatment Decisions

Since these studies were first published, a number of investigators have attempted to identify prognostic and predictive factors that would enable clinicians to provide a more tailored approach to therapy for DCIS, to insure that women are neither overtreated nor undertreated. The authors highlight appropriate specimen processing and specimen imaging techniques for ensuring an adequate resection, and they note the importance of margin status as a strong prognostic factor. In addition to obtaining specimen radiographs, imaging of the breast after surgical resection but prior to radiotherapy should be done to ensure that no residual calcifications remain. The effect of margin status on the risk of recurrence in DCIS has been assessed in a number of retrospective studies.[8] There is a consensus that negative surgical margins (no tumor at the ink) are associated with a reduced incidence of recurrence, but beyond that, there is little agreement on what constitutes a negative margin for DCIS and how this information can be used to make clinical decisions about adjuvant therapy. Among the reasons for this lack of consensus about margin status in DCIS are the following:

• Margin widths in the operating room can differ significantly from margin widths found in pathology because of the specimen compression that can occur as a result of specimen mammography after needle localization.

• Specimen processing can vary from institution to institution.

• It is difficult to study margin status prospectively.

The authors also include histologic grade and morphology as important factors that may impact the choice of surgical therapy and adjuvant therapy. Caution should be exercised in interpreting studies because of the different DCIS scoring criteria and the morphologic heterogeneity of DCIS lesions, which may not be apparent on the core biopsy.[9] Particular attention has been focused on identifying clinicopathologic variables that identify women who may forgo radiation therapy. Having margin widths greater than 1 cm has been suggested as a potential criterion for omitting radiation.[10,11] Based on the findings from ECOG 5194, women with low-grade DCIS appear to have a lower incidence of recurrence when radiation is omitted, but long-term follow-up data have not been reported.

Younger women are at increased risk of recurrence; at present, however, age alone should not sway the choice of surgical therapy towards mastectomy in women motivated to undergo breast conservation.[12] In addition, a number of tools that incorporate a range of pathologic and clinical factors—such as the Van Nuys Prognostic Index[10] and the Memorial Sloan-Kettering Cancer Center nomogram[13]—have been developed, although to date neither of these two tools has been validated in a prospective fashion.

Surgical Management of DCIS

Once the diagnosis of DCIS has been confirmed on core biopsy, the recommendation for surgical management should be based on the extent of microcalcifications identified on diagnostic mammography. MRI has been widely used at many centers in recent years to determine extent of disease. At present, however, its role in management is controversial, and MRI may in fact be detrimental, since it increases the number of women who undergo mastectomy.[14] Standard treatment for DCIS includes breast-conserving surgery, often involving wire or radioactive seed localization; whole-breast radiation therapy; and tamoxifen for localized DCIS. Simple mastectomy and sentinel node biopsy are recommended for extensive or multicentric DCIS and for women in whom adequate cosmesis cannot be achieved because of breast size. Women who undergo lumpectomy for pure DCIS do not require sentinel lymph node biopsy (SLNB) as part of their procedure. If there is a question of microinvasion on core biopsy, an associated mass, or extensive DCIS requiring mastectomy, then SLNB should be added. Some experts include the presence of high-grade DCIS as a criterion warranting SLNB, since this is yet another characteristic associated with an increased likelihood of finding invasive cancer. It should be remembered, however, that SLNB is an additional surgical procedure with associated risks and morbidity, including seroma, infection, temporary paresthesias, and lymphedema; thus, it should not be used as a tool for identifying the presence of occult invasion in women with pure DCIS on core biopsy. SLNB cannot be reliably performed in the absence of breast parenchyma; therefore, the rationale for performing SLNB in women undergoing mastectomy is to avoid having to do an axillary dissection, with all of its associated morbidities, in the event that invasive cancer is identified in the mastectomy specimen.

Current Status of Molecular Markers

Lari et al recently completed an extensive review of molecular markers in DCIS, and they concluded that for the most part, the data on the prognostic and predictive value of these markers are contradictory.[15] A greater understanding of the utility of estrogen receptor (ER) and HER2/neu status in DCIS will likely emerge with the upcoming publication of multicenter randomized trials—NSABP-B35, which randomly assigned women with DCIS to treatment with either tamoxifen or aromatase inhibitors, and B-43, which is examining the effect on HER2-positive DCIS of adding trastuzumab (Herceptin) to the treatment regimen. Going foreward, more research clearly needs to be focused on furthering our understanding of the biology of DCIS before we can comfortably stratify DCIS and offer patients a more individualized approach.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

REFERENCES

1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43-66.

2. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med. 1985;312:665-73.

3. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999;353:1993-2000.

4. Houghton J, George WD, Cuzick J, et al; UK Coordinating Committee on Cancer Research, Ductal Carcinoma in Situ Working Party, DCIS trialists in the UK, Australia, and New Zealand: radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet. 2003;362:95-102.

5. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet. 2000;355:528-33.

6. 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. 2011;103:478-88.

7. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Correa C, McGale P, Taylor C, et al. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr. 2010;2010:162-77.

8. Dunne C, Burke JP, Morrow M, et al. 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.

9. Allred DC. Ductal carcinoma in situ: terminology, classification, and natural history. J Natl Cancer Inst Monogr. 2010;2010:134-38.

10. Silverstein MJ, Lagios MD. Choosing treatment for patients with ductal carcinoma in situ: fine tuning the University of Southern California/Van Nuys Prognostic Index. J Natl Cancer Inst Monogr. 2010;2010:193-96.

11. Solin LJ. The impact of adding radiation treatment after breast conservation surgery for ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr. 2010;2010:187-92.

12. Solin LJ, Kurtz J, Fourquet A, et al. Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. J Clin Oncol. 1996;14:754-63.

13. 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.

14. Itakura K, Lessing J, Sakata T, et al. The impact of preoperative magnetic resonance imaging on surgical treatment and outcomes for ductal carcinoma in situ. Clin Breast Cancer. 2011;11:33-8.

15. Lari SA, Kuerer HM. Biological markers in DCIS and risk of breast recurrence: a systematic review. J Cancer. 2011;2:232-61.

 
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