Data on Ductal Carcinoma In Situ Encumbered by Opinion

September 15, 2016

Despite the much higher risk of local recurrence with lumpectomy and radiation compared with mastectomy, multiple retrospective studies and prospective randomized trials have established that survival is the same; however, this may not be so for the individual patient, depending on the type of recurrence.

Women with ductal carcinoma in situ (DCIS) are at risk for local recurrence and occurrence of a new primary in either breast following breast conservation therapy (BCT). Prevention of local recurrence or a new occurrence, particularly of invasive cancer, which, in principle, could metastasize, is a laudable goal. Many times, the physician concentrates on survival while the patients live with the fear of local recurrence every day, which is exacerbated by the side effects of treatment and follow-up screenings. Despite the much higher risk of local recurrence with lumpectomy and radiation compared with mastectomy, multiple retrospective studies and prospective randomized trials have established that survival is the same[1,2]; however, this may not be so for the individual patient, depending on the type of recurrence. Approximately half of recurrences are invasive disease and are more likely to occur in young women and those with high nuclear grade histology. Salvage mastectomy after BCT with radiation for an invasive recurrence results in a 10-year overall cause-specific survival rate of 95%. The European Organisation for Research and Treatment of Cancer (EORTC) 10853 trial reported that the hazard of dying after an invasive recurrence was five times higher compared with no local recurrence. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial reported a hazard ratio for breast cancer death after recurrence of 7.06, with a 10-year probability of breast cancer death of 10.4%.[1]

Disease recurrence is even higher in patients with DCIS who undergo lumpectomy without radiation.[3] In a recent Surveillance, Epidemiology, and End Results (SEER) study of local recurrence after treatment for DCIS, 69.5% of patients underwent BCT but only 43% were treated with radiotherapy.[4] As per multiple prospective randomized trials, there is no doubt that when conserving the breast, adjuvant radiation decreases local recurrence (16% absolute reduction and 50% relative risk at 10 years, collectively). The addition of an antiestrogen decreases local recurrence and recurrences elsewhere, but has no effect on survival.[1-6] In the NSABP B-24 trial, which was a follow-up to the B-17 trial, patients undergoing BCT with radiation were randomized to receive 5 years of tamoxifen vs placebo. After a median follow-up of 163 months, the absolute reduction in local recurrence was significant for invasive recurrence (9% vs 6.6%) but not for in situ recurrence (7.6% vs 6.7%). The rate of contralateral breast cancer was reduced from 8.1% to 4.9% with the use of tamoxifen (P = .0231). Last year, the Radiation Therapy Oncology Group (RTOG) 9804 study found that in favorable tumors with 7-year follow-up, the local failure rate was 0.9% with radiation and 6.7% in the observation arm.[7] However, overall survival was similar in both arms. Still, most patients did not benefit from the addition of radiation.

Patients are increasingly choosing mastectomy, including contralateral mastectomy.[8] Some would consider lumpectomy alone to be undertreatment and bilateral mastectomy, overtreatment. Recent predictive tools utilizing pathologic and molecular markers, as well as prospective trials, have failed to identify a group that does not benefit from radiation, although such studies can differentiate who will benefit the most. Young age, estrogen and progesterone receptor negativity, HER2/neu gene amplification, p21 positivity, and increasing pathologic size (difficult to measure accurately), as well as close or positive margins, all increase the risk of recurrence. The NSABP B-17 and EORTC 10853 randomized trials, the international collaborative DCIS study, the University of Southern California/Van Nuys experience, and others reported an increased risk of local recurrence in patients with close or positive surgical margins.[1-3,9-11] Recently, a consensus panel on DCIS performed a study-level meta-analysis-which was based on a meta-analysis and sponsored by the Society of Surgical Oncology and the American Society for Radiation Oncology-of the relationship between margin distance and local recurrence. The groups looked at women older than 50 years with DCIS undergoing BCT, and at local recurrence rates by numeric margin, with a follow-up of more than 4 years (20 studies were reviewed, with a total of 7,883 patients and 865 local recurrences). Median follow-up was 78.3 months, and 71% of patients had whole-breast radiation. The odds ratios relative to positive margins for 2 mm (0.32), 3 mm (0.30), and 10 mm (0.32) showed similar reductions in the odds of local recurrence, which was greater for positive margins > 0 or 1 mm (0.45).[12] Clearly, no tumor on ink is not sufficient for DCIS.

A multigene expression assay, the Oncotype DX DCIS Score, has also been developed to assist in decision making for DCIS patients and to assess the risk of local recurrence based on tumor genotype.[13,14] According to two validation studies, the Oncotype DX DCIS Score provides a probability of 10-year risk of any breast recurrence (DCIS or invasive), as well as invasive recurrence among women undergoing BCT alone.

Considerable effort has been made to improve the choices available to patients with DCIS. Hypofractionated whole-breast radiation and partial breast irradiation can be used in women with favorable risk factors. We have published work on the utilization of glutamine to prevent radiation injury and post-radiation pain.[15] In addition, we have studied the utilization of intracavitary hyperthermia (via radiofrequency) in favorable tumors as an alternative to radiation, which adds an additional 1-cm sterilization of the tumor bed to the lumpectomy procedure (similar to radiation), while maintaining a pristine breast for salvage procedures, if necessary.[16] We have also published work describing improved methods and cosmesis for bilateral total skin-sparing mastectomy, even for salvage treatment after radiation.[17] Research must continue to define risk-benefit categories in order to improve existing treatments and develop better alternative treatments.

Others have suggested that follow-up for patients diagnosed with DCIS should be performed with core needle biopsy. However, a systematic review and meta-analysis of local recurrence rates for DCIS showed that the 10-year local recurrence rate was 3% for mastectomy, 13% for BCT with radiation, and 25% for BCT alone vs 36% for core needle biopsy alone.[18] This is problematic at the present time, as our imaging and biopsy procedures are not 100% accurate. I believe that it is the patient’s choice, since we are treating the whole patient and not just her breasts. Thus, our job as clinicians is to educate patients on their risks and choices as best we can, and to take into consideration their preferences, as well as their social situation in terms of their ability to reliably adhere to follow up. I would not attempt to determine what kind of surgery a patient should have until I have completely understood her preferences. This should be the goal of all surgeons, but sometimes we let data get in the way instead of having it lead the way.

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:

1. 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.

2. 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. 2013;31:4054-9.

3. Virnig BA, Wang SY, Shamilyan T, et al. Ductal carcinoma in situ: risk factors and impact of screening. J Natl Cancer Inst Monogr. 2010;2010:113-6.

4. Worni M, Akushevich I, Greenup R, et al. Trends in treatment patterns and outcomes for ductal carcinoma in situ. J Natl Cancer Inst. 2015;107:djv263.

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. 2011;12:21-9.

6. 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. 2014;32:3613-8.

7. 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. 2015;33:709-15.

8. Hoskin TL, Hieken TJ, Degnim AC, et al. Use of immediate breast reconstruction and choice for contralateral prophylactic mastectomy. Surgery. 2016;159:1199-209.

9. Emdin SO, Granstrand B, Ringberg A, et al. SweDCIS: radiotherapy after sector resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered mammography screening. Acta Oncol. 2006;45:536-43.

10. 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.

11. Silverstein MJ, Lagios MD. Treatment selection for patients with ductal carcinoma in situ (DCIS) of the breast using the University of Southern California/Van Nuys (USC/VNPI) prognostic index. Breast J. 2015;21:127-32.

12. Marinovich ML, Azizi L, Macaskill P, et al. The association of surgical margins and local recurrence in women with DCIS with breast conservation therapy: a meta-analysis. J Clin Oncol. 2016;34(suppl):abstr 1020.

13. 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;105:701-10.

14. Rakovitch E, Nofech-Mozes S, Hanna W, et al. A population-based validation study of the DCIS score predicting recurrence risk in individuals treated by breast-conserving surgery alone. Breast Cancer Res Treat. 2015;152:389-98.

15. Rubio I, Suva LJ, Todorova V, et al. Oral glutamine reduces radiation morbidity in breast conservation surgery. J Parenter Enteral Nutr. 2013;37:623-30.

16. Klimberg VS, Ochoa D, Henry-Tillman R, et al. Long-term results of phase II ablation after breast lumpectomy added to extend intraoperative margins (ABLATE I) trial. J Am Coll Surg. 2014;218:741-9.

17. Boneti C, Yuen J, Santiago C, et al. Oncologic safety of nipple skin-sparing or total skin-sparing mastectomies with immediate reconstruction. J Am Coll Surg. 2011;212:686-93.

18. Stuart KE, Houssami N, Taylor R, et al. Long-term outcomes of ductal carcinoma in situ of the breast: a systematic review, meta-analysis and meta-regression analysis. BMC Cancer. 2015;15:890.