Omission of Adjuvant Radiation Therapy after Breast Conserving Surgery for DCIS

• Omission of RT for low-risk DCIS

• Radiation therapy (RT) reduces the odds of in-breast recurrence:

• But likely does not change the odds of distant recurrence or decrease mortality

• For patients with low-risk disease that has been fully resected with widely negative margins:

• The absolute reduction of in-breast recurrence:

• May not be large enough to justify the risks associated with RT:

• In such patients, it is reasonable to omit RT:

• Especially in the setting of:

• Comorbidity

• Advanced age

• Patient preference

• Some authors have a higher threshold to omit radiation:

• For young women given some data suggesting RT is more likely to benefit these patients

• While the results from the NSABP B-17 trial:

• Have been used to argue for RT in all women who undergo lumpectomy for pure DCIS:

• Methodological issues such as suboptimal pathologic evaluation and uncertainty about the completeness of excision:

• May have led to an overestimation of the benefit of RT in this study

• Moreover, RT is expensive, time consuming, and may be accompanied by significant side effects:

• So omission for patients likely to derive the least benefit is reasonable

• Since RT reduces the risk of ipsilateral recurrence without changing the risk of developing contralateral disease:

• Omission of RT would be a reasonable approach:

• For patients with an ipsilateral recurrence risk:

• Approximately equal to the risk of developing contralateral disease

• Among women diagnosed with DCIS:

• The long-term risk of developing a contralateral breast cancer or DCIS:

• Is approximately 3% to 10%

• Studies have tried to identify such a low-risk population using:

• Histopathologic and gene expression analysis

• While it is difficult to identify a clear-cut low-risk population:

• The benefit of RT becomes less clear:

• As the risk of ipsilateral recurrence approaches that of contralateral recurrence

• Histopathologic criteria:

• While there are no strict criteria for “low risk,” many authors have defined low risk as DCIS that is:

• Low- or intermediate-grade

• Small (less than 2.5 cm in size)

• Resected with widely negative margins (≥ 1 cm)

• Omission of RT in such patients is reasonable:

• Although associated with a small risk of ipsilateral recurrence

• Several studies suggest that clinical pathologic criteria:

• May define a low-risk cohort of patients with DCIS:

• For whom RT may be reasonably omitted given a low risk of recurrence

• These studies are summarized below:

• The Eastern Cooperative Oncology Group (E5194):

• Was an observational study:

• That investigated excision without RT in women with low- to intermediate-grade versus high-grade DCIS

• Eligible patients had:

• Less than 2.5 cm of low- to intermediate-grade DCIS or

• Less than 1.0 cm for high-grade DCIS

• Margins ≥ 3 mm were required and a negative post-excision mammogram was obtained for all participants

• Tamoxifen following excision:

• Was allowed but not mandated

• With a median follow-up of 6.7 years, the following local recurrent rates (LRR) were reported:

• Five-year LRR for low- or intermediate-grade DCIS (n = 565) was:

• 6.1% (95% CI 4.1-8.2)

• Five-year LRR for high-grade DCIS (n = 105) was:

• 15.3% (95% CI 8.2-22.5)

• The 12-year LRRs for the low- or intermediate-grade group was:

• 14.4%

• The 12-year LRRs for the high-grade group was:

• 24.6%

• These results suggest that patients with low- to intermediate-grade DCIS:

• May be better candidates for local excision alone than those with high-grade lesions who have a higher risk of recurrence

• However, a 10-year LRR approaching 15% in patients with low- or intermediate-grade DCIS:

• May not be low enough to justify the routine omission of post-excision RT even in this patient population:

• This 10-year rate of LRR occurred despite a median tumor size of only 6 mm

• The Radiation Therapy Oncology Group 9804 trial:

• Which was closed early due to low accrual:

• Investigated outcomes of RT omission in the setting of low-risk DCIS

• Randomizing 636 patients with low-risk disease to either RT or observation after surgery

• In this study, low risk consisted of:

• Low- or intermediate-grade DCIS measuring less than 2.5 cm with resection to negative margins of ≥ 3 mm

• Median tumor size was 5 mm

• While recurrence rates were decreased with RT:

• The recurrence rate was also low in the control group

• With a median follow-up of seven years, RT resulted in:

• A reduced risk of a local recurrence compared with observation:

• 0.9% versus 6.7% (HR 0.11, 95% CI 0.03-0.47)

• A higher rate of mild to moderate (grade 1 or 2) toxicities (76% versus 30%):

• Although the rate of serious toxicities was similar in both arms (4%)

• Of patients treated with RT, grade 1, 2, or 3 late toxicities were seen in 30%, 5%, and 0.7%, respectively

• No difference in either:

• Disease-free survival or

• Overall survival

• Results at longer follow-up:

• Also showed lower local recurrence rates with RT:

• 15-year ipsilateral breast recurrence rates of:

• 7.1% versus 15.1% without versus with RT, respectively (HR 0.36, 95% CI 0.20-0.66)

• Identifying patients who can safely be managed with surgical excision alone using clinicopathologic data:

• Remains a challenge, and some patients may value the reduction in recurrence (DCIS and invasive) enough to warrant pursuing post-excision RT regardless of their risk factors

• Gene expression analysis:

• Such as the Oncotype DX DCIS recurrence score has been studied as a tool for identification of patients for whom post-lumpectomy RT may reasonably be omitted:

• But data regarding its utility are still limited

• Although gene expression analyses in DCIS patients are not routine:

• If a DCIS recurrence score has already been obtained:

• It should be considered within the context of:

• Known prognostic factors (ie, tumor size, grade, and margin width) as well as radiation-related factors (ie, cost, convenience, and possible side effects) in consideration for omission of RT after lumpectomy

• The DCIS recurrence score:

• Utilizes a multigene assay that was prospectively evaluated in 327 patients with DCIS who participated in the E5194 trial

• In one analysis, patients were stratified by recurrence score into three groups that were associated with the following risks of an ipsilateral breast event (DCIS or invasive breast cancer):

• Low (< 39) – 12%

• Intermediate (39 to 54) – 25%

• High (≥ 55) – 27%

• Similar results were found in a large study of over 1200 patients with DCIS who were treated with breast-conserving surgery, with or without radiation:

• At a median follow-up of 9.4 years, the 10-year rate of developing a local recurrence, stratified by recurrence score, in patients treated with surgery and radiation was as follows:

• Low-risk – 7.5%

• Intermediate-risk – 13.6%

• High-risk – 20.5%

• Patients with a high-risk DCIS recurrence score:

• Had higher rates of local recurrence and experienced a greater absolute benefit from the addition of RT to surgery relative to those with a low-risk score

• Adjusting for propensity score and year of diagnosis in the high-risk group:

• The 10-year risk of local recurrence was 33% versus 20%, without or with radiation, respectively

• Adjusting for propensity score and year of diagnosis in the low-risk group:

• The 10-year risk of local recurrence was 16% versus 9%, without or with radiation, respectively

• These results demonstrate that patients with a low DCIS recurrence score have a lower risk of in-breast recurrence than those with intermediate or high DCIS scores and may derive a lesser benefit from radiation:

• However, the risk of ipsilateral recurrence in those in the low-risk group who did not undergo radiation therapy was still higher than the expected rate of contralateral breast disease

• Further validation of these results is required before the multigene assay can become a standard part of clinical practice

• Pathologic examination:

• For patients with DCIS, complete tissue processing is important to exclude small foci of invasive carcinoma, determine the size and / or extent of DCIS, ascertain the presence of contiguous or multifocal distribution, and evaluate the distance to the resection margins (margin width)

• However, for large specimens this may not be practical, and in such cases we focus on complete examination of the fibrous parenchyma (omitting the fatty tissue)

• Key pathologic components:

• The pathology report should include the following:

• Nuclear grade and necrosis:

• Low, intermediate, or high

• Presence or absence of comedo necrosis

• The size or extent of the lesion

• The distance to the closest margin, including:

• Whether the margins were only focally or extensively involved

• Specimen orientation by the surgeon:

• To identify specific margins and allow for targeted re-excision if necessary

• Estrogen receptor expression

• This result guides systemic therapy decisions