Avoiding Unnecessary Surgery and Radiation in Low-Risk DCIS

E. Shelley Hwang, MD, MPH

The routine use of screening mammography has drastically increased the identification of ductal carcinoma in situ (DCIS) over the past 3 decades. However, results from current research suggest that many cases of DCIS have a low risk for progression and thus may not require surgical excision and radiation therapy.

“For DCIS at low risk of progression to invasive cancer, such as low-grade, small, nonpalpable lesions, there may be no benefit to surgery and radiation, whereas for large, palpable, high-grade DCIS, intervention may prevent progression to invasive cancer,” E. Shelley Hwang, MD, MPH, wrote in the abstract for her presentation at the recent 2018 Miami Breast Cancer Conference^® (MBCC).

Hwang, who is vice chair of research and chief of breast surgical oncology at Duke University Medical Center, Durham, North Carolina, argues that the increasing detection of DCIS due to more widespread use of mammographic screening calls for “a treatment strategy that is based on biological risk of clinically significant disease, rather than continuing to treat all DCIS as 1 disease.”

Current treatment guidelines call for a combination of surgery, radiation, and hormonal therapy for all DCIS, but risk stratification tools exist that may be of value in identifying patients who would benefit from more aggressive treatment. Oncotype DX Breast DCIS Score and DCISionRT each have the potential for treatment refinement based on risk of recurrence and invasiveness, Hwang wrote. In her presentation, she suggested that a case can be made for tailoring intervention based on age and the presence of competing comorbidities, “given the lead time between development of DCIS and progression to invasive disease.”

Hwang also discussed trials under way to test active surveillance as a moderate approach for treatment of lowest-risk DCIS. The COMET trial, for example, will assess the risks and benefits of active surveillance compared with guideline-concordant care for cases of low-risk DCIS. It is 1 of 3 prospective randomized trials that are performing this evaluation. “The overarching hypothesis of these studies is that management of low-risk DCIS using an active surveillance approach does not yield inferior oncologic or quality-of-life outcomes compared with guideline concordant care,” she wrote.

TABLE. Change in Size-Specific Incidence of Breast Cancer After Introduction of Screening Mammography

Surgery or Radiation for Low-Grade, Low-Recurrence Score DCIS?

MBCC Chair Patrick I. Borgen, MD, noted that the nature of the progression of DCIS has long been misunderstood. “Our generation made an assumption that all DCIS would naturally progress into invasive breast cancer if you left it alone or if you didn’t treat it,” said Borgen, chairman of surgery and director of the Breast Cancer Program at Maimonides Medical Center in Brooklyn, New York. “We now know, based on a lot of evidence from a lot of different venues, that that simply is not true. A substantial proportion of DCIS was really never going to become an invasive, life-threatening cancer, or it was going to do so very slowly. That understanding about the basic biology of DCIS changes our approach very dramatically.” (Table)Although early detection of DCIS enables patients to receive treatment before the cancer becomes invasive, Anees B. Chagpar, MD, MSc, MPH, MA, MBA, pointed out that some patients are treated for low-grade precancerous lesions that probably would not develop into invasive cancers or affect longevity. “If they had never known about those lesions, they could have just as well lived their life,” said Chagpar, associate professor in the Department of Surgery at the Yale School of Medicine and the assistant director for global oncology at the Yale Comprehensive Cancer Center. “Now they are undergoing all kinds of treatments for these lesions, and is that really necessary?”

Whether low-grade DCIS is overdiagnosed is hotly debated, but Chagpar said that many experts agree that DCIS is often overtreated and that further research should focus on identifying the patients who can safely avoid radiation therapy and surgery. “Certainly, we do not want to give away the advantage that we’ve got by being able to essentially cure these patients before they get invasive disease,” Chagpar said. “But at the same time, we don’t want to treat patients whose lesions would have never caused them any harm, such that the treatment may do more harm than good.”

In a talk on screening versus overdiagnosis earlier this week at MBCC, Chagpar stressed the importance of the LORIS and COMET trials and their investigation into whether active monitoring (with endocrine therapy in the COMET trial) yields outcomes similar to those from surgical excision with or without radiation therapy in patients with low-risk DCIS.

Chagpar predicted that the group of patients who can be managed by active monitoring alone will likely be small, and experts are still debating which factors are associated with low risk for recurrence. “You’re looking at small areas of DCIS that are low-grade and hormone receptor—positive and do not present with symptoms,” she said. “You tend to get a small population who would be eligible for consideration for conservative management of their DCIS.”

Management of DCIS in the Era of Genomic Profiling

Chagpar also said that uncovering some of the molecular markers, such as those included in the Oncotype DX Breast DCIS Score, and basic tumor biology associated with recurrence risk will help to individualize treatment. “But we have to remember that no test is perfect,” she said. “At some point, we need to start thinking about how we blend that information into a patient’s clinical context—for example, how old is this patient, what is their life expectancy, and [what are their] comorbidities?—instead of deciding how much treatment is overtreatment.”The trend toward overtreatment of some patients in recent years stems from a flawed understanding of the natural history of DCIS, and genomic analysis can help identify the subset of patients who are at low risk for recurrence, according to Borgen. He discussed the role of genomic analysis in management of DCIS at MBCC in his talk, “DCIS: Rational Approach to Management in the Era of Genomic Profiling.”

Borgen said that the Oncotype DX DCIS Score, a 12-gene assay that predicts the risk for local recurrence following surgical excision, has become a routine part of his practice to identify patients who may be managed adequately with surgical excision alone based on their predicted risk for recurrence.

“About 60% of DCIS falls into a low risk for recurrence, and for those patients, it is appropriate to have a conversation about the role and benefits of radiation therapy,” he said.

Findings from the ECOG study¹ and the Ontario DCIS Cohort study² showed that in patients with DCIS treated with surgical excision, the Oncotype DX DCIS score predicted risk for local recurrence of DCIS or invasive carcinoma independent of conventional clinical and pathologic features, such as age, grade, DCIS subtype, multifocality, and presence of comedo necrosis.

Based on these findings, Borgen predicted that the genomics of DCIS will play a greater role in predicting risk than clinical and pathologic variables. However, he suggested that adding some of these variables to the DCIS score could help strengthen its predictive value, citing a combined analysis of the ECOG E5194 and Ontario DCIS Cohort studies³ showing that combining the DCIS score with age at diagnosis and tumor size predicted more women with very low (≤8%) or high (>15%) risk for local recurrence at 10 years compared with either the DCIS score or clinicopathologic factors alone.

Although the Oncotype DX DCIS assay is not specifically designed to determine whether patients should receive radiation therapy, Borgen said that the assay can estimate the benefits of radiation treatment for a patient, which will help her make an informed decision with her physician about whether to include it in her treatment.

Evidence for a 2-mm Margin

“We might test a 50-year-old woman with a 1-cm DCIS, and the score might suggest a recurrence risk of 15% without radiation therapy,” Borgen said. “The radiation oncologist sits down with the patient and explains that the radiation drops the risk for recurrence to 7% to 8%. The patient and oncologic team will make a decision using their own values for whether that is enough benefit to justify the radiation. There are patients in my practice who would certainly accept radiation therapy for a 5% reduction in the chance for a local recurrence. Other patients would say, ‘I’ll take the 95% chance that I don’t get a recurrence.’”With the goal of decreasing re-excision rates, improving cosmetic outcomes, and decreasing healthcare costs, the Society of Surgical Oncology, the American Society for Radiation Oncology, and ASCO issued a consensus guideline in 2016 stating that 2 mm should be used as the standard for an adequate margin for DCIS treated with whole-breast radiation therapy and that clinical judgment should be used to consider whether re-excision is needed for margins smaller than 2 mm.⁴ However, Borgen and Henry Kuerer, MD, professor of surgery at The University of Texas MD Anderson Cancer Center in Houston, said that using this 2-mm cutoff as an absolute indication for re-excision is overly simplistic considering that other factors, such as patient age and extent of margin involvement, could independently affect local recurrence.

“The main issue is that many multidisciplinary groups now use the 2-mm margin as an absolute indication for repeat surgery, and not all patients with DCIS and margins <2 mm need repeat surgery when receiving [radiation therapy],” Kuerer wrote in a recent abstract published in the American Journal of Hematology/ Oncology^®. ⁵ Kuerer discussed the data and controversy over this consensus guideline at MBCC in his talk, “DCIS: What Is the Evidence for a 2-mm Margin?”

In his talk, Kuerer showed that the 10-year rate of local recurrence was not very different between patients who underwent radiation therapy with negative margins of <2 mm versus negative margins of ≥2 mm (4.8% vs 3.3%, respectively) in a retrospective analysis of approximately 1500 patients at MD Anderson Cancer Center from 1996 to 2010. However, he noted that patients who had a small margin and did not receive radiation therapy had a much higher rate of recurrence (in the 30% range) and should undergo re-excision.

Borgen also said that not all 2-mm margins are equivalent because of inherent limitations with pathologic assessment. “It’s likely that pathology looks at less than 10% of the surface area of the specimen,” he said. “It’s difficult to know, patient to patient, which margins were assessed.”

He also noted a substantial difference between a single duct 2 mm from the surgical edge and a field of 50 ducts that were 2 mm from the surgical edge. “In the latter case, there’s really no chance that that’s a clear margin. You have to look at a broader picture, which is the volume of the DCIS that you’re treating and the volume of the specimen.”

Borgen and Kuerer concluded that while the 2-mm margin is important for surgeons to consider, it needs to be considered in the clinical context of the patient. “It’s hard to believe that the future of this is a ruler—that 1 mm is bad and 3 mm is good,” Borgen said. “I think that’s an overly simplistic way of thinking about DCIS. I think in the long run, it’s going to be far more valuable to talk about the biology of DCIS.”

References

1. 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(10):701-710. doi: 10.1093/jnci/djt067.
2. 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(2):389-398. doi: 10.1007/s10549-015-3464-6.
3. Rakovitch E, Gray R, Baehner FL, et al. Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies [published online January 31, 2018]. Breast Cancer Res Treat. doi: 10.1007/s10549-018-4693-2.
4. Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncology— American Society for Radiation Oncology–American Society of Clinical Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ. J Clin Oncol. 2016;34(33):4040-4046. doi: 10.1200/JCO.2016.68.3573.
5. Kuerer HM. Controversies and clinical trials for dcis: margins and active surveillance. Am J Hematol Oncol. 2017;13(9):4-7. gotoper.com/ publications/ajho/2017/2017october/controversies-and-clinicaltrials-for-dcis-margins-and-active-surveillance. Accessed February 1, 2018.