As physicians, we are charged with studying, diagnosing, and treating disease, listening to and respecting our patients, and leaving them better off than when they came to us. We have thousands of hours of hard-earned practice under our belts and we look to innovations and clinical advancements to guide our treatment recommendations. The treatment of Stage 0 breast cancer, also known as Ductal Carcinoma in Situ (DCIS), has evolved through the decades from modified radical mastectomy to lumpectomy plus adjuvant RT, to shorter whole breast RT regimens, and most recently accelerated partial breast irradiation & Stereotactic Body Radiation Therapy (SBRT).

Perhaps the most challenging question physicians who treat this disease face is whether every woman with DCIS who has breast conservation surgery, requires adjuvant radiation therapy or not. There have been multiple published papers and algorithms purported and currently being used to guide physicians and patients alike to make a collective informed decision as to utilizing RT in the treatment regimen. But up until the development of genomic testing, none have provided empirical data to substantiate a treatment recommendation. As a radiation oncologist treating DCIS, the introduction of genomic testing for biological risk assessment is as close as we have come to predicting potential future risk for our patients.

Traditional Management of DCIS
Traditionally, women diagnosed with DCIS are either treated with mastectomy or with breast conservation surgery, followed by radiation. We have learned from historical studies and randomized trials evaluating the use of radiation after breast conservation surgery, including the largest individual trial (NSABP B-06), that radiation for DCIS reduces recurrence by 50% overall, [1] with roughly half of those being invasive recurrences. More recently in the last two decades, the possibility of omitting radiation based on clinical and pathologic features has been explored, trying to determine who are the low recurrence risk patients. And pragmatically, that should make sense. Low-risk features should mean low-necessity for radiation and thus low rates of recurrence… except that is not what we are always seeing. Or perhaps, we need to re-define what low-risk actually looks like.

Clinical Studies Support Change
A pivotal prospective trial, the ECOG-ACRIN E5194 study [2] was performed to determine the risk of ipsilateral breast events (IBE) for selected low-risk patients with DCIS treated with lumpectomy alone (i.e., no radiation). The low-risk designation was based upon clinical and pathologic characteristics and separated patients into two groups. The first consisted of patients with grades 1 and 2, 2.5 cm or smaller in size, and >3 mm margins. The second group contained those with grade 3 DCIS, 1 cm or smaller, and with >3 mm margins. Only approximately 30% of patients took tamoxifen, which was not randomized. Initially, when the five-year results of this study became available, it showed great promise with fairly low rates of recurrence, 6.1% for “low-risk” and 15.3% for “high-risk.” [3] However, as is often seen with longer follow-up, when the 12-year results were presented, findings had changed significantly. The “low-risk” first group experienced a 14.4% IBE recurrence rate after 12 years and the “high-risk” second group was 24.6%. The recurrence rate for an invasive event was 7.5% for the “low-risk” and 13.4% for the “high-risk” group. Therefore, even in the NSABP B-06 “low-risk” group not everyone benefited from radiation.

These findings were mirrored in RTOG 9804, [4] a randomized trial essentially encompassing the first “low-risk” group of the ECOG trial. Patients in this group had mammographically detected DCIS with grades 1 or 2, tumors 2.5 cm or less, and margins 3 mm or greater. Approximately 70% of patients received tamoxifen. Patients were randomized to whole breast, hypo-fractionated radiation versus observation after surgery. Only one-third of patients actually accrued to the goal. At a median follow-up of 7 years, radiation again reduced the risk of recurrence significantly, for some but not all, with local failure recurrence rate of 0.9% in the RT group and 6.7% in the observation group. Long-term outcomes are pending.[5]

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So, if we cannot solely depend on clinical and pathologic features to identify the risk of recurrence and therefore the necessity of radiation, how do we know whom to radiate? Who will benefit and by how much? That is where genomic testing, specifically DCISionRT comes in. What it provides is proven study data to minimize the need for educated guessing. By using biomarkers and clinical-histopathologic features in a non-linear algorithm, it is able to identify an accurate risk of total ipsilateral and invasive disease recurrence within 10 years. Furthermore, studies have shown DCISionRT’s ability to reclassify between 40-50% of patients initially categorized into risk groups based upon clinical/pathology alone.[5]

In a recent podium presentation of the randomized SweDCIS Study [6] at the 2017 San Antonio Breast Cancer Symposium (SABCS), researchers randomized 506 patients to lumpectomy alone plus or minus radiation, with similar criteria to both the ECOG and RTOG trials, but using no tumor on ink as negative margin criteria. The DCISionRT assay demonstrated only a 1% absolute risk reduction from RT in the low-risk group but a significant 9% absolute risk reduction in the elevated risk group. Overall there was a 76% relative risk reduction from radiation therapy, which is significantly higher than the historic 50% benefit that has been shown with clinical/pathology criteria.

Even more recently published data from Kaiser Permanente NW [7] looking at 455 women with DCIS aged 26 years or older demonstrated at 10-year follow-up in what was otherwise considered to be a clinicopathologically low-risk subset (RTOG 9804-like criteria), DCISionRT was able to reclassify 49% of these patients into an elevated risk group. DCISionRT identified an elevated Risk Group with a 10-year Invasive Breast Cancer (IBC) risk of 21% and an Ipsilateral Breast Event (IBE) risk of 30%, receiving an RT benefit of a 70% relative risk reduction versus the historical 50%. DCISionRT identified a low-risk group with a 10-year IBC risk of 6% and a 10% IBE risk. This group received minimal RT benefits. The Kaiser independent validation was very consistent with previously presented UUH/UMass validation especially with a demonstration of a 70% RT benefit in appropriate high-risk group as well as a similar re-classification of 40% to 50% of patients from low to elevated risk groups.[8]

We know that genomic assays are crucial to accurate risk assessment, but how often do they reinforce our hypotheses and more clinically relevant, how often do they change our minds? In a study presented at SABCS 2020, [9] researchers looked at patients undergoing breast-conserving surgery and compared clinicians’ treatment recommendations and radiation preference before and after the DCISionRT genomic test. They divided patients into those who were and were not recommended radiation upfront based on traditional clinical/pathologic features. After DCISionRT, approximately 44-46% of clinicians overturned their initial treatment recommendation. Between 48-54% of what were thought to be “high-risk” patients were no longer recommended radiation and, just as importantly, 21-37% of those thought to be “low-risk” were newly recommended radiation in light of the genomic results. Genomic testing is clearly not a one-way street. As physicians use it to prevent patients from being overtreated, it is also used to catch those who would have slipped through the cracks and been undertreated based upon older risk criteria data.

Team Approach to Patient Outcomes
As oncology is multidisciplinary and inherently team-oriented, applying DCIS genomic assays to our individual practices requires communication between all specialties. All patients with a diagnosis of DCIS should be considered for tests such as DCISionRT, but it warrants a discussion with the breast surgeon making sure that they are comfortable with and informed on the approach. Of course, with the patient discussion, it is all about informed collaborative decision-making. It is important to explain the test and how it will enlighten treatment decisions to the patient both preoperatively and postoperatively, and why traditional clinical and pathological factors alone are no longer sufficient criteria for accurate classification and hence for treatment recommendations. We must walk them through how the test is interpreted and the diverse pathways that come about from various outcomes so that when discussing the results, they have an idea of what to expect. It is about the physician making a treatment recommendation based upon empiric data and the patient reaching a decision they are comfortable with after learning about their risk with and without radiation treatment.

Economic Implications
In terms of cost-effectiveness, not all genomic assays and diagnostic techniques are an easy sell. A study out of the University of California, Los Angeles (UCLA) [10] on DCISionRT divided treatment options into three approaches: no genomic testing and no radiation, genomic testing all DCIS patients and only radiating elevated risk patients, and finally radiating everyone and testing no one. Their findings revealed that genomic testing with DCISionRT was as cost-effective as radiating everyone without testing, and the genomic testing strategy with DCISionRT minimized the number of women undergoing RT per IBE prevented. They discovered that physicians would have to radiate only eight patients in order to prevent an ipsilateral breast event. An additional study out of the University of Pittsburgh Medical Center (UPMC) [11] further support the findings of DCISionRT being a cost-effective approach for the treatment of DCIS.

… a recent company webinar is a common clinical scenario many of us face in our practice…

DCIS Genomic Testing in Practice
A helpful case study highlighted in a recent company webinar is a common clinical scenario many of us face in our practice. A 60-year-old female presents with new calcifications on her mammogram. Her biopsy shows Grade 2 DCIS, ER+. She undergoes a lumpectomy which reveals 1.5 cm DCIS with margins negative at 2 mm. The physician orders a DCISionRT genomic test and she scores a 1. Her 10-year total risk of a noninvasive event is a 1% difference whether she gets radiation or not and the really important part- invasive risk recurrence- carries no difference whatsoever.

However, testing results have shown that if a patient with the exact same clinical/pathologic factors has a DCISionRT score of 7.3, for example, she still technically meets classic clinical/pathologic criteria for the potential omission of radiation, but her tumor’s biology begs to differ. This patient’s individualized DCISionRT assay results show a 15% difference in the risk of invasive recurrence at 10 years between surgery or surgery plus radiation. These findings would be reviewed with her along with treatment options and make an informed decision on how to proceed based on her unique circumstances.

In the end, the patient, her loved ones, and her physicians can all feel more informed and confident knowing that regardless of which treatment pathway they move forward with, it will be the right one for the patient. Genomic testing, in this case Radio-Genomic testing with DCISionRT, is an invaluable tool in treatment guideline recommendations for DCIS.

Reference
[1] Fisher B, Anderson S , Redmond CK . et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med. 1995;333(22):1456–61.
[2] Solin LJ, et al. Surgical Excision Without Radiation for Ductal Carcinoma in Situ of the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study. J Clin Oncol. 2015 Nov 20;33(33):3938-44.
[3] Hughes LL, et al. Local Excision Alone without Irradiation for Ductal Carcinoma In Situ of the Breast: A Trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2009 Nov 10;27(32):5319-5324.
[4] McCormick B, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015 Mar 1;33(7):709-15.
[5] Bremer T, et al. A biologic signature for breast ductal carcinoma in situ to predict radiation therapy (RT) benefit and assess recurrence risk. Clin Cancer Res. 2018; doi:10.1158/1078-0432.CCR-18-0842.
[6] Wärnberg F, et al. SABCS 2017. Publication Number GS5-08 – AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-08.
[7] Sheila Weinmann, Michael Leo, Pat W Whitworth, Rakesh Patel, James Pellicane, Fredrik Wärnberg and Troy Bremer et al., Validation of a ductal carcinoma in situ biomarker profile for risk of recurrence after breast-conserving surgery with and without radiation therapy. Clin Cancer Res April 27 2020 DOI: 10.1158/1078-0432.CCR-19-1152.
[8] Bremer T, et al. A biologic signature for breast ductal carcinoma in situ to predict radiation therapy (RT) benefit and assess recurrence risk. Clin Cancer Res. 2018; doi:10.1158/1078-0432.CCR-18-0842.
[9] Shah et al SABCS 2020: Clinical utility of biologic signature to assess DCIS recurrence risk in patients meeting ‘good-risk’ criteria (RTOG 9804, ECOG 5194): interim analysis of the DCISionRT PREDICT study.
[10] Raldow et al (2020). Cost Effectiveness of DCISionRT for Guiding Treatment of Ductal Carcinoma in Situ. JNCI Cancer Spectrum, 4(2), pkaa004–. doi:10.1093/jncics/pkaa004.
[11] Kim et al (2020). Cost-Effectiveness Analysis of Biological Signature DCISionRT use for DCIS treatment. Clinical Breast Cancer, (), S1526820920302664–. doi:10.1016/j.clbc.2020.10.007.

Featured image: Patient undergoing mammography test in hospital. Courtesy: © 2016 – 2020 Fotolia/Adobe. Used with permission.

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