7-gene DCIS Assay: For several decades in clinical oncology, when it comes to DCIS, or (invasive) ductal carcinoma insights, for several decades, we've recommended all women (diagnosed with Breast Cancer) who undergo lumpectomy receive radiation based on a 50% reduction in recurrence in the breast (cancer).
We've tried to identify (DCIS) patients that don't benefit from (adjuvant) radiation therapy, but using traditional clinical factors as well as pathologic factors has failed to identify a subset of residual risk patients that don't benefit from radiation therapy with respect to local. The decision RT assay is an assay that is a biosignature that incorporates four clinical and pathologic features with really seven targets.
They include estrogen expression (estrogen receptor) and proliferation that will help us pick out patients (study participants) who may or may not benefit from radiation. The score includes a low-risk group of patients, an elevated-risk group, and a residual risk factors. And the purpose of our abstract was really to take a large cohort of patients and see when the decision RT assay was applied.
And what the studies showed is that we had really three groups: the low group, the group at elevated risk, and residual risk patients group. And the residual risk (group) made up about 20% of the patients; the low risk made up about 37%; and the remaining elevated risk made up the remaining 12%. And what we found is that low-risk patients did not benefit from radiation therapy.
Elevated-risk patients benefited substantially from radiation therapy. And then finally, with the residual-risk patients, they had an even greater benefit from radiation therapy than the elevated risk, but their overall risk of recurrence remained elevated even after lumpectomy and radiation, reaching almost 15% at 10 years, which is quite high.
The other thing we were able to see is that patients who we would consider in the low-risk group based on their clinical and pathologic features had a high risk of being converted to elevated residuals. On the other hand, patients who are thought to be at a higher risk based on their clinical and pathologic features may have their decision RT score lowered and not get any benefit from radiation therapy.
7-gene DCSI Assay: 4 Key Takeaways
This study's objective was to prospectively validate a novel biomarker, Integrated Residual Risk Subtype (RRt), integrated (residual risk subtype) with the 7-gene DCIS assay to assess 10yr ipsilateral breast recurrence (IBR) rates and radiation therapy (RT) benefit compared to CP criteria alone.
At a CLIA laboratory, FFPE tissue (DCIS) samples from 926 women from four worldwide cohorts patients treated with BCS with negative margins were evaluated. Using an algorithm, the 7-gene DCIS assay combines biomarkers with CP variables (age, size, palpability, and margin status) to generate a decision score (DS).
The biosignature identified 37% of the women as Low Risk, with low 10-year IBR rates with or without RT (4.8% vs 5.6%), and 43% as Elevated Risk, with an IBR rate of 20.6% without RT and 4.9% after RT, an 80% IBR advantage from RT (p0.001). Even "good risk" CP patients experienced a considerable advantage (17% IBR without RT and 6% with RT, p0.03). 20% of women were classified as Residual Risk with an IBR rate of 42.1% without RT and an IBR rate of 14.7% after RT (p0.001).
The 7-gene predictive DCIS assay coupled with the unique Residual Risk Subtype (RRt) (breast cancer subtypes) biosignature categorized women into 3 risk categories with distinct IBR rates and RT-benefit profiles over 10 years.
When it comes to the methods of this study in clinical oncology, it's important to recognize that this was a foresight multinational cohort of four different groups of patients who are relatively modern and about 926 patients treated in total. And importantly, this was a study where we already had the data outcomes and then went back and did the testing, rather than doing the testing and following the patients for 10 years.
And what we did is we took those 926 (DCIS) samples, ran the test, broke them down into elevated and residual risk patients, and then looked at their rates of recurrence based on that breakdown. We then looked at traditional clinical pathologic features that were grouped up based on clinical trials, and we looked at how those patients fared based on the decision RTS Corps made with respect to radiation therapy fared.
The current standard of care for ductal carcinoma in situ (of the breast or situ breast carcinomas) in the management of breast cancer is that we counsel patients after lumpectomies on the pros and cons of radiation therapy.
We try to risk-stratify them. Until recently, we really didn't have the ability to have a prognostic test (DCIS Samples) as well as a predictive radiation test. Now, in my current clinical practice with women who have ductal carcinoma, after the lumpectomy, I talked to them about the results of these studies and other studies using this biosignature, and we talked about how we can find prognostic and predictive information with regards to the role of radiation.
Unfortunately, we don't have the same type of testing available for invasive breast cancer. At this time, though, ongoing (invasive breast cancer) research is hoping to identify SIM-like similar biosignatures for invasive PA breast cancer.
A common question is whether this type of biomarker can be used in other types of cancers. While this distinct (groups of) biomarker can be used in nearly all (pure) DCIS cases, there are other tumor genetics and tumor acids that are being used in different disease groups to help identify those patients that will benefit most from radiation therapy and those that will derive little to no benefit from radiation therapy.
What led to the increased use of this assay and the study of this assay was really that we, as clinicians, were struggling to identify which patients benefited from radiation and which didn't. When you look at studies omitting radiation, even in low-risk patients, the risk of disease recurrence was between 15 and 25% after 12 years, meaning that 75 to 85% of women weren't benefiting from radiation, but we weren't able to pick out the winners and the losers. This test allows us to better identify those patients at low risk who derive no.
Fitting that 75 to 85% that we previously talked about as well as those in that 15% to 25% that had a risk of recurrence and whom we can offer radiation therapy to. This has been confirmed by previous studies, including an assessment of the Swedish DCIS randomized trial, which was published and showed that this same biomarker was able to identify low-risk patients that didn't benefit from radiation as well as patients at elevated risk. Patients who did benefit from radiation.
So when we look at patients prior to the biosignature, we're trying to omit radiation. Two major clinical trials have recently concluded. The ECOG-ACRIN E5194 trial looked at low-risk patients (grades 1 or 2 with negative margins or grade 3 with negative margins) and followed them without radiation. And at 12 years the risk in the grades 1 and 2 group was around 14.5%.
And then the high-grade (DCIS) group was around 25%. Similarly, NRG/RTOG 9804 was a randomized trial of patients with that grade 1 or 2 disease, and they were randomized to receive radiation or not. Without radiation, the risk of recurrence was around 15%, and with radiation, that was cut in half. And so that's really where we started with (pure) DCIS.
When you look at the biometric signature, the data consistently shows two things. In the low-risk group, there really is no benefit to radiation. There's no difference in local recurrence. Overall. But, more importantly, there is no difference in invasive recurrences, which have been linked to an increased risk of breast cancer mortality in women with DCIS.
On the other hand, the elevated-risk patients are demonstrating a statistically significant benefit, meaning a reduction in both local recurrence and invasive breast recurrence when they receive radiation therapy. And this is a big difference than what we've seen in these other studies that preceded them, where really the benefit was seen by all patients and the assumption was made that all patients assumed. The same benefit comes from radiation. The new biosignature data says that some patients derive a benefit and some don't, and we're able to pick those patients out.
The conclusions are really threefold. I think the first conclusion is that in low risk patients, there's no benefit to radiation therapy with respect to overall recurrences in the breast or invasive recurrences in the breast following lumpectomy.
The conclusion is that radiation therapy greatly reduces the risk of both overall recurrences in the breast and invasive recurrences in the breast in patients with a high risk. And then the third main conclusion is that in patients at residual risk patients, radiation therapy reduces the risk of recurrence, both total and invasive. The recurrence rates remain high, and this is a group of patients we need to study to see how we can intensify or alter therapies so that we bring the recurrence risk in line with those seen for the low-risk patients and the elevated-risk patients who've received radiation, which is around 5% at 10 years.
When it comes to using the seven gene bio signature, my hope is that patients are able to use their own tumor data and their own clinical pathologic features to determine the treatments that are best for them. So, we can avoid giving them too much or too little care by really looking at their personal risk and figuring out the best strategies for them. There is a need for a method that can estimate recurrence risk and radiotherapy benefit to enable customized care of DCIS following breast conserving surgery (BCS).
As a closing statement, I'd like to say that breast radiation is evolving. We're continuing to look at strategies to reduce the duration and toxicities of radiation, but also to pick the patients who need it most. And I think using tests like this bio-signature allows us to pick out the breast cancer patients who truly need radiation therapy as well as those who can safely avoid it. It's my belief that in the years to come, this is going to become more and more common for all forms of breast (invastive) cancer, moving beyond DS to invasive cancers and node-positive cancers as well.
The Comprehensive Breast Program is run by Chirag Shah, MD, who works in the Department of Radiation Oncology. He is the Director of Clinical Research and the Director of Breast Radiation Oncology for the Cleveland Clinic's Department of Radiation Oncology. Dr. Shah is a graduate of Youngstown State University and Northeast Ohio Medical University. Between 2007 and 2012, he worked as an intern and a resident at William Beaumont Hospital. In 2015, he joined the staff at the Cleveland Clinic.
Dr. Shah reviews for a lot of medical journals and is a part of a lot of medical groups. His main scientific interests are breast cancer, sarcoma, new ways to treat breast cancer with radiation, and keeping lymphedema from happening. Numerous in-house, pharmaceutical, and cooperative group experiments have included him.