TAILORx Provides 'Clear Answer' for ER+ Breast Cancer

Interview With Joseph Sparano

Kathy D. Miller, MD; Joseph A. Sparano, MD


June 13, 2018

Kathy D. Miller, MD: Hi. I'm Dr Kathy Miller, professor of medicine and associate director of clinical research at the Indiana University Simon Cancer Center. Welcome to Medscape Oncology Insights. Today I'm joined by my colleague, Dr Joe Sparano. Joe is professor of medicine and women's health at the Albert Einstein University. Thank you for joining us, Joe.

Joseph A. Sparano, MD: It's a pleasure. Thank you.

Background of TAILORx

Miller: We want to talk to you about the TAILORx trial.[1] First, tell us about the design of TAILORx and why it came to be.

Sparano: We first started thinking about a precision medicine trial for early-stage breast cancer back in 2003. We knew we were overtreating a large number of women but we felt that treatment was essential because we were saving lives. But only a small percentage of patients were benefiting. Around that same time, one of the first gene expression assays became commercially available, the 21-gene assay recurrence score. This was helpful in providing guidance when the score was really high or really low, but unfortunately the majority of patients had midrange recurrence scores. We designed the trial specifically to address that population and also to prospectively assure ourselves that patients with a low score had a good prognosis. This was important because at the time we had data on only about 1500 patients.

Miller: For some diseases, 1500 patients might sound like a lot, but to breast cancer physicians used to seeing trials consisting of several thousand patients, 1500 patients felt like a skimpy dataset.

Sparano: Yes. There were two trials but only one really addressed what was of relevance and most important to clinicians and patients. What is the prediction associated with the 21-gene assay? Does it predict chemotherapy benefit? It turned out that it did in that study, and at least one subsequent study substantiated that.[2,3,4] We had a high level of confidence for that, but we were in uncharted waters in terms of patients who had lower scores, especially midrange scores.

TAILORx Results: Low Recurrence Score

Miller: The design of the TAILORx trial was very simple. You got the score in patients with ER-positive tumors who were node negative. If the score was clearly low, the recommendation was hormone therapy. Patients were followed, and you presented results of those patients about a year and a half ago. How did that group do?

Sparano: That group continues to do well. We first reported results back in 2015 at the ESMO meeting and they were published in New England Journal of Medicine.[5] The results now have worked their way into the 8th edition of the American Joint Committee on Cancer Staging Manual. Women with a recurrence score of 0 to 10 assigned to endocrine therapy alone were followed on this prospective registry and had a distant recurrence rate of only 1% at 5 years. This indicated that it would be impossible to show a chemotherapy benefit in this group of patients as it relates to distant recurrence, which is the type of recurrence or the type of event we fear most in women with early breast cancer.

Miller: Those results are still holding up because 5 years of follow-up for ER-positive disease is not a long time.

Sparano: You are absolutely right. We now have data out to 9 years. The distant recurrence rate is about 3%, which is pretty much what we expected based on what we have seen in the prior study, and we know that there is this continuous risk for recurrence beyond 5 years. We are not exactly sure when it ends. It's been shown to exist up to 15 years out, but in terms of preventing recurrence, the key thing is that the benefit of chemotherapy is largely within the first 5 years of diagnosis. We have pretty solidly ruled out that chemotherapy would be beneficial in this group of patients.

Miller: The main goal of the TAILORx trial was [to determine whether adjuvant chemotherapy is beneficial] in patients with midrange scores of 11 to 25 in the trial designation.[6] These women were randomized to hormone therapy alone or hormone therapy with the addition of chemotherapy. We have been waiting for about 9 years to know whether chemotherapy would be beneficial. Do we finally know?

TAILORx Results: Midrange Recurrence Score

Sparano: Some things are worth waiting for, and I think this was. We really had to be sure that chemotherapy was not beneficial in this group. If we are going to take a step back from something that we have been doing for a very long time, we better be sure about it. The trial was designed with that intention. One complicating factor was nonadherence to assigned therapy. This was expected, so we built it into the trial. The nonadherence rate was 12%. This may sound like a lot, but it was startling to me that as many as 88% were compliant.

Miller: That is really surprising. Thinking from a patient's perspective, you let a computer decide whether you get chemotherapy or not, and you try to be okay with either recommendation. The fact that only 12% of patients said, "I'm going to do the other thing" is really good.

Sparano: It's very consistent with other seminal trials in breast cancer. For example, the B-06 trial comparing mastectomy versus lumpectomy had a nonadherence rate in the same range.[7] The trial evaluating conventional chemotherapy with high-dose chemotherapy and stem cell transplant in women with very high-risk disease had same nonadherence rate.[8] We inflated the sample size in the randomized group to assure that we had enough power to detect a difference or lack of difference, from a statistical perspective.

Miller: Is there a benefit of chemotherapy for patients with midrange scores?

Sparano: The answer is simple for patients older than 50 years: There is absolutely no benefit of chemotherapy. The answer is somewhat more nuanced for women 50 years or younger. Women with a recurrence score of 0 to 15 (which partly overlaps with those having a score of 11 to 15) had a 3% distant recurrence rate at 9 years—not really different from those who had a recurrence score of 0 to 10. But we saw a three-way interaction between age, recurrence score, and chemotherapy treatment in younger women. For example, a woman 50 years or younger with a recurrence score of 21 to 25 had some benefit from chemotherapy in the range of a 6% to 7% reduction for the risk for distant recurrence. A woman with a score of 16 to 20 also had some reduction, but only about 2% in distant recurrence. There was some effect on preventing other events (eg, second primary cancers), which we knew from previous studies, but it played out in that specific group of patients.

Miller: That is tricky to interpret because chemotherapy in our younger premenopausal patients has both a chemotherapy effect and an endocrine effect. Many of those women would be rendered menopausal because of the ovarian effect of the chemotherapy. Do we know which of those accounts for that benefit?

Sparano: We don't. We won't be able to determine that from this trial. We did not capture the information regarding persistence of ovarian function/menopausal status after enrollment, but that question could potentially be answered by going back and doing additional studies on randomized trials that addressed that question, like the SOFT trial.[9] If bio-specimens are available, it may be possible to go back and try to address that specific question using samples from that trial, which also has a very mature follow-up.

TAILORx Results: Higher-Risk Patients

Miller: The TAILORx trial also followed the higher-risk patients, those with scores above 25. They had a recommendation to receive chemotherapy. The hope was that most of them would receive chemotherapy and that they would do well. What do we know about that high-risk group?

Sparano: As you might expect, the vast majority who were assigned to chemotherapy did agree to take it. We found that 13% of those women had a distant recurrence at 9 years. We know from previous studies that they are at that 13% level because they are getting a really large benefit from chemotherapy; otherwise, they would have about a 40% risk for recurrence. The good news is that they are benefiting, but we have more work to do.

Dr. Miller: They're still not as good as the low-risk group.

Dr. Sparano: Yes, and I think this study provides a foundation for using this as a biomarker to select patients for more aggressive therapies that could potentially further reduce that risk for recurrence.

How Impactful Are These Results?

Miller: What does this mean for patients and practitioners? One of the most common reasons I am asked for a second opinion is to evaluate patients with mid-range scores. Am I about to get less busy? I hope.

Sparano: There certainly will be more clarity about the recommendations you can make. I think how busy you will be regarding second opinions will depend upon how well we get the message out about the results of the trial and how clear that message is. I hope that we can do that.

Miller: How many women potentially will be impacted by this? How many women will this potentially spare the toxicities of chemotherapy because they are in that group that we now know does not need it?

Sparano: There are two ways to look at this. If you look at it just from the view of how many women present with this type of breast cancer, in 2016 or 2017 about 135,000 women presented with ER-positive (or hormone receptor positive), HER2-negative, node-negative breast cancer. If you assume that about 25% of those patients are not suitable candidates for chemotherapy because of their age—we did not study patients older than 75 years in TAILORx— or because of medical conditions that would make chemotherapy not practical, that comes out to about 100,000 women. If you then extrapolate and consider that two thirds of those women would have a midrange recurrence score if tested, that is about 65,000 or so women in whom we now have a clear answer about what the right path is.

Viewed another way, back in 2000 before the National Cancer Institute/National Institutes of Health issued a consensus statement recommending that pretty much all women be considered for adjuvant chemotherapy,[10] it was estimated that about 60% of women were receiving adjuvant chemotherapy in that space. Since then, that percentage has come down. Where it is right now is difficult to say but it's probably in the range of 35% to 40%.

We are probably overtreating some patients and we may be undertreating some as well. Clinicians have used this assay mainly for treatment-sparing in situations where they are in a therapeutic equipoise, meaning that chemotherapy would be recommended, but they use the assay results to spare a recommendation of chemotherapy. What we don't have is a clear answer on treatment selection—in other words, patients who have low-risk characteristics and the clinician says you don't need chemotherapy. However, sometimes if you test those patients, you can be surprised to find an assay result suggesting that a large benefit from chemotherapy [can be derived].

Where Do We Go From Here?

Miller: Where will you go next? This is a huge study with really important results that will change practice for our patients. But we still have patients who are not doing well. We still have a lot of questions. What is the next question to be answered?

Sparano: We can still learn a lot from this study in terms of subset analysis, both planned and unplanned. We collected bio-specimens in these patients so we will be able to go back and try to figure out why that 3% of patients with a low recurrence score relapsed and what were the characteristics of [their] tumors. Also, what drove the relapses in women who had the high-risk scores? We also have blood specimens so we can look at blood-based biomarkers.

Second, other studies[11,12,13] have been completed that have evaluated this assay in patients with one to three positive nodes to see if we can expand the use of the assay further into a higher-risk population. Trials are ongoing elsewhere in the world testing a similar approach—risk stratification by integration of a biomarker. We have entered the age of biomarker-directed adjuvant chemotherapy. We have sort of been there for the past 10 or 15 years as it relates to the use of the 21-gene assay and other assays, but this has launched us full-steam into that realm. It complements what we have been doing for a long time as it relates to using ER/PR for selecting endocrine therapy and HER2 for selecting anti-HER2 therapy.

Miller: It's a great day for patients. Thank you, Joe, for coming in and discussing this trial with us. We'll look forward to the next results.

Sparano: Thank you. It's been my pleasure.

Miller: And to you, our audience, thank you for joining us as well. This is Kathy Miller for Medscape.


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