Jane L. Meisel, MD, discusses the clinical implications of the TAILORx trial and how it has affected practice.
Kristie L. Kahl: Can you provide a general overview of the TAILORx trial?
Jane L. Meisel, MD: It helps first to talk about what Onctotype is. Anyone who has studied estrogen-positive breast cancer or has had estrogen-positive breast cancer, probably will be familiar with Oncotype. Essentially it is a genomic test that takes a woman’s tumor after it has been removed and analyzes that tumor to look at levels of expression of different genes in the tumor. If you have high levels of expression of high-risk genes – genes that portend a poor prognosis or a high risk of recurrence – and your Oncotype score, which is a numerical score you get back, is higher. And if you have higher levels of low-risk genes, then your score will typically come back lower. That score is on a continuum.
This is a test that has been validated for a long time. We’ve known for a long time as a clinical community, based on large studies, that is you have a very low Oncotype score, below 10, then you don’t benefit from chemotherapy. If you have an early-stage lymph node negative breast cancer, you can get away with anti-estrogen therapy alone, not need chemo, and still have a great outcome. Conversely, if you have a high risk score, typically defined as 26 or higher, then you do benefit from chemotherapy in addition to endocrine therapy. This has been really helpful already. If you have a high-risk score, you need chemo, if you have a low-risk score, you don’t need chemo.
But the vast majority of scores fall in this intermediate-risk category, between 11 and 25 generally. You have to use the patient’s preferences, the doctor’s estimation of risk, and all sorts of other things to take into account to make a decision about chemo or no chemo.
What the TAILORx trial was deigned to do was take a closer look at that intermediat-risk group – those women whose Onctotype scores fall between 11 and 25. What that trial did was it randomized those women to receiving chemo in addition to endocrine therapy or just endocrine therapy alone and looked at outcomes. It essentially tried to answer : Can these women get away without chemotherapy? Do they all need chemotherapy? Or can many of them get away without chemo, and perhaps there is a subset of women who might benefit from being more aggressive (with their treatment)?
Kristie L. Kahl: What were the main findings?
Jane L. Meisel, MD: It was a very interesting study. It was a landmark trial that has changed a lot of the way we practice. What they found in this trial…was that the vast majority of women who had risk scores between 11 and 25 did not benefit from chemotherapy. They did just as well if they got anti-estrogen therapy alone.
However, the primary results of the trial, when they were initially published, showed that there was a group of women under 50 who had scores between 16 and 25 who may benefit from chemotherapy in addition to endocrine therapy. The trial was first presented, and then subsequently there was additional analyses done, a lot of thought was put into who are these women who might still benefit from some chemo. And how do we determine who they are as best as possible so that we give the right treatment to the right woman. You don’t want to withhold chemotherapy from someone who needs it, and for them that might make the difference between cure or not cure. But you also don’t want to give chemotherapy to people who don’t need it.
The biggest challenge in the current era with (the coronavirus disease 2019 [COVID19]), to take into consideration with other risks really highlight the need to make these decisions thoughtfully.
Kristie L. Kahl: Can you explain the differences between the low- and high-risks in women under 50?
Jane L. Meisel, MD: In the TAILORx trial, there was a subset of patients who were under 50 and had recurrence scores of 16 to 25 for whom there was a hint that maybe they did need chemotherapy and couldn’t get away with anti-estrogen therapy alone, which the rest of study population seemed to be able to do. TAILORx trial, at the end of the day, had clarified beyond a shadow of a doubt, if you were node-negative and your age was over 50 and your recurrence scored was under 25, you didn’t need chemotherapy. If you were any age, and you had a recurrence score under 15, you didn’t need chemotherapy. The 16 to 25 group was thought to be on the border, and potentially worthy of more study. Investigators took a closer look at that subset of patients, and they looked at the clinical risk of each of those patients. They looked at tumor size and grade and put those in the same clinical risk categories from MammaPrint and the MINDAct trial.
Then, they looked at clinical risk and genomic risk to determine can you integrate clinical risk into your decision making about whether or not to use chemotherapy. We’re also doing that fundamentally if you see a patient in your clinic who has an Oncotype score of 22, you think about whether that woman need chemo – is it high grade or low grade? Is it 3 cm or 1 cm? You’re thinking about all of these things as risk factors. What this study did was clarify how we should be thinking about this.
What they determined in the exploratory analysis, when they look at women with a score of 16 to 25, and look at clinical risk, basically all of those women under 50, regardless of clinical risk, if your score was 21 to 25, you would benefit from chemotherapy. If your score is 16 to 20, however, you benefit from the chemotherapy if your clinical risk is high, but you don’t really need the chemotherapy if your clinical risk is low.
It was able to further parse out a lot of limitations. It was a subset analysis, but it was a pretty large subset analysis. Maybe a subset of women under 50 in the intermediate risk category who also don’t need chemo, namely the 16 to 20 clinical risk score group, could avoid it.
Kristie L. Kahl: Why is it important that this is the largest landmark trial to determine treatment decisions?
Jane L. Meisel, MD: The fact that this was a study that looked at thousands of women, prospectively, meaning it randomized large numbers of women to one treatment or another, allows you to really have faith in the integrity of the data. What the trial was looking at was non-inferiority to make sure that if you withheld chemo, was not inferior to a regimen including chemotherapy. It really made a huge difference.
I remember when this trial release data at ASCO 2018, and I had a woman in my practice who had had an intermediate risk score. She was in her 70’s, and did not want to do chemotherapy. Before the TAILORx trial, a score in the 20’s for a woman, even at 70 years old and is in good shape, would be one of those situations we talked about. But I said to the patient, “We’re going to have these results in a few weeks, why don’t I call you after ASCO?” I called her the day after that presentation and I told her she didn’t need chemotherapy. It was the happiest day of her life.
It really was a meaningful moment for her. And there are so many other women like her who can make this decision to withhold chemotherapy based on data from thousands of patients. We can talk about data and hazard ratios and P values, but each woman who gets to make a treatment decision and do so without having to look back, can mean the world.
Kristie L. Kahl: How has the trial had a positive impact on treatment decisions?
Jane L. Meisel, MD: This is one of those things where before the TAILORx trial, we were saying to women with these intermediate risk scores, we’re all anxiously awaiting the results of this huge trial. Until we had those, we really had to think about risks and benefits, what patient preferences are as we make this decision on whether to give chemotherapy or withhold it. Once we had the study, the decision became a lot more clear, particularly for those over 50. For women under under 50, who fall under the score of 15 or less, it also provided a lot of clarity because those women also did not need chemotherapy. For those women who remained in a grey zone, this didn’t answer the question unequivocally, but it did give us a lot of data with which to enhance our conversation.
Kristie L. Kahl: Why is it important that the exploratory analysis occurred?
Jane L. Meisel, MD: We know from experience that younger women who get breast cancer tend to have more aggressive breast cancers. So, this finding in the initial TAILORx trial data really underscored the fact that we don’t want to be so quick to withhold chemotherapy from all of these women, because there may be a subset of the population that may actually benefit from it. So, you have to be careful…It’s complicated, but you there are flowcharts that exist to help oncologists and patients to understand a little bit better on who needs the chemotherapy and who doesn’t. The other thing to take into account is that many women who got anti-estrogen therapy, the premenopausal women under 50, few women had ovarian suppression. So, it’s possible some of the benefit we’re seeing from chemotherapy may not be the chemotherapy itself but the ovarian suppression. It’s an indirect anti-estrogen benefit from giving chemotherapy.
Kristie L. Kahl: Can you give an example of one of the flow charts?
Jane L. Meisel, MD: One example would be for patients who have a high clinical risk, meaning they have a grade 3 tumor or it’s larger in size, that puts them into one box. And they have an intermediate recurrence score in addition to that. Then you think about what is their score. If it’s over 25, they’re definitely going to get chemotherapy. If their score is between 16 and 25, and they are high risk, they would benefit from chemotherapy. Or if they don’t want chemotherapy, then probably from ovarian suppression. If the score is 16 to 20 and high clinical risk, that same decision would be there, thinking about chemotherapy or ovarian suppression to give additional support. If their score is 16 to 20 and low clinical risk, they probably can forego chemotherapy.
Kristie L. Kahl: How has this been implemented in practice?
Jane L. Meisel, MD: This is something we talk about pretty explicitly. A lot of it depends on who your patient is. Some patients come in and have already read the trials and know everything. Some women have a much simpler mindset and they’re coming in saying, “What do you think I should do?” At a lot of the academic centers, the women are very educated and interested not only in what you would recommend, but why you would recommend it. I do find that many of my patients that fall into this grey zone, I talk to them about this trial and the subset analyses and what is the potential gain you have from giving chemotherapy or being more aggressive with anti-estrogen therapies. We have ovarian suppression in a setting where we may not have thought about ovarian suppression before. I think these have changed clinical practice in an easy way for women who fall into the category of being over 50 and have a score lower than 25 because then we can say, as long as they are lymph-node negative, they don’t need chemotherapy. Also, for women under 50, who are between 0 and 15, because those are also women who may not benefit from chemotherapy. This trial doesn’t give an unequivocal answer for the women under 50 with scores between 16 and 25, but it does give you a lot of information to help treatment decision-making. Could we estimate what their benefit would be if we looked at more aggressive treatment. Could we consider ovarian suppression to give them some of the benefit chemo would have provided?
Kristie L. Kahl: Do you have a patient case showing how the assay has changed practice?
Jane L. Meisel, MD: We use this all the time and it’s a wonder tool and dataset to have at our disposal. Another example is a woman who was 45, had a 6-cm tumor, grade 2, her recurrence score was 22 and really did not want to do chemotherapy. She did not want to lose her hair, come in for infusions. Her mother had chemotherapy for a different type of cancer and had a horrible experience, so it was something she did not want to pursue. She had 2 young children and a job and really wanted to reduce her risk for cancer as much as she could. So, we talked about all of this and the potential for chemotherapy. I presented her with a few different options. So, I talked to her about the fact that she was still menstruating regularly, and that some of the benefit of chemo might be in the form of ovarian suppression. So, we could give her some benefit by suppressing her ovaries. Before, we would have been borderline to go that extra type of ovarian suppression in someone in stage 1 ER-positive breast cancer, she was someone who wanted to as aggressive as possible so ovarian suppression made sense. She started Lupron and tamoxifen and after 3 months, transitioning from tamoxifen to an aromatase inhibitor. She’s been doing really well with that combination and she feels good about her decision she made. We were able to tailor the treatment plan to be as aggressive as she wanted it to be with data to support it.
Kristie L. Kahl: What are the pros of this assay for healthcare providers and patients?
Jane L. Meisel, MD: The big plus to this is that it adds a lot of clarity for this population. For women who have early-stage, node-negative, ER-positive breast cancer, it can give us a lot of good information about what we should do for these patients in terms of chemotherapy versus no chemotherapy, or if people don’t want to do chemotherapy are there other options like anti-estrogen therapy to help them. Even for the women where they are in that grey zone, there is still that conversation that needs to be happening. There has been a lot of meat to add to the substance of that conversation; whereas, with women on both ends of the spectrum, we’ve added a lot more clarity. Before the TAILORx trial, we only had clarity for women with a score of over 25 or under 10. Now, we have clarity for anyone who is postmenopausal, with a score over or under 25, we know what to do. For the premenopausal population, we’ve reduced our grey zone to a much more narrow niche. That has been helpful.
The challenge is that this only applies to women with early-stage, node-negative breast cancers. There are patients who have a 2-mm nodal metastasis and it’s hard to know how to apply Oncotype to these patients where we don’t have the data yet. But we do have some smaller trials showing that Oncotype is valid in those patients with node-positive disease. Getting more information on that would be helpful.
The thing to note about these studies is that almost 75% of patients who were in the TAILORx trial were deemed clinically low risk. If we look at the size of the cancers treated in this trial, the vast majority of tumors were under 2 cm. So, these were very early stage, low risk patients from a clinical standpoint. So, it’s important to remember that when extrapolating these results in women with larger tumors. Only 20 patients on the trial had tumors that were 5 cm or larger. So, patients come to me with a 6.5-cm tumor and an Oncotype score of 16, and it’s hard to interpret that. Making sure your patient fits the profile of the patients studies is important when extrapolating these results.
Transcription edited for clarity.