Breast Cancer Index: Predict Treatment SABCS 2022 Ruth O’Reagan
What is the Breast Cancer Index? Ruth Regan, who is a professor and chair of the Department of Medicine at the University of Rochester. And her presentation is evaluation of the breast cancer index in premenopausal women with early stage HR+ breast cancer in the soft trial.
Thank you, Virginia. Good afternoon, everybody, and thank you for staying for this.
What is the Breast Cancer Index (BCI)?
So I’m happy to present the (BCI test) results of the analysis of Breast Cancer Index in premenopausal women who enrolled in the soft trial. Now, I suspect most of you know about the soft trial. Just to remind you, this was a trial for premenopausal women with ER-positive early stage breast cancer, in which we looked to escalate endocrine therapy, specifically with the addition of ovarian suppression.
So it was over 3000 patients all premenopausal to be eligible they had either get chemotherapy and remain preme premenopausal after chemotherapy, or be premenopausal and have not received chemotherapy. And you can see they were randomized to tamoxifen for 5 years as standard of care, tamoxifen plus ovarian suppression, or the aromatase inhibitor, exemestane plus ovarian suppression.
Last year at this meeting, we saw results from a 12 year median follow up of the breast cancer index, which continues to show a significant improvement in the overall population for the use of exemestane plus ovarian suppression compared to tamoxifen and exemestane plus, ovarian suppression is a little bit more effective than tamoxifen plus ovarian suppression.
What’s the Problem With Ovarian Suppression in Breast Cancer Patients?
The problem is that ovarian suppression is associated with more toxicity. So really we want to try and identify which women really need the addition of ovarian suppression. What we’ve found so far is that younger women under the age of 35 who receive chemotherapy appear to be a significant benefit from ovarian suppression.
Dr. Regan developed a composite risk, value. Value, which incorporated patient and tumor (grade) related factors, which can be used to predict which patients are high enough to justify ovarian suppression. But as yet, unlike another ER-positive early stage (breast cancer) scenarios, there is no genomic biomarker (a predictive biomarker) available to predict which patients need ovarian suppression.
As I mentioned, this is pretty important because there is not just short term toxicity, but also longer term toxicity that we probably haven’t realized as most of, you’re probably familiar with the breast cancer index. This incorporates it’s the genomic assay incorporating the molecular grade index with what’s referred to as the H/I ratio, which is the ratio of HOXB13/IL17BR.
So BCI has been shown to be prognostic, is able to predict risk of late recurrence in patients with ER-positive breast cancer, and also the cumulative of overall distant recurrence. In year zero to 10, the BCIN+ (Breast Cancer Index node-positive) further incorporates tumor size and (tumor) grade specifically for patients with N1 disease.
BCI or the H/I component of it has also been shown to be predictive of who needs endocrine therapy beyond 5 years. So there’s been a number of trials that have shown that. And when you use the H/I, you either get a high score or a low score, patients with a high score benefit from longer durations of endocrine therapy patients that low scores do not.
So our hypothesis to be tested within the soft population was that BCI and BCIN+ (Breast Cancer Index node-positive) are prognostic in patients with N0 and N1 disease who are premenopausal ER-positive breast cancer, who are treated with endocrine therapy, with or without chemotherapy. Our second hypothesis was that the h i high status would be predictive of benefit from ovarian suppression whereas the BCI low status would not, and this was based on our observations from the prior.
What Were the Objectives of the Breast Cancer Index Trial?
The objectives are shown here. The primary objective was to look at H over the bci, H/I, being predictive of benefit from XM eczema, ovarian expression versus tamoxifen. The secondary objectives were to look at its prognostic ability and also the ability of the H/I to predict benefit from tamoxifen, blood ovarian expression versus tamoxifen.
Endpoints were breast cancer free interval and distant recurrence free interval, BCFI was for the predictive analysis, DRFI was for the prognostic analysis. And just to point out that the clinical outcome data that we use in this analysis was based on the data presented a year ago at this meeting with 12 years of median follow up.
So out of the 3000 or so patients, there was about 1700 or so who had available bio specimens. Only 30 of them had insufficient RNA quantity. So we ended up with just under 1700 samples for this. Within this cohort, about 573 received tamoxifen. 550 received tamoxifen plus ovarian expression, and 560 received exemestane plus ovarian expression.
In the interesting times, I’m not gonna go through this, but I will just tell you that the characteristics of the BCI analysis cohort really closely married the intent to treat population from the soft study. Also, wanna point out that 12% of patients. Sorry. In the our cohort and also the intended cohort, we had HER2+ breast cancers.
So first looking at the prognostic ability. So in the NODE- cancers about 60% them were BCI low, 22% intermediate and 17% high. And what you can see in the left hand part of this slide is that the BCI was highly prognostic. In that is the store score increased, the risk of distant recurrence also increased.
And the bottom left hand part of this slide, what you can see is that patients with low scores had an improved outcome to patients with high score. In the, no the patients with N1 disease, 22% of them had BCIN+ (Breast Cancer Index node-positive) low, and 78% of them had BCIN+ (Breast Cancer Index node-positive) high, and we saw the same kind of results on the right hand part of the slide showing as the BCIN+ (Breast Cancer Index node-positive) score goes up.
So that’s a rate of distant recurrence and if you compare low versus high patients with low scores better than patients with high scores. I will say that within the BCIN+ (Breast Cancer Index node-positive) group the, those risk groups were very highly correlated with grade in the patients with lowest scores, almost all had low grade cancers, and patients with high score all had either grade 2 or grade 3 cancer.
Predictions of the Breast Cancer Index For Patients with Early Stage Breast Cancer
So moving on to prediction. So in this we’re looking at BCI H/I ratio, specifically in the unselected group. You can see that the results really mirror the overall intense population from the soft study. Within this group, about 60% had H/I low scores, and 42% had high scores. In contrast to hypothesis, what we found was that in the BCI H/I high group, this was not predictive.
There was no difference between the arms at all. In this, as you can see on the right hand, part of this slide in the log group, however you can see that patients who got exemestane post ovarian suppression had quite a 12% (predict) benefit compared to tamoxifen alone. And likewise, the tamoxifen post ovarian suppression had about a 7% difference.
And the treatment (predictive) biomarker interaction was statistically significant for the exemestane plus ovarian suppression compared to tamoxifen, but less so for the other group looking specifically at patients with hormone receptor positive, HER 2 negative cancer, so that’s without the 12%. With HER2+ cancers, we see really identical results.
You can see 13% for exemestane plus ovarian expression, 7% for tamin plus ovarian expression in the low group versus no difference in the high group looking at patients who had prior chemo or not, which we know is important in this study. And the upper part of this is looking at patients who receive chemotherapy.
Again, very similar results to what we just showed you, with markedly improved outcomes for exemestane plus ovarian expression compared to tamoxifen, and also for tamoxifen plus ovarian suppression compared to tamoxifen in the low H/I group, but again, not in the H/I. And in patients who did not receive chemotherapy, they overall had a better prognosis.
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But again, the same results where patients were doing better if they had the low over. I’m looking at nodal status. So N0 diseases on the top here again, very similar results. Patients with the low H/I you can see better with exemestane plus ovarian suppression. No difference in the high group and likewise in patients with N1 disease.
A smaller number of patients, again, you see the same. And then lastly, just breaking it down in age, in patients that were younger than 40. Again, you can see in the low H/I group this benefit for eczema plus ovarian suppression compared to tamoxifen. None in the high group, and likewise in the patients over 40, the same trend.
To Summarize the Breast Cancer Index (BCI) Trial and Other Clinical Findings
So to summarize, the BCI translational cohort was very representative of the soft parent. BCI risk scores were prognostic in premenopausal patients with hormone receptor positive tumors receiving (primary) adjuvant chemotherapy plus, or sorry, adjuvant, the adjuvant endocrine therapy, plus or minus chemotherapy. The highest risk scores were associated with the worst outcome.
The BCI H/I ratio was predictive of ovarian suppression benefit, but contour hypothesis in the low H/I group those were the patients that derived significant clinically meaningful benefit versus the BCI high group did not. These results point to different to potential differences in the tumor biology underlying ovarian suppression response.
But just end, for this is the first genomic assay will it demonstrate benefit from ovarian suppression, supporting additional clinical utility of this test and further validation. And I should have put my disclosure first. I apologize for that, but there they are.
Thanks Ruth. So you and I talked about this a couple times because this is pretty surprising, but, so interesting.
Questions About the Breast Cancer Index (BCI)
So how are you speculating that it’s the low group that has the benefit? Is that just because it’s more endocrine sensitive, you think? Or how is that?
It’s a very good question and I don’t think we’ve got a great explanation for it. You could almost say it was the opposite because, we know that, endocrine resistant cancers, they’re more likely to recur the first 2 years.
But we really don’t know the answer to this and I think we’ll need more analysis to look at it. But I think also it’s a very different setting than extended adjuvant endocrine therapy. This is upfront, so I think it’s a little bit different. And then I thought about it. Is it because of the chemotherapy during some things, the cancer milia, but we saw the same difference in chemo versus not.
And obviously you had fewer HER2+ patients, but was there any any signal in those patients? I don’t think we specifically looked at those yet because the numbers are quite small, but you certainly think about that.
Any questions? Yeah.
Caroline Helwick, ASCO Post. So how much are physicians actually using the BCI (Breast Cancer Index)? I know Oncotype and all that, used to that, but just tell us that, and do you think this will increase interest in use of this? I think potentially, so I think, when we think about the 21 gene recurrence score, obviously something we use up front and as is a 70 gene scores determine whether patients need chemotherapy or not.
What we’ve typically done with BCI is use it later on when we start getting the decision tree of whether to continue endocrine therapy or not. You could think that there’s no real reason you couldn’t do it earlier because then the patient would know how long she’d be on endocrine therapy. But I do think just that we are planning to validate these results further, but I think if they are validated, I expect that they would be used, yes.
And I’ll add as well this is a struggle because obviously for many of these patients, we do get a genomic score, whether it’s Oncotype or MammaPrint, to just decide whether to give him chemotherapy or not. And then you typically, I also wait the 5 years to then potentially do the BCI to ask my next question, who will benefit from extended endocrine therapy.
So my concern is if I do the BCI (testing) right after chemotherapy, will insurance companies pay for 2 genomic tests or is this going to be, put onto the patient to pay for this? And these are expensive tests, so this is something we definitely need some validation, but I was pretty impressed with the results.
Yeah, I think so. And I do think this is an incredibly important question because, there are a lot short term toxicities. It can affect compliance. So people maybe stop not just the ovarian suppression, but also their endocrine therapy. And then that can lead to, obviously increased risk of recurrence.
So it is a very important question and hopefully it will get validated. So we will have a good, a genomic test that we can use.
And again, I’m thinking how much does giving a another prognostic every month for 5 years cost, for the women that we end up giving it to, that may not benefit based on BCI.
And I think the long term toxicities as well, which I just don’t think we know what they are right now. No, for sure.
So just to clarify, so you’d be saying that it would be useful used much earlier as you’re starting your endocrine therapy because you wanna know whether to do ovarian suppression or not?
Yeah, I think if it’s valid. Yes, there would be a double whammy because I could tell you this patient needs a variant suppression, but also maybe help you decide, how long they need to be under different therapy for.
Ruth O’Regan, MD – About The Author, Credentials, and Affiliations
Dr. Ruth O’Regan, M.D., is the Chair of Medicine and Charles A. Dewey Professor at the University of Rochester. She is also the Chief Medical Officer at Strong Memorial Hospital and the Associate Director of Education and Mentoring at the Wilmot Cancer Institute at the University of Rochester.
She was formerly Division Chief of Hematology, Medical Oncology, and Palliative Care in the Department of Medicine and Deputy Director of the Carbone Cancer Center at the University of Wisconsin School of Medicine and Public Health (UWSMPH). She served as Chief Scientific officer of the Big Ten Cancer Research Consortium leading the research and scientific objectives of the consortium and as Vice-Chair of the National Comprehensive Cancer Network Board of Directors. Before joining the UWSMPH faculty, she was the Director of the Glenn Family Breast Cancer Program at the Winship Cancer Institute and the Vice-Chair for Education and Director of the Hematology Oncology Fellowship program in the Department of Hematology and Medical Oncology at Emory University. She additionally served as Chief of Hematology and Medical Oncology at the Georgia Cancer Center for Excellence at Grady Memorial Hospital.
Dr. O’Regan got her Medical Degree from University College, Dublin, Ireland and completed her Internal Medicine residency at the Medical College of Wisconsin and her Clinical Hematology/Clinical Oncology fellowship at Northwestern University.
Her research program focuses on finding mechanisms of resistance to breast-cancer medicines and on the development of novel therapies with a specific focus on triple negative breast cancer.