This video features Angela DeMichele, MD, MSCE presenting on ER+ Adjuvant. This presentation was given at our January 19th 21st Annual Highlights of the 2022 San Antonio Breast Cancer Symposium in 2023.
Thank you so much for the opportunity to speak tonight about the SAn Antonio update on er positive adjuvant breast cancer. Here are my disclosures. So tonight I'm going to cover several important topics. First several abstracts on the use of genomic predictors to make decisions about adjuvant therapy for er positive disease. We'll talk about the taylor X. Trial in differentiating chemo benefit. Will look at the B. C. I. In the soft trial to differentiate benefit of ovarian function suppression and ma'am a print in the ideal trial to identify those who benefit from late recurrence. Then we'll move to two abstracts on adjuncts to endocrine therapy in the adjuvant setting. First the initial analysis of the phase three of rely mus adjuvant trial that's the swab 12 07 trial. And then an updated analysis of the phase three Obama cycle of adjuvant trial. That's monarchy. And then finally I'll end with a very provocative study for aggressive relapse disease. The right choice trial. So let's start with genomic predictors. The first abstract I'm gonna cover was the 12 year update of the taylor X trial presented by joe sparano. So as we all know, taylor X was a prospective randomized trial of chemotherapy versus no chemotherapy in women with er positive no negative breast cancer who had a recurrence score of 11 to 25. Now up to this point we've learned many important things from this trial. We've learned that patients who have a recurrence score of 0 to 10 have an excellent outcome with A. D. R. F. I. Of 97%. At nine years. We've learned that for those who have an aqua type recurrence score of 11 to 25 endocrine therapy alone is not inferior to chemo plus endocrine therapy. And we've learned that for those with a recurrence score 26 to 100 the recurrent score is prognostic for recurrence. We've learned that Political pathologic features add important information that modifies these risks and that has led to the development of the RS clean tool. We've learned that there is some chemotherapy benefit for premenopausal women under the age of 50 who have a recurrence score in the 16-25 range. And we've learned that in this trial black race was associated with worse outcomes. But the recurrence score was still prognostic and predictive and we don't exactly know where this disparity is coming from. In this analysis, we now have a median follow up of 11 years in the randomized group, 10.4 years overall in approximately 30% more recurrence events and twice as many survival events. And here's what was shown first on the right, you can see the results comparing endocrine therapy alone and yellow to endocrine therapy plus chemotherapy in green for I. D. F. S on the left and D. R. F. I. On the right. And the conclusions here are that there is no change in the primary trial conclusions there is no benefit to chemotherapy overall in the group of patients who have a recurrent score of 11 to 25. We also now see that there is a distant recurrence rate overall of 7% at 12 years, which is approximately 0.5% per year. But in fact that is not a linear recurrence risk. Late recurrence is actually a little bit more prevalent than early recurrence. Um So you can see that there are differences early versus late for our F. I. And for D. R. F. I. We also see that there are non recurrent survival events occurring about a rate of 1% per year. And overall survival rates are similar with most deaths after year five. Finally, it was shown that the Rs 26 to 100 group, this very high risk group remains at substantial risk of recurrence with A. D. R. F. I. Rate of 84.8% in an R. F. I. Rate of 80.9% suggesting we still need better therapies for these patients. In addition, we see that chemotherapy benefit is still seen for premenopausal women to some degree. And on the right you can see how this plays out because it varies by the degree of clinical risk and the recurrence score. So you see an incremental increase in chemotherapy benefit when you go from an RS of 16-22. An RS of 21-25. Sorry about that as well as an incremental increase as you move from low clinical risk to high clinical risk with the highest risk and the greatest benefit being in those patients who have an RS of 21-25 and high clinical risk getting 11.7% benefit from chemotherapy also was shown that the disparities for black women do not persist beyond five years. So all of that increased risk is front loaded within the first five years. Again we don't know exactly why that is. These models have been adjusted for many of the factors that may have accounted for this. Uh leaving us to wonder whether this is truly a biological effect. Moving forward. Now we're gonna talk about the data that was shown for the breast cancer index and premenopausal women who were on the soft trial. And as you would call the soft trial compared tamoxifen to tamoxifen plus ovarian suppression or XMS stain plus ovarian suppression and premenopausal women, about half of whom had chemotherapy as well. The 12 year follow up was presented last year and there was a additional 3% benefit to O. F. S. In D. R. F. I. For both XMS stain and tamoxifen over tamoxifen alone and factors associated with the benefit of ovarian function suppression primarily age under 35. Although there was some lesser impact from node status tumor size grade and other factors in this analysis. They apply the B. C. I. Genomic index which is consisting of both the molecular grade index and the H. I ratio. And was developed for early recurrence. Um But it also has prognostic and predictive components here. The goal was actually to determine the prognostic uh effect based on Bc. I. As well as whether B. C. I could determine whether or not. There was an O. F. S. Benefit to the endpoints here where B. C. F. I. And D. R. F. I. And the analysis cohort was about half of the original patients evenly divided across all of the groups. And here are the results first and I haven't shown you all of the primary data but first it was clear that B. C. I. Is associated with distant recurrence risk in the overall study. What you can see in this first set of um curves here is that the B. C. I. Score discriminates between intermediate and high risk from low risk in terms of the benefit. Um and and overall prognosis um It discriminates benefit for O. F. S. In the Bc. I lo patients only. So what we see here is when we look at the arms that have ovarian function suppression compared to tamoxifen alone. There's clearly a benefit and this is in the B. C. I lo patients only. We don't see that similar discrimination here in the B. C. I. Hae patients moving now to the mammoth print to predict the benefits of extended endocrine therapy. Um We looked at this at the authors looked at this within the ideal trial. And so if you want to call mama Prince, both a prognostic and predictive genomic classifier. And there are four categories of risk, ultra low low and high, which is subdivided into mammoth print high one and mammoth print high to mind. Act defined the role of mammoth print and predicting chemo chemotherapy benefit. Um But these analyses are now designed to look at whether this could also tell us about benefit from extended endocrine therapy. There was an analysis of the N. S. A. B. P. B 42 trial presented at Asco in 2021 which showed that in the mammoth print low but not ultra low group. There was a benefit from extended under print therapy which was not seen in the mammoth print high or the mammoth print ultra low groups. So to validate this, the authors use the ideal trial and you can see the the study designed for ideal here on the right patients got five years of adjuvant therapy with one of these combinations and then we're rand either 2.5 or five years of extended therapy with Letrozole. There's no group here that doesn't get additional therapy beyond five years who are essentially looking at 7.5 years of therapy versus 10 years of therapy. It was a three phase three randomized trial. All of the patients were postmenopausal and the primary findings from this trial showed no improvement in um D. F. S. D. M. F. S. Or overall survival with the additional 2.5 years of Elektra's all. So now we're looking at the results of Ma'am, a print, the translational cohort in which they could do. The mammoth print was 515 of the original 1820 patients. Only about a third of the patients are in this analysis. The authors say that the two groups were comparable. There is now a median follow up of 10 point two years and the primary endpoint in this biomarker analysis is distant recurrence or D. R. And they started follow up 2.5 years after randomization. So that's how much follow up time and where their their actual start time is. Um And there was no a priority power calculation provided. So what we see here is that there is amongst the mammoth print high risk patients, there is no difference in whether the patients got 2.5 years of additional electric salt or five years of additional electricity with the hazard ratio of 50.88. But in this group of mammoth print low risk which also includes the ultra low, there was the beginnings of an effect where you see a hazard ratio of 0.42 um and a slight separation of the curves here. But the interaction term was not significant and similar findings were shown for relapse free interval. However, when they looked at the mammoth print low group and took out the ultra low group. So this is just Ma'am a print low without mammoth ultra low. Now in these 223 patients we do see a much bigger effect with a hazard ratio of 2230.35 significant and a significant interaction term. So this validates the finding an N. S. A. B. P. B 42 showing a benefit to longer out of an endocrine therapy in the mammoth print low but not ultra low group. But again remember there wasn't a no treatment group. So this is really looking at 7.5 versus 10 years of therapy needless regardless all of the endpoints in this low risk non ultra low risk group did show a benefit to longer therapy. So to summarize these three abstracts, looking at the use of genomic predictors to make decisions about adjuvant therapy and taylor X. Using anca type to identify those who do not need chemotherapy. I would conclude that our current practice and use of this tool should not change Based on these data. Finding that late recurrence occurred at a higher rate than early recurrence is actually surprising and it emphasizes the need for trials to address this very real risk. But it's quite challenging because this is a very small population of the overall survivor population. One way to attack this problem is to use something like C. T. D. N. A. To find these patients and there are trials and progress designed to do this. It means screening a lot of patients um to find the patients who are at risk. In addition these findings really also emphasize our need to figure out why black patients are doing more poorly in the first five years and whether there is a biologic explanation for this. Moving to the B. C. I. Study to help us predict benefit from ovarian function suppression in the soft trial. This is still a tough thing to do and we err on the side of giving it to probably more patients who need it. What we saw was that the Bc I lo patients do much better with XMS stain and ovarian function suppression than other options. While the Bc I hae patients seem to do more poorly as a group regardless of whether or not they got ovarian function suppression. So this actually was a little bit um counter to what the investigators hypothesized and so we don't quite understand this either. Um And this question will be further addressed but not really um fully addressed or really focused by the energy trial that's coming. That's actually asking whether or not chemotherapy is needed if you give ovarian function suppression. So we don't have a trial that's specifically focused on this question. You think that it would be helpful to have additional corroborating data here before we use the V. C. I. For this purpose. And then ma'am a print to identify those who benefit from extended edge of an endocrine therapy. Well both be 42 ideals suggest that it's only the mp lows excluding the ultra lows that benefit. But this was not the ideal data set in which to answer this question and it may be better to try to validate in another group as well. Moving on now to additions to adjuvant therapy, let's first look at the swap 12 07 trial which was the much awaited phase three randomized placebo controlled clinical trial of adjuvant ever lima's given to standard endocrine therapy. Um And this was based on the knowledge that this regulation of the P. I. Three chinese pathway plays a role in endocrine therapy. Resistance that ever LIMAs adds to endocrine therapy and a resistant metastatic population. So they wanted logically I think to move this to the edge of in setting. But we also saw that the sort of companion study done in europe called rod was negative. So we were waiting for these results to see if we would see something different. This is a phase three randomized trial was placebo controlled. There were four different high risk groups. So this is a very high risk group of patients. As you can see there it was a 1 to 1 randomization to standard endocrine therapy with or without a year of ever Linus at 10 mg a day powered for a primary endpoint I. D. F. S hazard ratio 100.75. So improving that five year I. D. I. D. F. S. From 77% to 82%. really reflecting this very high risk group initially planned to be 3500 patients but it was revised to 1900 based on risk assessment. And here what we see is that there was no benefit overall and I. D. F. S. Or overall survival. The patients actually did worse than what was predicted. There was a benefit seen in the premenopausal subgroup which was considered an exploratory analysis significant for both idea FS and overall survival in the premenopausal patients. Um but again considered exploratory because it was not um power for this analysis, moving now to Obama psych lib. Uh here is the update from monarchy. Looking at the four year efficacy outcomes um we know that this trial tested two years of venice I clip added to standard endocrine therapy versus endocrine therapy alone. The initial positive outcomes that led to its approval were done when analyzed at 15.5 months of follow up when many patients were still on their first two years of endocrine therapy with the Obama psych lib. Um Now, all patients have completed two years of treatment, there's a medium follow up of 42 two months, roughly, twice as many events. And they also presented the overall survival analysis which was pre specified to be analyzed two years after the primary outcome analysis, I just call your attention here in the scheme to these two study cohorts, One that was based specifically on risk and one that was based on having a high K II 67 And here are the results as you can see up here. These are the primary analysis and the curves continue to separate with a difference of 79.4% I. DFS at four years for the control group and 85.8% for the F. M. A cyclist group. This is still a highly significant finding benefit was seen in all the subgroups and it continued beyond the time that patients were on Obama sigh clip. So really there had been this thought that perhaps we're just treating micro metastatic disease. But the question is, is this actually a cure for some of these patients? We don't know because the overall survival data are still quite immature, but there was no apparent separation in the curves that were shown and no real difference in the number of events seen still pretty early for that. So, that remains to be seen in this. Lower occur. What I want to show you is the K I 67 effect turns out that it's all Prague Mastic, there's no differential treatment effect by K I 67. So, patients with a high K 67 in blue do much worse than patients with a high K II 67 red. But both groups get a similar bump in their outcomes when they added the Obama cyclone. So, so just the summary here to adjuncts to underpin therapy forever LIMAs. It appears to have a potential benefit and premenopausal women but not postmenopausal women. If that's true, why would it be it is overall a negative trial. And even if we were to think about how to use it in premenopausal women, we don't really know how this would integrate with other therapies that weren't given in the trial. Like wearing function suppression or Obama cyclops. I think this really ask the question of what this means for ever alignments and adjuvant setting. I don't know if there's a future in terms of looking at it further for premenopausal women we do have many other options for high risk women. But there are pre clinical data showing that ever lima's does have activity against dormant disease. And we are testing it actually in models of dormancy and particularly in our clever trial looking at women who have disseminated tumor cells. So the question remains whether it could still have a role Obama cyclops. I mean these results just continue to strengthen over time. I would argue that this is the true definitive analysis since all the patients have now completed their intervention and some have and have some follow up beyond the intervention. One interesting and important finding is that K 67 status did not differentiate activity counter to the fact that that high K. 67 was part of the approved indication by the FDA. So we wonder if this were be changed in the future and notably there's no hint, no hint of a survival advantage. Now we know there's a long natural history to her two positive. I mean to er positive disease may be way too early to expect. This question is whether that's going to be necessary really to drive its use in our patient population. And then finally I just want to end with this provocative study called the right choice trial in the last two minutes. The goal of this trial was to determine how use of a C. D. K 46 inhibitor plus endocrine therapy compares to chemotherapy as first line therapy and aggressive er positive relapse metastatic disease. Wondering whether C. D. K +46 inhibitor is a gentler form of chemotherapy as an anti proliferated agent. Um And they they actually hypothesized that the C. D. K inhibitor endocrine therapy armed would do better than chemotherapy. They chose robo cyclops as the C. D. K inhibitor because it has a survival benefit in the 1st and 2nd line against endocrine therapy alone. They really appropriately in my mind to find aggressive year positive metastatic disease as you can read here. So visceral meds, rapid progression symptomatic disease and the primary endpoint was progression free survival designed to detect a hazard ratio of 0.67 222 patients. And here where the really sorry just for one more thing. Um you look here at the study design the rival was given 600 mg three weeks on one week off and then the chemo could be one of these investigators choice. Which interesting it's combination chemotherapy. So aggressive chemotherapy perhaps more than we often give patients as induction chemotherapy. And what you can see here in the study population is that it was not only well balanced but very high levels of patients and visceral crisis symptomatic who had both liver and lung disease. And now here are the results. So it met the primary endpoint with a progression free survival benefit to rival cyclo plus endocrine therapy over induction chemotherapy for these patients with aggressive disease. Medium progression free survival of 24 months for the rival are 12.3 months for the chemo arm, hazard ratio of 0.54. This benefit was seen across all subgroups also extended to benefit to time to treatment failure. So 18.6 months versus 8.5 months benefit to Revo sick lib, 50% improvement in three month treatment failure rate. Even though the overall survival rate and clinical benefit rates were similar. They both had a similar time to onset of response, which I might not have guessed we often think endocrine therapy takes longer to kick in and as might have been expected but important. Endocrine Revo arm was less toxic with fewer a ES and fewer discontinuation. So this is important because it's quite reassuring about the potential to forestall chemotherapy in patients presenting with aggressive disease and actually could change practice. And those of us who typically might give induction chemo to these patients, it actually continue to improve quality of life by extending the time before patients need chemotherapy. It also shows that rebel cyclops, highly active and aggressive disease which may bode well for the Natalie a german trial that we should be seeing the results of later this year. Finally really ask the question of whether chemo could be avoided in some patients. Even in the adjuvant setting, you have highly responsive disease to endocrine therapy and a c. D. K. Inhibitor. And lots of discussions going on within the cooperative groups to really think about how we might apply this in the advent setting. With that, I will just say thank you and I'm happy to take questions.