At the 2022 San Antonio Breast Cancer Symposium, Ruth O’Regan, MD, University of Rochester, NY, presented updated data from the SOFT trial, investigating the potential of the breast cancer index genomic assay to determine which premenopausal patients with HR-positive breast cancer would most benefit from ovarian suppression treatment.

Dr O’Regan discussed importance of identifying which patients most need ovarian suppression, as the high levels of toxicity associated with the treatment that can lead to a lack of patient compliance. She noted that the trial found a specific component of the breast cancer index score – a low H/I ratio – to be most predictive of ovarian suppression efficacy in patients with ER-positive breast cancer. 

Transcript

Hi, I’m Ruth O’Regan. I’m a professor of medicine at the University of Rochester, and I’m here at the 2022 San Antonio Breast Cancer Symposium. I wanted to talk about one of the abstracts, which was basically looking at the breast cancer index genomic assay in the SOFT study.

The SOFT trial was a trial that was designed to evaluate endocrine therapy escalation, specifically the addition of ovarian suppression to endocrine therapy in premenopausal patients with hormone receptor-positive early-stage breast cancer. In the trial, about 50% of patients received chemotherapy and were premenopausal after the chemotherapy, and another 50% did not receive chemotherapy and were premenopausal. They were randomized to tamoxifen for 5 years of standard of care, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression.

Updated data from this trial at 12 years of follow up was presented at this meeting last year and continues to show that patients who got exemestane plus ovarian suppression, or indeed tamoxifen plus ovarian suppression, had a lower occurrence rate than patients who got tamoxifen. The problem is that ovarian suppression has quite a bit of short-term toxicity, as well as long-term toxicity that we probably haven’t recognized yet, and some of this can lead to lack of compliance. We need to know which premenopausal patients really require ovarian suppression. What we’ve done up to now is patients who are young, less than 35, who get chemotherapy, we almost always recommend ovarian suppression to them because they appear to benefit, from the SOFT study.

There’s also a composite risk score that takes into account patient and tumor characteristics that we can use as well to make those decisions. However, unlike other scenarios with ER-positive breast cancer, we currently have no genomic assay to kind of help us predict which patients need ovarian suppression, and that was really the whole base of this abstract. The breast cancer index is a genomic assay that’s made up of what’s called a molecular grade index, and the ratio of 2 genes called H/I [HOXB13/IL17BR]. So BCI has been found to be prognostic for determining which patients are at highest risk of late relapses from ER-positive breast cancer. Additionally, the H/I ratio component has been used to predict which patients need longer durations of adjuvant endocrine therapy.

The hypothesis that we had was that BCI itself, so including the genomic greater index and the H/I ratio, would be prognostic for premenopausal patients with ER-positive breast cancer, and that the H/I ratio would be predictive for patients who would benefit from ovarian suppression. Based on some prior trials that were available, we predicted that patients who had high H/I ratio would benefit from ovarian suppression and patients with low H/I would not.

From the SOFT study, we had tumor blocks available from just over half the patients enrolled, and BCI was performed on those specimens. The first thing that we noted was that looking at the cohort that we were able to do the BCI on, the patient and consumer characteristics very much mirrored what we saw in the overall SOFT study. Looking at the prognostic value of BCI, which incorporates the molecular grade index and the H /I, we found that the BCI was prognostic for patients with node negative breast cancer, in that the higher the BCI score, the more likely to have distant recurrence. Likewise, when we looked at patients with node positive disease, specifically N1 disease, using the BCIN+, which is BCI, but we also take into account various other tumor characteristics, we were able to show that in those patients, the BCIN+ score also correlated with distant recurrence. As the score went up, the patients had a higher risk of distant recurrence.

Looking at the predictive part of this, this was specifically the H/I index. We found that about 60% or so of patients had a low H/I and about 40% had a high H/I. But contrary to hypothesis, we found that in patients whose cancers were low H/I, that was predictive for ovarian suppression. In that group, patients who got exemestane plus ovarian suppression had a dramatic improvement in outcome compared to patients who just got tamoxifen. To a lesser extent we saw the same thing with tamoxifen plus ovarian suppression compared to tamoxifen. In the high H/I group, we didn't find that to be predictive of ovarian suppression. We looked at it in patients based on lymph node status, and we found the same was true whether they had positive lymph nodes or negative lymph nodes. We looked at it based on age, using a cutoff of 40. Same results. We saw that the low H/I was predictive for ovarian suppression benefit. The low was, but the high was not.

Overall, these are very interesting findings because it's the first genomic assay that's been used to try and predict which patients need ovarian suppression. Again, as I mentioned earlier, that's a very, very important decision that we make for our patients. There are some limitations because the patient number was fairly large but still on the smaller side. We do believe it does require validation, and we are planning on doing further validation. I think if we find that the findings are correct, what might make sense is to do the BCI earlier at the time of diagnosis. If the patients have a high H/I, what you would do is recommend no ovarian suppression and longer duration of treatment, like 10 years of endocrine therapy, versus if the ratio is low, then you would recommend ovarian suppression to those patients, but they would stop their treatment at 5 years.

Source:

O’Regan RJ, R, Zhang Y, Fleming GF, et al. “Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT trial” Presented at San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, Texas. Abstract GS1-06