Tamoxifen for Premenopausal Breast Cancer
Thank you for your interest in our research. We've got no conflicts of interest to disclose for this research. I would like to point out for those of you, who are interested in some more information about our study after the meeting, that I'm pleased to say that I have my study co-chair Jeanne Fleming in the audience. I also have Meredith Regan, who did the trial analysis here.
So, the soft trial was the suppression of a function trial. And this trial was a phase 3 randomized trial comparing adjuvant hormonal therapy with Tamoxifen plus ovarian function suppression, versus Tamoxifen alone in premenopausal women with hormone receptor-positive early breast cancer. This was conducted by collaboration of groups. It was led by the international breast cancer study group and with the collaboration of cooperative groups from around the world, from the breast international group and the North American breast cancer group. It was federally funded in the US by the National Cancer Institute.
The soft trial looked at different hormonal therapies for premenopausal women with early breast cancer. And we concluded that, when ovarian suppression was added to either Tamoxifen or an aromatase inhibitor exemestane, and then there was reduced recurrence of breast cancer in higher risk young women, who did not reach menopause after receiving prior chemotherapy. The soft trial also showed that ovarian suppression did not benefit all young women.
Our study of Tamoxifen spent the standard adjuvant hormonal therapy after surgery for premenopausal women with hormone receptor positive breast cancer for many years now. For a long time it's been uncertain, as to whether adding ovarian function suppression for premenopausal women, who receive adjuvant Tamoxifen, will provide any additional advantage. Premenopausal women, who receive adjuvant chemotherapy, can have their ovaries stop functioning, and the ovaries normally produce jejunum, when they stop functioning for the women into menopause with cessation of the eastridge and production.
We know from previous trials that premenopausal women, who go into menopause after chemotherapy, have a lower risk of their breast cancer recurring. The other bit of data that's been noted previously by the SG in their research, in their chemotherapy trials with women, who are under 35, who were diagnosed with hormone-sensitive breast cancers, were found to have a higher risk of relapse, compared to the other premenopausal women. And it was thought that this might be partly due to the fact that their ovaries were continuing to function and continuing to produce estrogen.
The other backgrounds of this trial was that we know in the last decade or two that aromatase inhibitors have been shown to be more effective than Tamoxifen as adjuvant hormonal therapy for postmenopausal women. But aromatase inhibitors do not work effectively in women, who have active ovaries, and women, who are premenopausal, because there's too much estrogen coming from the ovaries.
So, when we set out to design the soft trial, we were trying to address two questions. The primary question was: What is the value of adding ovarian function suppression to treatment with adjuvant Tamoxifen in premenopausal women with hormone-sensitive breast cancer? The secondary question: What is the role of treatment with an aromatase inhibitor eczema stone, combined with ovarian function suppression in premenopausal women?
So, the soft trial randomized more than 3,000 women to three different treatments. The first treatment was Tamoxifen for five years. The second treatment was Tamoxifen plus ovarian function suppression also for five years. And the third treatment was an aromatase inhibitor exemestane, combined with ovarian suppression for five years.
Women, who were assigned to receive ovarian suppression, could choose from either a monthly injection or if they preferred a permanent method of ovarian suppression by surgical removal of their ovaries, or a radiation of both ovaries.
When we enrolled women in the soft trial, there were two different cohorts of women, who were able to participate in the trial. The first cohort was a group of women, who had not received chemotherapy. Now the use of prior chemotherapy before women went into the soft trial was optional in the soft trial, and it was decided between the women and their doctor on the basis of the features of their cancer, their age and other factors.
The group that did not receive chemotherapy on average had lower risk breast cancers. They were on average older. And this was the reason that the decision was made for them not to receive chemotherapy. Those women enter the study within 12 weeks of having undergone their surgery. Tamoxifen was their only post-operative systemic or drug therapy. The second group of patients, who had received prior chemotherapy, was quite different. These women on average were younger. And they had higher risk tumors. Their tumors tended to be larger. They were more likely to be lymph node positive. They had more aggressive features under the microscope.
And the other difference with the group that could enter after prior chemotherapy was that these women were allowed to enter the study up to eight months after they completed their chemotherapy, and in that eight-month period the patients and their doctor were trying to see whether their ovaries were still functioning and still producing estrogen. Now, in that time they could start Tamoxifen, which was the standard of care, and then to decide if they could go in the study or not. They needed to have a blood test at their local hospital or centre to see if they still had enough estrogen in a blood level that showed that their ovaries were still functioning.
The primary analysis for soft compared the first two arms, so it was the comparison of Tamoxifen alone versus Tamoxifen plus ovarian suppression. The primary analysis looks at all the women combined together, so the women, who did not receive chemotherapy, and the women, who did receive chemotherapy. And with a median follow-up of 5.6 years we saw that adding ovarian suppression to Tamoxifen resulted in a small but not a significant improvement in disease-free survival. And the p-value was not significant. So, overall in the trial, there was not a benefit from ovarian suppression added to Tamoxifen.
However, there were important differences between the two distinct patient groups that we entered in the trial. So, the patients of the group that received prior chemotherapy on average were younger, and the reason they were younger is that women, who are closer to the natural age of menopause, are more likely to go into menopause with chemo. So, the group that was producing eastridge intended to be younger with a median age of 40 years. And in this group we've achieved improved outcomes from the addition of ovarian function suppression to Tamoxifen. We saw a 22 % reduction in the relative risk of recurrence of breast cancer with Tamoxifen plus ovarian suppression, compared with Tamoxifen alone.
We saw further improvement in the disease free survival with exemestane plus ovarian suppression, compared to Tamoxifen alone, with a 35% reduction in the relative risk of recurrence of breast cancer. Basically, the best treatment in this group, who'd had prior chemotherapy and was still premenopausal, was the exemestane plus ovarian suppression. And this treatment, as compared to giving the standard treatment, which is Tamoxifen alone, resulted in 7-8 and fewer women out of 100 experiencing further breast cancer within the next five years.
We had been particularly interested in the very young women with breast cancer based on our previous research, suggesting that women under 35 have a particularly high risk of relapse with hormone-sensitive breast cancers. In this age group we saw the most striking effects of the advantage of adding ovarian suppression to the treatment. The women, who were assigned to Tamoxifen alone, who are in the black curve, experienced a much higher rate of further breast cancer within the next five years.
When we looked at what happened over the next five years for women, who received the standard of care treatment for the under 35 age group, so if they got Tamoxifen alone, one in three of those women experienced further breast cancer within five years, as compared with one in six of the women, who are assigned to the newer treatment exemestane the aromatase inhibitor plus ovarian suppression. Now, you'll recall that there was another cohort of women enrolled in the trial, the women who did not receive chemotherapy after discussion with their doctor. On average these women were older than the group, who received chemotherapy, who were 40 in this group, on average for 46.
As for the outcomes in this group of women, who did not receive chemotherapy, then they were selected on the basis that their breast cancers look to be more favorable. These women have had excellent outcomes with all three treatments. And we see no advantage for adding ovarian suppression in this group.
Basically, for the women, who received the standard of care in this treatment arm, at five years of follow-up more than 95 % of the women have experienced no further breast cancer. We cannot see any meaningful benefit from the addition of ovarian suppression in this group at this point in follow-up. These women were older. They were 46 years of age. They were closer to the natural age of menopause. And so, if you can imagine, we're following them for five years. Some of these women will naturally have gone into menopause during that time.
We conclude that women, who received chemotherapy and did not reach menopause, had reduced breasts for cancer recurrence with the addition of ovarian suppression to Tamoxifen, and especially if they were under 35 years of age. Furthermore, if we combined ovarian suppression with an aromatase inhibitor eczema stone, we got further reduction in breast cancer in this same group of women.
Overall quality of life was not reduced for women's general health. However, ovarian suppression did result in increased menopausal symptoms, which were particularly troublesome for the women in the first couple of years. For women, who were allocated to receive exam ovarian suppression, they did notice effects and report effects on their sexual functioning. It's important to note from this trial that not all premenopausal women benefit from ovarian suppression, and some did not receive chemotherapy. They do very well with Tamoxifen alone.
So, treatment with an aromatase inhibitor exemestane plus ovarian suppression is more effective than standard Tamoxifen for hormone receptor-positive early breast cancer in women, for whom chemotherapy is indicated and who do not reach menopause. And for women under 35 years of age with hormone receptor-positive breast cancer ovarian suppression is an important treatment.