Ovarian suppression with tamoxifen reduced recurrence for some women with premenopausal breast cancer

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Published: 12 Dec 2014
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Dr Prudence Francis - Peter MacCallum Cancer Centre, Melbourne, Australia

Dr Francis talks to ecancer at the 2014 San Antonio Breast Cancer Symposium (SABCS).

Among premenopausal women with early-stage, hormone receptor-positive breast cancer, adding ovarian suppression to tamoxifen reduced breast cancer recurrence for those who had previously received chemotherapy and remained premenopausal, according to data from the randomised, phase III suppression of ovarian function trial (SOFT).

Watch the press conference or read the news story for more.

You’ve been looking at ovarian function suppression and its role, potentially, in pre-menopausal patients with breast cancer. Can you tell me what exactly you were trying to do?

For a long time in pre-menopausal women with hormone sensitive breast cancer Tamoxifen has been the standard of care for their adjuvant hormonal therapy and it has long been a question whether adding ovarian suppression would provide any additional benefit. So in this trial, the SOFT trial, we analysed more than 3,000 pre-menopausal women and they were randomised either to receive standard of care, Tamoxifen alone, or Tamoxifen plus ovarian suppression or an aromatase inhibitor, exemestane, plus ovarian suppression, with all the treatments given for five years.

And this was first line for their breast cancer?

This was an adjuvant hormonal therapy study so they were early breast cancer, they’d had their surgery, they had either had chemotherapy or didn’t need chemotherapy and they were starting their adjuvant endocrine therapy.

What did you find in the study?

Basically in the overall population when we added ovarian function suppression to Tamoxifen, which was the primary comparison as compared with Tamoxifen alone, there was a small improvement but it wasn’t significant, there was a p-value of 0.10.

In?

In the overall population that was randomised.

In disease free survival or…?

In disease free survival. But when we looked at the patient population that was enrolled in the trial there were almost half the patients received no chemotherapy and just over half the patients had received prior adjuvant chemotherapy. Those populations were different when we looked at them; the patients who received the prior chemotherapy, they were only allowed on the study if they were still pre-menopausal after the chemotherapy and they were on average younger, median age 40, they had higher risk tumours, larger tumours, more high grade tumours, more node positive tumours.

So the overall effect of adding ovarian function suppression was not evident?

Was not significant in the overall population but when we looked in the two distinct cohorts of patients, the ones who remained pre-menopausal after having received adjuvant chemotherapy, that was the group where we saw improvement with adding ovarian function suppression.

What do you think this is telling us about the nature of breast cancer and the best way to treat it using endocrine therapy?

I think the trial is telling us that in pre-menopausal women who are at higher risk and are receiving adjuvant chemotherapy because their tumour is a high risk tumour, that in that population, if they’re still pre-menopausal after they’ve completed their chemotherapy, then we can get incremental gains by changing our adjuvant endocrine therapy. So what we saw was some improvement from adding ovarian suppression to Tamoxifen and then we saw further improvement by having ovarian suppression combined with an aromatase inhibitor, exemestane. So we could see incremental gains but only in the subpopulation who were that high risk group who had had the chemotherapy and remained pre-menopausal.

What’s the explanation of why ovarian function suppression was not working in the other patients?

The other population of patients, which was almost half the patients, so a reasonably large group, they tended to be older patients, on average median age 46, they tended to have small node negative tumours, low to intermediate grade tumours. So they had low risk tumours and one of the things that struck us in this trial was they had excellent outcomes with any of the three adjuvant endocrine treatments they were assigned. So they did well with Tamoxifen alone.

So it’s like a law of diminishing returns in the older women?

They weren’t old in one sense, they were median age 46, so they were pre-menopausal but they were closer to the natural age of menopause and their tumours were lower risk. But what we were really pleased to see was how good the outcomes were, that Tamoxifen was their only systemic therapy and more than 95% of that cohort were free from breast cancer at five years.

What does your study tell us about very young patients and the role of ovarian function suppression?

The very young patients were part of the hypothesis for the trial in the first place because our group had noted that women who are diagnosed with an ER positive breast cancer under 35 are a group that have been at higher risk for relapse compared to other pre-menopausal women. When we looked in that subgroup, and nearly all those women got chemotherapy, 94%, there was a really striking benefit in that subpopulation of women under 35. What we found was that both the treatment groups that got ovarian suppression did quite a lot better than the group that got Tamoxifen alone. When we looked at five years the group that got Tamoxifen alone who were under 35, one in three of those women had experienced some further breast cancer and it was only one in six of those women under 35 in the group that got the aromatase inhibitor exemestane with ovarian suppression. So ovarian suppression seems to be important in women under 35.

So you’ve got a very clear recommendation now for women under 35?

For that group that have ER positive breast cancer under 35, to me it looks like it makes an important difference to include ovarian suppression. But obviously there were other women in the trial that can benefit from this that were older than 35 but the benefit was most striking in that age group.

Could you sum up, then, your clinical recommendations or the apparent recommendations coming out of this?

There are two. There are a group of pre-menopausal women with relatively lower risk hormone receptor positive breast cancers who can do very well with no chemotherapy and with Tamoxifen alone as their sole systemic therapy. There is another group of women who are relatively young, median age of 40, who have higher risk tumours and because of the clinicopathologic features they’re receiving adjuvant chemotherapy. If they’re still producing oestrogen there may be an advantage in maximal oestrogen suppression with a combination of ovarian suppression plus an aromatase inhibitor that comes at a trade-off, there are side effects. I think doctors need to talk to the patients about the different options but when we looked at the disease and the breast cancer free interval absolute difference for that sub-population who had had chemotherapy and then remained pre-menopausal, there was about a 7.7% absolute difference in five year breast cancer free interval going from Tamoxifen to going to an aromatase inhibitor plus ovarian suppression.

And then for the very young patients it’s a cert, you use OFS?

Yes. Well they did best if they had OFS; they did well with Tamoxifen and OFS and they did a little bit better with OFS plus an aromatase inhibitor. When we looked at distant metastases in the overall group that got the aromatase inhibitor plus ovarian suppression the absolute difference in distant metastases was just over 4% compared to Tamoxifen alone. So we don’t have mature survival data at this time and we really need to follow these women.

A quick bottom line message for doctors around the world?

It’s important to look at the age of the patient, the clinicopathologic features, but adjusting endocrine therapy can make important differences for very young women.

And ovarian function suppression does have a role?

I believe it does have a role for some women.