SUPPRESSING OVARIAN FUNCTION INCREASES BREAST CANCER SURVIVAL IN HIGH-RISK PREMENOPAUSAL WOMEN

Up to 12 years from diagnosis, premenopausal women at higher risk of relapse following treatment for the most common form of breast cancer continue to benefit from 5 years of post-operative treatment suppressing ovarian function in combination with the drugs tamoxifen or exemestane.

That’s the general conclusion of two papers published in December 2022, following the latest analysis of data from two long-term international studies, the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT). Prior analysis was published providing results five years and eight years into the study.

“Twelve years is now long enough that you can start to see how much difference in survival you might get, particularly for some of the higher risk women,” says Professor Prue Francis of the Peter McCallum Cancer Centre.

Professor Francis, who is co-chair of SOFT and chaired the steering committee for both trials says the addition of ovarian suppression is providing at least a 4% improvement in overall survival at 12 years. “So that’s something that most women would consider potentially meaningful.”

Among premenopausal women with breast cancer, 80% have hormone-responsive breast cancer, where the hormone oestrogen can stimulate the growth of cancer cells.

To stop this from happening to any cancer cells that remain after the primary cancer has been removed, women may be treated with one or more hormone blocking drugs. These either prevent the uptake of oestrogen by cells (oestrogen blockers like tamoxifen), switch off the production of oestrogen in the ovaries (ovarian function suppression), or block oestrogen production in body fat (aromatase inhibitors such as exemestane).

SOFT and TEXT are independent, long-term, clinical trials involving thousands of women from all over the world, including 489 from Australia and New Zealand. These trials are investigating the effects of different hormone treatment combinations on survival and the recurrence of cancer in premenopausal women.

The research partly stemmed from the observation that women under 35 treated for hormone receptor positive breast cancer often had worse outcomes than women closer to menopause. One suggestion was that by placing younger women into a state of menopause, by suppressing their ovaries, might help prevent recurrence of the cancer.

The SOFT trial was established specifically to study if ovarian suppression was beneficial by testing two regimens. One added ovarian function suppression to the five years of either tamoxifen or exemestane prescribed for premenopausal women after surgery for breast cancer, and the other involved treatment with tamoxifen alone. The suppression could be permanent, with the ovaries removed via keyhole surgery, or temporary, using injectable drugs. Professor Francis says fewer than 10% of women, typically those close to menopause, opted for surgery.

The TEXT trial was set up to identify the difference between adding ovarian suppression to tamoxifen therapy and exemestane therapy. The protocols for adding ovarian function suppression were similar to those in SOFT. So, for those purposes, data from the two trials could be pooled, providing a larger sample for statistical analysis.

“At 12 years in SOFT, we can now see that some sub-groups of women at particularly high risk of recurrence seem to benefit from the more intense endocrine therapy with ovarian function suppression and exemestane,” Professor Francis says. They include women with larger tumours, who had chemotherapy before surgery. “Also, women under 35 look like they are getting a good survival benefit from ovarian suppression, and those with aggressive grade-3 tumours.”

On the other side of the coin, women with a lower risk of breast cancer have done well on average using tamoxifen alone without ovarian suppression. “This is a reassuring finding, that there are premenopausal women who don’t need chemotherapy and don’t need ovarian suppression. More than 95% in this group who did not receive chemotherapy are still alive.”

After 12 years the combined TEXT-SOFT analysis shows a continuation of trends that became apparent after five and eight years. Treatment with exemestane and ovarian suppression significantly improved disease-free survival and reduced distant metastases compared to tamoxifen and ovarian suppression, but not overall survival.

Additionally, the two oral drugs have different side-effect profiles, Professor Francis says. “Aromatase inhibitors (like exemestane) can have challenging side-effects. They certainly can cause more musculoskeletal complaints. They are harder on your sex life, and can cause more loss of bone density. Tamoxifen has side-effects, such as increasing the risk of blood clots, but these are not common.”

“What you need to understand in patients is to what extent a woman is willing to accept more side-effects to try and improve her breast cancer outcomes. Having a more intensified treatment may come at a physical cost. Women have different preferences.”

Publications:

1. Prudence Francis, Gini Fleming, István Láng, Eva Ciruelos, Hervé Bonnefoi, Meritxell Bellet, Antonio Bernardo, Miguel Climent, Silvana Martino, Begoña Bermejo, Harold Burstein, Nancy Davidson, Charles Geyer Jr, Barbara Walley, James Ingle, Robert Coleman, Bettina Mller, Fanny Le Du, Sibylle Loibl, Eric P. Winer, Barbara Ruepp, Sherene Loi, Marco Colleoni, Alan Coates, Richard Gelber, Aron Goldhirsch, and Meredith M. Regan (2023) Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT. Journal of Clinical Oncology 41 (7): 1370-1375. https://ascopubs.org/doi/10.1200/JCO.22.01065
2. Olivia Pagani, Barbara Walley, Gini Fleming, Marco Colleoni, István Láng, Henry Gomez, Carlo Tondini, Harold Burstein, Matthew Goetz, Eva Ciruelos, Vered Stearns, Hervé Bonnefoi, Silvana Martino, Charles Geyer Jr, Claudio Chini, Fabio Puglisi, Simon Spazzapan, Thomas Ruhstaller, Eric Winer, Barbara Ruepp, Sherene Loi, Alan Coates, Richard Gelber, Aron Goldhirsch, Meredith Regan and Prudence Francis (2023) Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. Journal of Clinical Oncology 41 (7): 1376-1382. https://ascopubs.org/doi/abs/10.1200/JCO.22.01064