Abstract DEB1-2: Con - RxPONDER: Was it all OFS?
Authors: Loibl S 
Published: March 2022

Abstract
Introduction: In Rx ponder patients with nodal involvement and a recurrence score between 0-25 were randomised to receive either chemotherapy followed by endocrine therapy or endocrine therapy alone. Patients were stratified by recurrence score (RS) 0-13 vs 14-25, menopausal status and type of axillary surgery. 50% of the patients randomised to chemotherapy received TC (4 or 6 cycles) and ovarian function suppression (OFS) was used in 16% in the ET arm and 3% in the chemotherapy plus ET arm (CET). 33% of the patients enrolled were premenopausal. The overall analysis demonstrated that patients with CET had a significantly higher iDFS at 5 years than those with ET (92.4% vs 91%); HR 0.81, p=0.026. There was a significant interaction of menopausal status and chemotherapy. 5-year iDFS was 94.2% with CET and 89% with ET (delta 5.2%); HR 0.54; p=0.0004, which was larger in the group with a RS 13-25. Because the use of OFS in the CET arm was only 3% it was hypothesised that the main effect of chemotherapy is due to ovarian function suppression. Main Part: OFS added to tamoxifen or AI is very effective in premenopausal women as shown by the SOFT and TEXT studies. The majority of women in SOFT and TEXT received chemotherapy and the effect was observed mainly in the group receiving chemotherapy (a surrogacy for high risk). Adding OFS to tamoxifen plus chemotherapy vs chemotherapy plus tamoxifen is better. The LHRH metaanalysis demonstrated that LHRH was about equally effective to chemotherapy. However, the majority of trials used 2 years LHRH, chemotherapy consisted mainly of CMF and the effect was seen in women under 40 years. The subsequent metaanalyses by the EBCTCG support chemotherapy regardless of ET and menopausal status. Anthracycline and taxane containing chemotherapy is more effective than CMF and dose-dense chemotherapy is even more effective than standard chemotherapy. Chemotherapy can induce amenorrhoea and women with chemotherapy induced amenorrhea have a better outcome than those without. Cyclosphosphamide and especially in the CMF regimen have the highest rate of amenorrhea and the main effect is seen in women between 40 and 50 years. Younger women regain menses, so the ovarian function suppression is temporarily, especially in women below 40 years. The dose of cyclophosphamide in the TC regimen, which was predominantly used in Rx-Ponder is lower than in the CMF regimen but similar to modern type chemotherapy regimen. In RX-Ponder the chemotherapy effect was seen in all premenopausal women but there was no difference of the point estimate in women between 40-50 and younger than 40 years of age. The ovarian function suppression effect is transient and women under 40 year of age tend to regain menopause and should receive an LHRH in addition. In very young women the ovarian function suppression with an LHRH analogue is about 80% leaving 20% without adequate OFS. The toxicity rate of 5 years of LHRH containing ET is high and should not be underestimated compared to 4-6 months chemotherapy. Compliance of LHRH is lower than in adjuvant chemotherapy affecting the effectiveness of adjuvant therapy. If LHRH is discontinued at 2years of LHRH the patient will receive only tamoxifen, which is too little in high risk, premenopausal women. The recurrence score mainly measures endocrine sensitivity of the tumour which does not imply chemoresistance. Nodal status remains still the most important prognostic factor and chemotherapy reduces the risk of recurrence by 30-40%.The data from Rx-Ponder are comparable to the data generated in the Mindact trial. In women younger than 50 years being at clinical high risk but with a genomic low risk tumour chemotherapy improved 8-year DDFS to 93.6% compared to 88.6% without chemotherapy (HR 0.54 95%; CI 0.30-0.98).In conclusion: Premenopausal women with node-positive HR+/HER2- breast cancer benefit from the use of chemotherapy in addition to LHRH even if the RS indicates a biological low risk.
Citation Format: S Loibl. Con - RxPONDER: Was it all OFS? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr DEB1-2.