Combined Study Analysis Determines Best Drug Choices for Patients with Advanced Breast Cancer

October 21, 2020
Hannah Slater

Detection of ESR1 mutations in baseline ctDNA was associated with inferior progression-free survival and overall survival in patients with advanced HR-positive breast cancer treated with exemestane versus fulvestrant.

Detection of ESR1 mutations in baseline circulating tumor DNA (ctDNA) is associated with inferior progression-free survival (PFS) and overall survival (OS) in patients with advanced hormone receptor (HR)-positive breast cancer treated with exemestane (Aromasin) versus fulvestrant (Faslodex), according to a combined analysis of the phase 3 SoFEA and EFECT trials published in Clinical Cancer Research.1

“This work supports the argument for the use of liquid biopsies as part of routine care for those with advanced cancer, as they can be used to improve outcomes by ensuring that we select the most appropriate treatments,” Nicholas Turner, PhD, professor of Molecular Oncology at the Institute of Cancer Research (ICR) and head of the Ralph Lauren Centre for Breast Cancer Research at The Royal Marsden, said in a press release.2

The phase 3 EFECT and SoFEA trials randomized patients with HR-positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy to receive either 250 mg of fulvestrant or exemestane. Baseline serum samples from 227 patients in EFECT and baseline plasma from 161 patients in SoFEA were evaluated for ESR1 mutations by digital PCR.

The dual primary end points of the study were to assess the impact of ESR1 mutation status on PFS and OS in a combined analysis of both studies.

Overall, ESR1 mutations were detected in 30% of baseline samples. Of those with the ESR1 mutation detected, PFS was 2.4 months (95% CI, 2.0-2.6) on exemestane and 3.9 months (95% CI, 3.0-6.0) on fulvestrant (HR, 0.59; 95% CI, 0.39-0.89; P = .01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7-6.2) on exemestane and 4.1 months (95% CI, 3.6-5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81-1.37; P = .69).

Ultimately, there was an interaction observed between ESR1 mutation and treatment (P = .02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%-75%) on exemestane and 80% (95% CI, 68%-87%) on fulvestrant (P = .04; restricted mean survival analysis). Further, patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%-85%) on exemestane and 81% (95% CI, 74%-87%) on fulvestrant (P = .69).

“It is clear from this study that there is an interaction between the ESR1 mutation, and the treatment chosen,” Turner explained. “The 2 trials examined here showed, without measuring ESR1 mutations, that exemestane and fulvestrant worked similarly. But by adding ESR1 status to the picture, we can see that is not the case. Patients with ESR1 mutations were at a higher risk of early progression and death if treated with exemestane.”

Importantly, the researcher emphasized that patients treated with fulvestrant in the EFECT and SoFEA trials were treated with a dose half that is used currently (250 mg of fulvestrant vs 500 mg of fulvestrant in the CONFIRM study) and this has important implications for interpreting the results of patients with undetected ESR1 mutations. Although there was no difference found between exemestane and fulvestrant in the ESR1-undetected group, this may reflect the lower dose of fulvestrant used; thus, it is reasonable to speculate that such patients treated with fulvestrant may have had improved PFS on a 500 mg dose of fulvestrant compared with exemestane.

Moving forward, the investigators suggested that further investigation of whether different ESR1 mutations have differing responsiveness to fulvestrant, or tamoxifen (Nolvadex), will still be necessary.

“Our data provides evidence of clinical utility of ctDNA liquid biopsies in breast cancer, suggesting the potential to improve outcome, to monitor for the presence of ESR1 mutations in advanced breast cancer, and to aid in selection of the most appropriate subsequent endocrine therapy backbone, if further aromatase inhibitor-based therapy is being considered,” the study authors concluded.


1. Turner NC, Swift C, Kilburn L, et al. ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials. Clinical Cancer Research. doi: 10.1158/1078-0432.CCR-20-0224

2. New study sheds light on the best drug choices for some patients with advanced breast cancer [news release]. Published October 8, 2020. Accessed October 9, 2020.