Circulating ESR1 mutations at the end of aromatase inhibitor adjuvant treatment and after relapse in breast cancer patients

Aromatase inhibitors (AI) are a key treatment in post-menopausal hormone receptor positive (HR+) breast cancer (BC). Estrogen receptor (ESR1) mutation emergence has been recently highlighted as a frequent mechanism of acquired AI resistance in the metastatic setting, as well as a prognostic marker of poor outcome [1‐3]. ESR1 mutations are characterized by a frequency of no more than 2% in primary tumour [4] compared to 30% in metastatic tissues among AI-resistant patients [1, 3]. Furthermore, ESR1 mutations located in four hot-spots (Y537N/S/C, D538G) count for 74% of all described mutations [5], and can be successfully detected in circulating tumour DNA (ctDNA) [6, 7].

Besides its use in the metastatic setting, AI are widely administered as adjuvant treatment of HR+ early BC (EBC) with a usual exposure of 5 years [8]. Despite this long time of exposure, data concerning circulating ESR1 mutation emergence under adjuvant AI therapy are lacking. It has been reported that circulating ESR1 mutations at the time of metastatic diagnosis in patients previously exposed to AI in the adjuvant setting may be detected at rates ranging from 2.6 [6] to 11.3% [1]. Until now, circulating ESR1 mutation emergence between adjuvant treatment ending, relapse and AI re-exposure remains not clearly established.

To our knowledge, this study is the first addressing the frequency of circulating ESR1 mutation at the end of AI adjuvant treatment in patients treated for an EBC. Our results highlighted that no circulating ESR1 mutation was detectable at the end of AI-based adjuvant treatment in HR+ EBC patients who also subsequently experienced a relapse during follow-up. In contrast, re-exposure to AI in the metastatic setting induced circulating ESR1 mutation emergence among 33% of patients, which was close to the 30–50% circulating ESR1 mutation frequency usually observed for metastatic patients progressing on AI [1‐3, 9]. Interestingly, we observed that circulating ESR1 mutation was detectable in a small proportion of patients (5.3%) at metastatic diagnosis, which is also a finding in line with previous data reporting a frequency ranging from 2.6 to 11.3% in that setting [1, 8].

Our study has some inherent limitations due to its retrospective design. First, considering the limited number of patients, the emergence of a circulating ESR1 mutation at the end of the adjuvant phase by AI cannot be formally excluded. Thus, larger prospective studies with pre-defined sample processing are needed to confirm our results. Second, since we focused the analysis on the four main ESR1 mutations, we cannot exclude the presence of rare circulating mutations [10]. In terms of daily practice, our results suggest that screening for a circulating ESR1 mutation detection at the end of adjuvant AI treatment would not be of interest. In contrast, we found that ESR1 mutations at relapse were present in 5.3% of patients and that their levels increased under AI exposure. Even rare, circulating ESR1 mutation at relapse after an AI exposure limited to the adjuvant setting has already been reported by others [8]. Thus, early treatment change in cases of detected circulating ESR1 mutations should be assessed by clinical trials as soon as metastatic relapse in case of previous AI exposure, and not only after AI treatment in the metastatic setting.

Concerning ESR1 mutation emergence during the metastatic phase, it has to be noted that despite long-term exposure to adjuvant AI (median of 5 years), most of the patients with a detectable ESR1 mutation in the metastatic setting had a detected circulating mutation only after 20 months of AI re-exposure. On the other hand, the observation that two patients harboured ESR1 mutations at relapse confirms the hypothesis that mutational clone emergence was selected by AI therapy during the adjuvant setting, but not detectable at that time given a low tumour burden [8]. Interestingly, these two patients had a comparable delay (20 and 48 months) between end of AI adjuvant treatment and metastatic relapse compared to the other patients of the cohort (median of 25 months).

To conclude, ours results show that detection of circulating ESR1 mutation at the end of AI-based adjuvant treatment in HR+ EBC patients is not clinically useful. Even if technical advances—such as plasmapheresis or use of implanted ultrasensitive devices [11]—may increase the amount of evaluable ctDNA and thus improve sensitivity of mutation detection in the future, ongoing efforts to detect circulating ESR1 mutations should be focused on the metastatic setting.