Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer.

Acquired estrogen receptor gene (ESR1) mutations have been recently reported as a marker of resistance to aromatase inhibitors in hormone receptor positive metastatic breast cancer. We retrospectively considered seven patients treated for metastatic breast cancer with available samples from the primary tumor before any treatment, cryopreserved metastasis removed during progression and concomitant plasmas. All these seven patients were in disease progression after previous exposure to aromatase inhibitors for at least 6 months, and were assessed for ESR1 mutations detection in tumor and circulating DNA. For these patients, Sanger sequencing identified four metastases with clear ESR1 mutation and one possible, whereas digital PCR identified six mutated metastases. Then, under blind conditions and using digital PCR, corresponding circulating ESR1 mutations were successfully detected in four of these six metastatic breast cancer patients. Moreover, in two patients with serial blood samples following treatments exposure, the monitoring of circulating ESR1 mutations clearly predicted disease evolution. In the context of high interest for ESR1 mutations, our results highlight that these acquired recurrent mutations may be tracked in circulating tumor DNA and may be of clinical relevance for metastatic breast cancer patient monitoring.

Sefrioui D ，Perdrix A ，Sarafan-Vasseur N ，Dolfus C ，Dujon A ，Picquenot JM ，Delacour J ，Cornic M ，Bohers E ，Leheurteur M ，Rigal O ，Tennevet I ，Thery JC ，Alexandru C ，Guillemet C ，Moldovan C ，Veyret C ，Frebourg T ，Di Fiore F ，Clatot F ... -  《-》

Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor.

Clatot F ，Perdrix A ，Augusto L ，Beaussire L ，Delacour J ，Calbrix C ，Sefrioui D ，Viailly PJ ，Bubenheim M ，Moldovan C ，Alexandru C ，Tennevet I ，Rigal O ，Guillemet C ，Leheurteur M ，Gouérant S ，Petrau C ，Théry JC ，Picquenot JM ，Veyret C ，Frébourg T ，Jardin F ，Sarafan-Vasseur N ，Di Fiore F ... -  《Oncotarget》

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

Allouchery V ，Beaussire L ，Perdrix A ，Sefrioui D ，Augusto L ，Guillemet C ，Sarafan-Vasseur N ，Di Fiore F ，Clatot F ... -  《-》

Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer.

Clatot F ，Perdrix A ，Beaussire L ，Lequesne J ，Lévy C ，Emile G ，Bubenheim M ，Lacaille S ，Calbrix C ，Augusto L ，Guillemet C ，Alexandru C ，Fontanilles M ，Sefrioui D ，Burel L ，Guénot S ，Richard D ，Sarafan-Vasseur N ，Di Fiore F ... -  《-》

Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer.

Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to the first-line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer. Eighty-three patients on the first-line AI therapy for metastatic breast cancer were enrolled in a prospective study. Plasma samples were collected every 3 months to disease progression and ctDNA analysed by digital droplet PCR and enhanced tagged-amplicon sequencing (eTAm-Seq). Mutations identified in progression samples by sequencing were tracked back through samples before progression to study the evolution of mutations on therapy. The frequency of novel mutations was validated in an independent cohort of available baseline plasma samples in the Study of Faslodex versus Exemestane with or without Arimidex (SoFEA) trial, which enrolled patients with prior sensitivity to AI. Of the 39 patients who progressed on the first-line AI, 56.4% (22/39) had ESR1 mutations detectable at progression, which were polyclonal in 40.9% (9/22) patients. In serial tracking, ESR1 mutations were detectable median 6.7 months (95% confidence interval 3.7-NA) before clinical progression. Utilising eTAm-Seq ctDNA sequencing of progression plasma, ESR1 mutations were demonstrated to be sub-clonal in 72.2% (13/18) patients. Mutations in RAS genes were identified in 15.4% (6/39) of progressing patients (4 KRAS, 1 HRAS, 1 NRAS). In SoFEA, KRAS mutations were detected in 21.2% (24/113) patients although there was no evidence that KRAS mutation status was prognostic for progression free or overall survival. Cancers progressing on the first-line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic diversity of AI resistant cancers may limit subsequent targeted therapy approaches.

Fribbens C ，Garcia Murillas I ，Beaney M ，Hrebien S ，O'Leary B ，Kilburn L ，Howarth K ，Epstein M ，Green E ，Rosenfeld N ，Ring A ，Johnston S ，Turner N ... -  《-》