Abstract P3-04-04: Detection of ESR1 mutations in matched primary and metastatic samples from endocrine-resistant lobular breast cancer patients
Authors: Desmedt C , Pingitore J , Rothé F , Rouas G , Bertucci F , Galant C , Rotmensz N , van den Eynden G , Salgado R , Larsimont D , Pruneri G , Sotiriou C 
Published: March 2017

Abstract
Background:
Invasive lobular breast cancer (ILBC) represents the second most common histology of breast cancer (BC) and accounts for 10-15% of all invasive cases. Since &gt;90% of ILBCs express the estrogen receptor (ER, coded by the ESR1 gene), the vast majority of these patients receive endocrine therapy. ESR1 mutations have mainly been identified in metastases from ER-positive BC at a frequency ranging from 11 to 50% and were shown to be associated with resistance to endocrine therapy. Nevertheless, ESR1 mutations have never been assessed in metastatic ILBC, hence the present study.
Patients and methods:
We aimed at interrogating the five most commonly reported ESR1 mutations (Y537S/C/N, D538G, E380Q) by droplet digital PCR (BioRad) in matched primary, axillary and metastatic ILBC samples (N=212) from 69 endocrine-resistant patients collected retrospectively from five hospitals.
Results:
We present here the results for the two most frequent ESR1 mutations (Y537S and D538G); data from the remaining mutations will be available at the time of the conference. We observed Y537S and D538G mutations in metastases from three and four patients, respectively. For one patient, the sampled metastasis harbored both the Y537S and the D538G mutations, confirming that ESR1 polyclonality can be present in the same metastasis. For another patient, two metastases were sampled and the D538G mutation was only present in one metastasis. Intriguingly, for two patients we observed D538G mutations only in the primary tumor but not in the corresponding metastasis, and for another only in an axillary lymph node. We could hypothesize that the clone carrying the mutation in the early setting has been removed either by the primary surgery or subsequent adjuvant chemotherapy. The ESR1 Y537S and D538G mutational frequencies observed in our metastatic ILC cohort (3/69, 4.35% and 4/69, 5.80%, respectively) are not statistically different from the frequencies reported in breast cancer metastases in the literature across the different studies (6.62% and 6.20%, respectively). All patients with ESR1-mutated metastases received at least 4 years of endocrine therapy and all but one were treated with an aromatase inhibitor (AI). However, half of these patients received exclusively endocrine therapy in the adjuvant setting.
Conclusion:
This is to the best of our knowledge, the first metastatic ILBC series in which the most frequently reported ESR1 mutations are being investigated, and the largest series in which ESR1 mutations are being investigated in matched metastatic, primary tumor and axillary lymph node samples. The frequencies that we found for the Y537S and D538G mutations are in line with those reported in the literature in metastatic biopsies for the general BC population. We further demonstrated using multiple samples from the primary tumor and an ultra-sensitive technology that there was no patient presenting an ESR1 mutation both in the early and metastatic disease. Data on the remaining mutations (Y537S/N, E380Q) will complete these results.
Citation Format: Desmedt C, Pingitore J, Rothé F, Rouas G, Bertucci F, Galant C, Rotmensz N, van den Eynden G, Salgado R, Larsimont D, Pruneri G, Sotiriou C. Detection of ESR1 mutations in matched primary and metastatic samples from endocrine-resistant lobular breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-04.