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ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis.

ABSTRACT: BACKGROUND:Emerging mutations in the ESR1 gene that encodes for the estrogen receptor (ER) are associated with resistance to endocrine therapy. ESR1 mutations rarely exist in primary tumors (~?1%) but are relatively common (10-50%) in metastatic, endocrine therapy-resistant cancers and are associated with a shorter progression-free survival. Little is known about the incidence and clinical implication of these mutations in early recurrence events, such as local recurrences or newly diagnosed metastatic disease. METHODS:We collected 130 archival tumor samples from 103 breast cancer patients treated with endocrine therapy prior to their local/metastatic recurrence. The cohort consisted of 41 patients having at least 1 sample from local/loco-regional recurrence and 62 patients with metastatic disease (of whom 41 newly diagnosed and 28 with advanced disease). The 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) were analyzed either by targeted sequencing or by droplet digital PCR. Progression-free survival (PFS), disease-free survival (DFS), and distant recurrence-free survival (DRFS) were statistically tested by Kaplan-Meier analysis. RESULTS:The prevalence of ESR1 mutations was 5/41 (12%) in newly diagnosed metastatic patients and 5/28 (18%) for advanced metastases, detected at allele frequency >?1%. All mutations in advanced metastases were detected in patients previously treated with both tamoxifen (TAM) and aromatase inhibitors (AI). However, in newly diagnosed metastatic patients, 4/5 mutations occurred in patients treated with TAM alone. PFS on AI treatment in metastatic patients was significantly shorter for ESR1 mutation carriers (p?=?0.017). In the local recurrence cohort, ESR1 mutations were identified in 15/41 (36%) patients but only 4/41 (10%) were detected at allele frequency >?1%. Again, most mutations (3/4) were detected under TAM monotherapy. Notably, 1 patient developed ESR1 mutation while on neoadjuvant endocrine therapy. DFS and DRFS were significantly shorter (p?=?0.04 and p?=?0.017, respectively) in patients that had ESR1 mutations (>?1%) in their loco-regional recurrence tumor. CONCLUSIONS:Clinically relevant ESR1 mutations are prevalent in newly diagnosed metastatic and local recurrence of endocrine-treated breast cancer. Since local recurrences are amenable to curative therapy, these mutations may inform the selection of subsequent endocrine therapies.

SUBMITTER: Zundelevich A

PROVIDER: S-EPMC6998824 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis.

Zundelevich Adi A Dadiani Maya M Kahana-Edwin Smadar S Itay Amit A Sella Tal T Gadot Moran M Cesarkas Karen K Farage-Barhom Sarit S Saar Efrat Glick EG Eyal Eran E Kol Nitzan N Pavlovski Anya A Balint-Lahat Nora N Dick-Necula Daniela D Barshack Iris I Kaufman Bella B Gal-Yam Einav Nili EN

Breast cancer research : BCR 20200203 1

<h4>Background</h4>Emerging mutations in the ESR1 gene that encodes for the estrogen receptor (ER) are associated with resistance to endocrine therapy. ESR1 mutations rarely exist in primary tumors (~ 1%) but are relatively common (10-50%) in metastatic, endocrine therapy-resistant cancers and are associated with a shorter progression-free survival. Little is known about the incidence and clinical implication of these mutations in early recurrence events, such as local recurrences or newly diagn ...[more]

PMID: 32014063

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Project description:ObjectiveIgD multiple myeloma (MM) is a rare type of MM, accounting for about 1%-2% of all MMs. IgD MM always causes kidney damage and even leads to renal failure, which is the most common complication. This study aimed to explore the risk factors of renal damage and prognosis of IgD MM patients.DesignFrom March 2018 to November 2021, 85 patients with IgD MM diagnosed for the first time at the First Affiliated Hospital of Zhengzhou University were included in this study. We collected information on clinical features and laboratory examinations. Patients were divided into the renal impairment (RI) (47/85) and non-renal impairment (no-RI) (38/85) groups. Binary logistic regression was used to explore risk factors of renal damage. The Chi-square test was used to analyze the difference in chemotherapy effect between the two groups. We also analyzed whether early dialysis was beneficial to acute renal failure (RF) in IgD MM patients. Finally, Kaplan-Meier was used to compare the survival of the two groups.ResultsIn IgD MM, 55.3% of patients had renal damage as a complication, of which up to 59.6% presented with acute renal failure as the first manifestation. Serum β2-microglobulin (β2-MG) was an independent risk factor for renal damage in IgD MM (p = 0.002), but cytogenetic analysis suggested that it had no effect on patients' renal damage. There was also no significant difference in the effect of chemotherapy between the two groups (p = 0.255). In patients with acute renal failure, there was no significant difference between dialysis and no dialysis groups in the proportion of patients with improved renal function after treatment. The median overall survival (OS) of the RI group was significantly shorter than that of the no-RI group (p = 0.042). In the RI group, the median OS was 29 months, and in the no-RI group, the median OS was > 40 months.ConclusionElevated serum β2-MG is an independent risk factor for renal damage. Compared with the no-RI group, patients in the RI group had poorer prognosis and shorter median OS. For patients with acute renal failure as the first manifestation, the treatment of primary disease is more meaningful than dialysis.

Dataset Information

ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis.

Publications

ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis.

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