For these patients, Sanger sequencing identified four metastases with clear ESR1 mutation and one possible, whereas digital PCR identified six mutated metastases.
ESR1 mutations are rarely acquired during adjuvant AI but are commonly selected by therapy for metastatic disease, providing evidence that mechanisms of resistance to targeted therapy may be substantially different between the treatment of micrometastatic and overt metastatic cancer.
ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1-mutant clones are enriched by endocrine therapy.
The results suggest that polymorphisms in ESR1, ESR2 and LHCGR contribute to the risk of developing TGCC, histological subtype, and risk to metastasis.
In this study, we compared somatic mutations and gene copy number alterations of primary breast cancers and their matched metastases from patients with estrogen receptor (ER)-negative disease.
Retrospective analyses of ESR1 mutations in baseline plasma circulating tumor DNA from completed clinical trials suggest that these mutations are prognostic and predictive of resistance to aromatase inhibitors in metastatic disease.
In contrast to its role in breast cancer (BCa) initiation, estrogen signaling has a protective effect in later stages, where estrogen receptor (ER)α loss associates with aggressive metastatic disease.
Furthermore, ESR1 mutations express a unique transcriptional profile that favors tumor progression, suggesting that selected ESR1 mutations may influence metastasis.
Outgrowth of metastases expressing ERα mutations Y537S and D538G is common after endocrine therapy for estrogen receptor α (ERα) positive breast cancer.
Recent studies have confirmed that ESR1 point mutations frequently occur in metastatic breast tumors that are refractory to endocrine therapy, and suggest the development of novel strategies that may be more effective in controlling ER signaling and benefit patients with recurrent and metastatic disease.
In summary, this study has demonstrated androgen receptor (ARStuI) and estrogen receptor (ER325) genetic polymorphisms in prostate cancer patients and its association with disease progression and metastasis.
The association of estrogen receptor alpha (ERα) expression with differentiated breast tumors presenting a lower metastasis risk could be explained by the estrogen modulation of cell adhesion, motility and invasiveness.
A specific haplotype association to TP53 mutation (P<0.01) distant metastases (P<0.05) and estrogen receptor status (P<0.05) was also observed in the case group.
We identified downregulation of RAI2 as a novel metastasis-associated genetic alteration especially associated with early occurring bone metastasis in ERα-positive breast tumors.
The TIL distributions were significantly associated with nodal metastasis (P=0.004), ER status (P=0.045), progesterone receptor (PgR) status (P=0.002), tumor grade (P=0.021), and the Ki67 labeling index (LI) (P=0.002) in the no recurrence group and with the Ki67 LI in the recurrence groups (P=0.002 in early recurrence group, P=0.023 in late recurrence group).
Single nucleotide variants in metastasis-related genes are associated with breast cancer risk, by lymph node involvement and estrogen receptor status, in women with European and African ancestry.
Early identification of ESR1 mutations by liquid biopsy might allow for cessation of ineffective endocrine therapies and switching to other treatments, without the need for tissue biopsy and before the emergence of metastatic disease.
These questions have provoked new mechanistic hypotheses that link resistance to endocrine agents to: (1) Specific defects in single strand break repair are associated with increased mortality from ER+ breast cancer [1,2]; (2) Loss/mutations of certain single strand break repair proteins that disrupt estrogen-regulated cell cycle control through the ATM, CHK2, CDK4 axis [1,2] thereby directly coupling endocrine therapy resistance to specific DNA repair defects; (3) Acquired mutations that drive metastasis include the generation of in-frame ESR1 gene fusions that activate epithelial-to-mesenchymal transition (EMT) driven metastasis as well as endocrine drug-resistant proliferation [3].
Conversely, the IFN metagene was associated with a low risk of metastasis in 104 ERBB2+ tumors (P = 0.0099) whereas it did not prove to significantly affect prognosis in 123 ESR1-/ERBB2- tumors (P = 0.2235).
Impaired p53 function leads to centrosome amplification, acquired ERalpha phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts.