Repeated stereotactic radiosurgery for recurrent brain metastases: An effective strategy to control intracranial oligometastatic disease.

Due to improvements in systemic therapies and longer survivals, cancer patients frequently present with recurrent brain metastases (BM). The optimal therapeutic strategies for limited brain relapse remain undefined. We analyzed tumor control and survival in patients treated with salvage focal radiotherapy in our center. Thirty-three patients with 112 BM received salvage stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) for local or regional recurrences. Local progression was observed in 11 BM (9.8 %). After 1 year, 72 % of patients were free of distant brain failure, and the 2-year overall survival (OS) was 37.7 %. No increase in toxicity or neurologically related deaths were observed. The 2- and 3-year whole brain radiation therapy free survival (WFS) rates were 92.9 % and 77.4 %, respectively. Hence, focal radiotherapy is a feasible salvage of recurrent BM in selected group of patients with limited brain disease, achieving a maintained intracranial control and less neurological toxicity.

Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer.

Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations. Understanding how these mutations impact on ER function is a prerequisite for identifying methods to treat breast cancer patients featuring such mutations. Towards this end, we used CRISPR-Cas9 genome editing to make a single allele knock-in of the most commonly mutated amino acid residue, tyrosine 537, in the estrogen-responsive MCF7 breast cancer cell line. Genomic analyses using RNA-seq and ER ChIP-seq demonstrated that the Y537S mutation promotes constitutive ER activity globally, resulting in estrogen-independent growth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen and fulvestrant. Further, we show that the basal transcription factor TFIIH is constitutively recruited by ER-Y537S, resulting in ligand-independent phosphorylation of Serine 118 (Ser118) by the TFIIH kinase, cyclin-dependent kinase (CDK)7. The CDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growth of MCF7-Y537S cells. These studies confirm the functional importance of ER mutations in endocrine resistance, demonstrate the utility of knock-in mutational models for investigating alternative therapeutic approaches and highlight CDK7 inhibition as a potential therapy for endocrine-resistant breast cancer mediated by ER mutations.