Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy.

BACKGROUND: Modulating the DNA damage response and repair (DDR) pathways is a promising strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related protein, which is crucial for DDR. PATIENTS AND METHODS: This phase II trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma who had failed anti-programmed cell death protein 1 therapy. RESULTS: Among the 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Responses were evident across patients with acral, mucosal, and cutaneous melanoma. The median duration of response was 8.8 months (range, 3.8-11.7 months). The median progression-free survival was 7.1 months (95% confidence interval, 3.6-10.6 months), and the median overall survival was 14.2 months (95% confidence interval, 9.3-19.1 months). Common adverse events were largely hematologic and manageable with dose interruptions and reductions. Exploratory biomarker analysis suggested that tumors with an immune-enriched microenvironment or alterations in the DDR pathway were more likely to respond to the study treatment. CONCLUSION: We conclude that ceralasertib in combination with durvalumab has promising antitumor activity among patients with metastatic melanoma who have failed anti-programmed cell death protein 1 therapy, and constitute a population with unmet needs.

A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance.

BACKGROUND: Germline mutations in the BRCA1 or BRCA2 (BRCA) genes predispose to hereditary breast and ovarian cancer and, mostly in the case of BRCA2, are also prevalent in cases of pancreatic and prostate malignancies. Tumours from these patients tend to lose both copies of the wild-type BRCA gene, which makes them exquisitely sensitive to platinum drugs and poly(ADP-ribose) polymerase inhibitors (PARPi), treatments of choice in these disease settings. Reversion secondary mutations with the capacity of restoring BRCA protein expression have been documented in the literature as bona fide mechanisms of resistance to these treatments. PATIENTS AND METHODS: We analysed published sequencing data of BRCA genes (from tumour or circulating tumour DNA) in 327 patients with tumours harbouring mutations in BRCA1 or BRCA2 (234 patients with ovarian cancer, 27 with breast cancer, 13 with pancreatic cancer, 11 with prostate cancer and 42 with a cancer of unknown origin) that progressed on platinum or PARPi treatment. RESULTS: We describe 269 cases of reversion mutations in 86 patients in this cohort (26.0%). Detailed analyses of the reversion events highlight that most amino acid sequences encoded by exon 11 in BRCA1 and BRCA2 are dispensable to generate resistance to platinum or PARPi, whereas other regions are more refractory to sizeable amino acid losses. They also underline the key role of mutagenic end-joining DNA repair pathways in generating reversions, especially in those affecting BRCA2, as indicated by the significant accumulation of DNA sequence microhomologies surrounding deletions leading to reversion events. CONCLUSIONS: Our analyses suggest that pharmacological inhibition of DNA end-joining repair pathways could improve durability of drug treatments by preventing the acquisition of reversion mutations in BRCA genes. They also highlight potential new therapeutic opportunities when reversions result in expression of hypomorphic versions of BRCA proteins, especially with agents targeting the response to DNA replication stress.

Radiotherapy-induced miR-223 prevents relapse of breast cancer by targeting the EGF pathway.

In breast cancer (BC) patients, local recurrences often arise in proximity of the surgical scar, suggesting that response to surgery may have a causative role. Radiotherapy (RT) after lumpectomy significantly reduces the risk of recurrence. We investigated the direct effects of surgery and of RT delivered intraoperatively (IORT), by collecting irradiated and non-irradiated breast tissues from BC patients, after tumor removal. These breast tissue specimens have been profiled for their microRNA (miR) expression, in search of differentially expressed miR among patients treated or not with IORT. Our results demonstrate that IORT elicits effects that go beyond the direct killing of residual tumor cells. IORT altered the wound response, inducing the expression of miR-223 in the peri-tumoral breast tissue. miR-223 downregulated the local expression of epidermal growth factor (EGF), leading to decreased activation of EGF receptor (EGFR) on target cells and, eventually, dampening a positive EGF-EGFR autocrine/paracrine stimulation loop induced by the post-surgical wound-healing response. Accordingly, both RT-induced miR-223 and peri-operative inhibition of EGFR efficiently prevented BC cell growth and reduced recurrence formation in mouse models of BC. Our study uncovers unknown effects of RT delivered on a wounded tissue and prompts to the use of anti-EGFR treatments, in a peri-operative treatment schedule, aimed to timely treat BC patients and restrain recurrence formation.

Abducens paralysis repaired with muscle transposition and intraoperative botulinum toxin.

Surgical management of abducens paralysis has been modified frequently since the turn of the century in a continuing effort to produce not only orthotropia in the primary position but good or excellent abduction. We report a bilateral case repaired surgically by a single, whole-muscle, superior rectus transposition. Secondary medial rectus contracture, a common problem, is usually managed by surgical weakening procedures which it is difficult, if not impossible, to grade. We attempted to avoid the problem by weakening the antagonist medial rectus by intraoperative injection of botulinum toxin which might allow a self-adjusting mechanism. Using this approach, fusion in down-gaze without correction and in the primary position with a small amount of vertical and horizontal prism correction was achieved. Good to excellent abduction was restored.