Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Diagnosis and treatment of Eagle's syndrome and possible complications.

BACKGROUND: Eagle's syndrome (ES) is a term describing a group of symptoms associated with the elongation of the styloid process (SP) of the temporal bone or with ossification of the stylohyoid ligament. Clinically, it manifests through pain in the orofacial and pharyngeal regions, similar to that experienced by patients with temporomandibular joint disease. The presented paper aims to assess the evaluation of the success of surgical treatment and the complications associated with such treatment. METHODS: Our retrospective study includes nine patients with ES treated in our Department Oral and Maxillofacial Surgery in years 2019-2023 (median age of 47 years) - all patients affected with this disease out of 2,716 patients examined at our department due to a temporomandibular joint disease. Eight of these patients underwent a surgical resection of the SP. The success and complications in these patients are evaluated in this study. RESULTS: In seven patients, the problems disappeared or at least diminished, which is consistent with data from the literature. Postoperative complications such as deficit of the marginal branch of the facial nerve (n. VII), limited sticking the tongue out (n. XII), and velopharyngeal insufficiency (n. IX) occurred in three patients. CONCLUSION: The wide spectrum of clinical manifestations makes ES a condition that should be considered in the differential diagnosis of temporomandibular joint disorders, post-traumatic conditions, or complicated eruption of wisdom teeth or their extraction. ES can be treated conservatively or (mostly) surgically. Surgical treatment can be relatively successful and effective, but it is necessary to respect the anatomical placement of the SP, which can be associated with the development of complications, especially in cases with extremely long SP.