Molecular profiling for precision cancer therapies

Abstract The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several cancer types. Molecular pathology has therefore become fundamental not only to inform on tumor diagnosis and prognosis but also to drive therapeutic decisions in daily practice. The introduction of next-generation sequencing technologies and the rising number of large-scale tumor molecular profiling programs across institutions worldwide have revolutionized the field of precision oncology. As comprehensive genomic analyses become increasingly available in both clinical and research settings, healthcare professionals are faced with the complex tasks of result interpretation and translation. This review summarizes the current and upcoming approaches to implement precision cancer medicine, highlighting the challenges and potential solutions to facilitate the interpretation and to maximize the clinical utility of molecular profiling results. We describe novel molecular characterization strategies beyond tumor DNA sequencing, such as transcriptomics, immunophenotyping, epigenetic profiling, and single-cell analyses. We also review current and potential applications of liquid biopsies to evaluate blood-based biomarkers, such as circulating tumor cells and circulating nucleic acids. Last, lessons learned from the existing limitations of genotype-derived therapies provide insights into ways to expand precision medicine beyond genomics

Selinexor for the treatment of recurrent or metastatic salivary gland tumors: Results from the GEMS‐001 clinical trial

Abstract Objectives We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent or metastatic salivary gland tumors (SGT). Methods GEMS‐001 is an open‐label Phase 2 study for patients with recurrent or metastatic SGT with two parts. In Part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER‐2 and ALK. For Part 2, patients with no targeted therapies available were eligible to receive selinexor 60 mg given twice weekly every 28 days. The primary endpoint was objective response rate. Secondary endpoints included progression‐free survival (PFS) and prevalence of druggable alterations across SGT. Results One hundred patients were enrolled in GEMS‐001 and underwent genomic and immunohistochemistry profiling. A total of 21 patients who lacked available matched therapies were treated with selinexor. SGT subtypes (WHO classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2), myoepithelial carcinoma (n = 2), carcinoma ex pleomorphic adenoma (n = 2) and other (n = 2). Of 18 evaluable patients, stable disease (SD) was observed in 17 patients (94%) (SD ≥6 months in 7 patients (39%)). However, no objective responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4–10). The most common treatment‐related Grade 1–2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)], and dysgeusia [12 patients (57%)]. Most common treatment‐related Grade 3–4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment‐related deaths were observed. Conclusions Although tumor reduction was observed across participants, single agent selinexor anti‐tumor activity was limited