LKB1 Down-Modulation by miR-17 Identifies Patients With NSCLC Having Worse Prognosis Eligible for Energy-Stress–Based Treatments

Abstract Introduction Preclinical models recently unveiled the vulnerability of LKB1/KRAS comutated NSCLC to metabolic stress-based treatments. Because miR-17 is a potential epigenetic regulator of LKB1, we hypothesized that wild-type LKB1 (LKB1WT) NSCLC with high miR-17 expression may be sensitive to an energetic stress condition, and eligible for metabolic frailties-based therapeutic intervention. Methods We took advantage of NSCLC cell lines with different combinations of KRAS mutation and LKB1 deletion and of patient-derived xenografts (PDXs) with high (LKB1WT/miR-17 high) or low (LKB1WT/miR-17 low) miR-17 expression. We evaluated LKB1 pathway impairment and apoptotic response to metformin. We retrospectively evaluated LKB1 and miR-17 expression levels in tissue specimens of patients with NSCLC and PDXs. In addition, a lung cancer series from The Cancer Genome Atlas data set was analyzed for miR-17 expression and potential correlation with clinical features. Results We identified miR-17 as an epigenetic regulator of LKB1 in NSCLC and confirmed targeting of miR-17 to LKB1 3′ untranslated region by luciferase reporter assay. We found that miR-17 overexpression functionally impairs the LKB1/AMPK pathway. Metformin treatment prompted apoptosis on miR-17 overexpression only in LKB1WT cell lines, and in LKB1WT/miR-17 high PDXs. A retrospective analysis in patients with NSCLC revealed an inverse correlation between miR-17 and LKB1 expression and highlighted a prognostic role of miR-17 expression in LKB1WT patients, which was further confirmed by The Cancer Genome Atlas data analysis. Conclusions We identified miR-17 as a mediator of LKB1 expression in NSCLC tumors. This study proposes a miR-17 expression score potentially exploitable to discriminate LKB1WT patients with NSCLC with impaired LKB1 expression and poor outcome, eligible for energy-stress-based treatments

Abiraterone Acetate in Patients With Castration-Resistant, Androgen Receptor-Expressing Salivary Gland Cancer: A Phase II Trial

The activity of androgen-deprivation therapy (ADT) in androgen receptor-positive (AR+) salivary gland carcinomas (SGCs) has been established in the past few years. Second-line treatment in castration-resistant patients is still unknown. We investigated the activity of abiraterone acetate as second-line treatment in ADT-resistant, AR+ patients with SGC

Successful treatment of triple EGFR mutation T785A/L861Q/H297_E298 with afatinib

Patients with non-small cell lung cancer (NSCLC) and uncommon epidermal growth factor receptor (EGFR) mutation are characterized by high heterogeneity, and globally considered to have a worse prognosis than patients with the two common mutations; exon 19 deletion, and exon 21 L858R. Nevertheless, some uncommon mutations do confer sensitivity to tyrosine kinase inhibitors (TKIs) which is comparable with common mutations. In particular, some compound EGFR mutations seem to be characterized by a favorable prognosis. Unfortunately, the rarity of complex EGFR mutations results in difficult clinical decision-making. Herein, to the best of our knowledge, we report the first case of an NSCLC patient with an EGFR triple mutation containing T785A/L861Q/H297_E298 who was successfully treated with afatinib

Prevalence of BRCA homopolymeric indels in an ION Torrent-based tumour-to-germline testing workflow in high-grade ovarian carcinoma

Abstract Tumour DNA sequencing is essential for precision medicine since it guides therapeutic decisions but also fosters the identification of patients who may benefit from germline testing. Notwithstanding, the tumour-to-germline testing workflow presents a few caveats. The low sensitivity for indels at loci with sequences of identical bases (homopolymers) of ion semiconductor-based sequencing techniques represents a well-known limitation, but the prevalence of indels overlooked by these techniques in high-risk populations has not been investigated. In our study, we addressed this issue at the homopolymeric regions of BRCA1/2 in a retrospectively selected cohort of 157 patients affected with high-grade ovarian cancer and negative at tumour testing by ION Torrent sequencing. Variant allele frequency (VAF) of indels at each of the 29 investigated homopolymers was systematically revised with the IGV software. Thresholds to discriminate putative germline variants were defined by scaling the VAF to a normal distribution and calculating the outliers that exceeded the mean + 3 median-adjusted deviations of a control population. Sanger sequencing of the outliers confirmed the occurrence of only one of the five putative indels in both tumour and blood from a patient with a family history of breast cancer. Our results indicated that the prevalence of homopolymeric indels overlooked by ion semiconductor techniques is seemingly low. A careful evaluation of clinical and family history data would further help minimise this technique-bound limitation, highlighting cases in which a deeper look at these regions would be recommended

Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma

Background—There are currently no effective therapies for diffuse malignant peritoneal mesothelioma (DMPM) patients with disease recurrence. In this study, we investigated the biology of DMPM by analyzing the EGFR family, Axl, and MET, in order to assess the presence of cross-talk between these receptors, suggesting the effectiveness of combined targeted treatments in DMPM. Method—We analyzed a series of 22 naïve epithelioid DMPM samples from a single institute, two of which showed higher-grade malignancy (“progressed”). EGFR, HER2, HER3, Axl, and MET activation and expression were investigated by biochemical analysis, real-time PCR immunofluorescence, immunohistochemistry, next-generation sequencing, miRNA, and mRNA in situ hybridization. Results—In most DMPMs, a strong EGFR activation was associated with HER2, HER3, Axl, and MET co-activation, mediated mainly by receptor heterodimerization and autocrine-paracrine loops induced by the expression of their cognate ligands. Axl expression was downregulated by miRNA34a. Mutations in MET Sema domain were exclusively found in two “progressed” DMPMs, and the combined Axl and MET inhibition reduced cellular motility in a DMPM cell line obtained from a “progressed” DMPM. Conclusion—The results indicate that the coordinated activity of multiple cross-talks between RTKs is directly involved in the biology of DMPM, suggesting the combined inhibition of PIK3 and mTOR as an effective strategy that may be easily implemented in clinical practice, and indicating that the combined inhibition of EGFR/HER2 and HER3 and of Axl and MET deserves further investigation

Molecular Tumor Board as a Clinical Tool for Converting Molecular Data Into Real-World Patient Care

PURPOSE The investigation of multiple molecular targets with next-generation sequencing (NGS) has entered clinical practice in oncology, yielding to a paradigm shift from the histology-centric approach to the mutational model for personalized treatment. Accordingly, most of the drugs recently approved in oncology are coupled to specific biomarkers. One potential tool for implementing the mutational model of precision oncology in daily practice is represented by the Molecular Tumor Board (MTB), a multidisciplinary team whereby molecular pathologists, biologists, bioinformaticians, geneticists, medical oncologists, and pharmacists cooperate to generate, interpret, and match molecular data with personalized treatments. PATIENTS AND METHODS Since May 2020, the institutional MTB set at Fondazione IRCCS Istituto Nazionale Tumori of Milan met weekly via teleconference to discuss molecular data and potential therapeutic options for patients with advanced/metastatic solid tumors. RESULTS Up to October 2021, among 1,996 patients evaluated, we identified >10,000 variants, 43.2% of which were functionally relevant (pathogenic or likely pathogenic). On the basis of functionally relevant variants, 711 patients (35.6%) were potentially eligible to targeted therapy according to European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets tiers, and 9.4% received a personalized treatment. Overall, larger NGS panels (containing >50 genes) significantly outperformed small panels (up to 50 genes) in detecting actionable gene targets across different tumor types. CONCLUSION Our real-world data provide evidence that MTB is a valuable tool for matching NGS data with targeted treatments, eventually implementing precision oncology in clinical practice

sj-pdf-2-tmj-10.1177_03008916231157837 – Supplemental material for Breast implant associated anaplastic large cell lymphoma: Evidence for an efficient diagnostic workup

Supplemental material, sj-pdf-2-tmj-10.1177_03008916231157837 for Breast implant associated anaplastic large cell lymphoma: Evidence for an efficient diagnostic workup by Laura Vittoria, Laura Sala, Valeria Summo, Iolanda Capone, Elena Conca, Martina Toma, Joseph Ottolenghi, Francesca Testa, Umberto Cortinovis, Biagio Paolini, Antonello Cabras, Antonella Aiello and Fabio Bozzi in Tumori Journal</p

sj-pdf-4-tmj-10.1177_03008916231157837 – Supplemental material for Breast implant associated anaplastic large cell lymphoma: Evidence for an efficient diagnostic workup

Supplemental material, sj-pdf-4-tmj-10.1177_03008916231157837 for Breast implant associated anaplastic large cell lymphoma: Evidence for an efficient diagnostic workup by Laura Vittoria, Laura Sala, Valeria Summo, Iolanda Capone, Elena Conca, Martina Toma, Joseph Ottolenghi, Francesca Testa, Umberto Cortinovis, Biagio Paolini, Antonello Cabras, Antonella Aiello and Fabio Bozzi in Tumori Journal</p

sj-pdf-6-tmj-10.1177_03008916231157837 – Supplemental material for Breast implant associated anaplastic large cell lymphoma: Evidence for an efficient diagnostic workup

Supplemental material, sj-pdf-6-tmj-10.1177_03008916231157837 for Breast implant associated anaplastic large cell lymphoma: Evidence for an efficient diagnostic workup by Laura Vittoria, Laura Sala, Valeria Summo, Iolanda Capone, Elena Conca, Martina Toma, Joseph Ottolenghi, Francesca Testa, Umberto Cortinovis, Biagio Paolini, Antonello Cabras, Antonella Aiello and Fabio Bozzi in Tumori Journal</p

sj-pdf-5-tmj-10.1177_03008916231157837 – Supplemental material for Breast implant associated anaplastic large cell lymphoma: Evidence for an efficient diagnostic workup

Supplemental material, sj-pdf-5-tmj-10.1177_03008916231157837 for Breast implant associated anaplastic large cell lymphoma: Evidence for an efficient diagnostic workup by Laura Vittoria, Laura Sala, Valeria Summo, Iolanda Capone, Elena Conca, Martina Toma, Joseph Ottolenghi, Francesca Testa, Umberto Cortinovis, Biagio Paolini, Antonello Cabras, Antonella Aiello and Fabio Bozzi in Tumori Journal</p