<div>AbstractPurpose:<p>MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in <i>MET</i> exon 14–altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed.</p>Experimental Design:<p>We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, selected reaction monitoring mass spectrometry (SRM-MS), and immunohistochemistry on patient samples of <i>MET</i> exon 14–altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression-free survival (PFS), and putative genomic alterations and MET protein expression were evaluated.</p>Results:<p>Seventy-five of 168 <i>MET</i> exon 14–altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole-genome duplication) and known (copy-number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS (<i>P</i> > 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS (<i>N</i> = 15) or immunochemistry (<i>N</i> = 22) responded to MET TKI therapy, and cancers with H-score ≥ 200 had a higher PFS than cancers below this cutoff (10.4 vs. 5.5 months, respectively; HR, 3.87; <i>P</i> = 0.02).</p>Conclusions:<p>In <i>MET</i> exon 14–altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials.</p></div>
227 Background: The decisional conflict scale (DCS) measures personal perception of uncertainty when facing a decision. In patients with cancer, decision conflict is likely when considering uncertainty in oncologic systemic treatment outcomes. Cancer genomic information can introduce more uncertainty and complexity in care. This study aims to evaluate patients’ DCS score pre or post discussing next generation sequencing (NGS) results with a medical oncologist, and assess factors that correlate with high decision conflict. Methods: Patients diagnosed with incurable/metastatic cancer who underwent molecular characterization with tissue+/- liquid NGS testing were enrolled. Survey instruments included the validated DCS (five subscales: informed, values clarity, support, uncertainty, effective decision), and EQ-5D-5L. DCS was administered pre or post medical oncology consultation that included review of tissue +/- liquid NGS results and treatment options. Higher DCS score correlates with higher perception of uncertainty. Descriptive statistics were used to assess clinical and demographic risk factors. Multivariable logistic regression analysis estimated the correlation between high DCS and clinical factors. Results: 335 DCS surveys were completed by 227 patients: 188 before and 147 after discussing tissue+/- liquid NGS results with a medical oncologist. Baseline characteristics: 56% female, median age 65, ECOG 0-1 58%, median EQ5D VAS score 68, GI/lung/gyne/breast/other 42/32/10/5/11%, white/Asian/other/unknown 66/12/5/17%. Tier 1 variants were identified in 35% of patients. Patients reported decreased decision conflict after consultation. Multivariable logistic regression analysis including sex, age, race and tumor group did not predict for high DCS pre-consultation. MVA post NGS results that also included Tier 1 variants (present / absent) did not predict for high DSC post consultation. Conclusions: Communication regarding genomic-based tumor assessment can positively support patients in decision conflict, and improve their confidence in their treatment choice, regardless of the findings of the report. Low DCS after consultation supports the goal of shared decision making for cancer treatment. Clinical trial information: NCT05057234 . DCS subscale Pre-consultation Post-consultation p value Informed 49.3 37.5 <0.001 Values clarity 45.3 35.5 <0.001 Support 34.4 28.2 0.005 Uncertainty 46.8 36.1 <0.001 Effective decision 40.0 31.4 <0.001 TOTAL 42.9 33.6 <0.001
<div>AbstractPurpose:<p>In patients with >1 non–small cell lung carcinoma (NSCLC), the distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is a common diagnostic dilemma with critical staging implications. Here, we compared the performance of comprehensive next-generation sequencing (NGS) with standard histopathologic approaches for distinguishing NSCLC clonal relationships in clinical practice.</p>Experimental Design:<p>We queried 4,119 NSCLCs analyzed by 341–468 gene MSK-IMPACT NGS assay for patients with >1 surgically resected tumor profiled by NGS. Tumor relatedness predicted by prospective histopathologic assessment was contrasted with comparative genomic profiling by subsequent NGS.</p>Results:<p>Sixty patients with NGS performed on >1 NSCLCs were identified, yielding 76 tumor pairs. NGS classified tumor pairs into 51 definite SPLCs (median, 14; up to 72 unique somatic mutations per pair), and 25 IPMs (24 definite, one high probability; median, 5; up to 16 shared somatic mutations per pair). Prospective histologic prediction was discordant with NGS in 17 cases (22%), particularly in the prediction of IPMs (44% discordant). Retrospective review highlighted several histologic challenges, including morphologic progression in some IPMs. We subsampled MSK-IMPACT data to model the performance of less comprehensive assays, and identified several clinicopathologic differences between NGS-defined tumor pairs, including increased risk of subsequent recurrence for IPMs.</p>Conclusions:<p>Comprehensive NGS allows unambiguous delineation of clonal relationship among NSCLCs. In comparison, standard histopathologic approach is adequate in most cases, but has notable limitations in the recognition of IPMs. Our results support the adoption of broad panel NGS to supplement histology for robust discrimination of NSCLC clonal relationships in clinical practice.</p></div>
ABSTRACT We have identified four synthetic compounds (DFD-VI-15, BD-I-186, DFD-V-49, and DFD-V-66) from an amino acid-derived 1,2-benzisothiazolinone (BZT) scaffold that have reasonable MIC 50 values against a panel of fungal pathogens. These compounds have no structural similarity to existing antifungal drugs. Three of the four compounds have fungicidal activity against Candida spp., Cryptococcus neoformans , and several dermatophytes, while one is fungicidal to Aspergillus fumigatus . The kill rates of our compounds are equal to those in clinical usage. The BZT compounds remain active against azole-, polyene-, and micafungin-resistant strains of Candida spp. A genetics-based approach, along with phenotype analysis, was used to begin mode of action (MOA) studies of one of these compounds, DFD-VI-15. The genetics-based screen utilized a homozygous deletion collection of approximately 4,700 Saccharomyces cerevisiae mutants. We identified mutants that are both hypersensitive and resistant. Using FunSpec, the hypersensitive mutants and a resistant ace2 mutant clustered within a category of genes related directly or indirectly to mitochondrial functions. In Candida albicans , the functions of the Ace2p transcription factor include the regulation of glycolysis. Our model is that DFD-VI-15 targets a respiratory pathway that limits energy production. Supporting this hypothesis are phenotypic data indicating that DFD-VI-15 causes increased cell-reactive oxidants (ROS) and a decrease in mitochondrial membrane potential. Also, the same compound has activity when cells are grown in a medium containing glycerol (mitochondrial substrate) but is much less active when cells are grown anaerobically.
