In a randomized trial, the addition of atezolizumab to carboplatin and etoposide resulted in significantly longer overall survival than carboplatin and etoposide alone (12.3 months vs. 10.3 months).
Purpose The phase III OAM4971g study (METLung) examined the efficacy and safety of onartuzumab plus erlotinib in patients with locally advanced or metastatic non-small-cell lung cancer selected by ...MET immunohistochemistry whose disease had progressed after treatment with a platinum-based chemotherapy regimen. Patients and Methods Patients were randomly assigned at a one-to-one ratio to receive onartuzumab (15 mg/kg intravenously on day 1 of each 21-day cycle) plus daily oral erlotinib 150 mg or intravenous placebo plus daily oral erlotinib 150 mg. The primary end point was overall survival (OS) in the intent-to-treat population. Secondary end points included median progression-free survival, overall response rate, biomarker analysis, and safety. Results A total of 499 patients were enrolled (onartuzumab, n = 250; placebo, n = 249). Median OS was 6.8 versus 9.1 months for onartuzumab versus placebo (stratified hazard ratio HR, 1.27; 95% CI, 0.98 to 1.65; P = .067), with a greater number of deaths in the onartuzumab arm (130 52% v 114 46%). Median progression-free survival was 2.7 versus 2.6 months (stratified HR, 0.99; 95% CI, 0.81 to 1.20; P = .92), and overall response rate was 8.4% and 9.6% for onartuzumab versus placebo, respectively. Exploratory analyses using MET fluorescence in situ hybridization status and gene expression showed no benefit for onartuzumab; patients with EGFR mutations showed a trend toward shorter OS with onartuzumab treatment (HR, 4.68; 95% CI, 0.97 to 22.63). Grade 3 to 5 adverse events were reported by 56.0% and 51.2% of patients, with serious AEs in 33.9% and 30.7%, for experimental versus control arms, respectively. Conclusion Onartuzumab plus erlotinib did not improve clinical outcomes, with shorter OS in the onartuzumab arm, compared with erlotinib in patients with MET-positive non-small-cell lung cancer.
The Nrf2 pathway is frequently activated in human cancers through mutations in Nrf2 or its negative regulator KEAP1. Using a cell-line-derived gene signature for Nrf2 pathway activation, we found ...that some tumors show high Nrf2 activity in the absence of known mutations in the pathway. An analysis of splice variants in oncogenes revealed that such tumors express abnormal transcript variants from the NFE2L2 gene (encoding Nrf2) that lack exon 2, or exons 2 and 3, and encode Nrf2 protein isoforms missing the KEAP1 interaction domain. The Nrf2 alterations result in the loss of interaction with KEAP1, Nrf2 stabilization, induction of a Nrf2 transcriptional response, and Nrf2 pathway dependence. In all analyzed cases, transcript variants were the result of heterozygous genomic microdeletions. Thus, we identify an alternative mechanism for Nrf2 pathway activation in human tumors and elucidate its functional consequences.
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•Recurrent removal of NFE2L2 exon 2 occurs in lung cancers and head and neck cancers•Exon removal results in Nrf2 stabilization and downstream pathway activation•Exon deletions explain Nrf2 activation in patients without mutations in Nrf2 or KEAP1
Goldstein et al. report recurrent removal of exon 2 from NFE2L2 transcripts in lung cancers and head and neck cancers. Exon 2 loss prevents Nrf2 degradation and results in protein stabilization and transcription of Nrf2 target genes. Exon deletions explain Nrf2 activation in patients without detectable mutations in the pathway.
Inhibitors of the programmed cell death-1 (PD-1/PD-L1) signaling axis are approved to treat non-small cell lung cancer (NSCLC) patients, based on their significant overall survival (OS) benefit. ...Using transcriptomic analysis of 891 NSCLC tumors from patients treated with either the PD-L1 inhibitor atezolizumab or chemotherapy from two large randomized clinical trials, we find a significant B cell association with extended OS with PD-L1 blockade, independent of CD8+ T cell signals. We then derive gene signatures corresponding to the dominant B cell subsets present in NSCLC from single-cell RNA sequencing (RNA-seq) data. Importantly, we find increased plasma cell signatures to be predictive of OS in patients treated with atezolizumab, but not chemotherapy. B and plasma cells are also associated with the presence of tertiary lymphoid structures and organized lymphoid aggregates. Our results suggest an important contribution of B and plasma cells to the efficacy of PD-L1 blockade in NSCLC.
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•Three populations of intratumoral B and plasma cells identified by scRNA-seq in NSCLC•Plasma cells show the strongest predictive association with OS to PD-L1 blockade•Plasma cell benefits are independent of intratumoral CD8 T cells and PD-L1 expression•B and plasma cells are present in tertiary lymphoid structures in NSCLC tumors
Patil et al. utilize scRNA-seq of NSCLC tumors to identify three main populations of intratumoral B and plasma cells. Deconvolution of bulk RNA-seq of two large randomized NSCLC clinical trials demonstrates a strong association of increased intratumoral plasma cells with longer overall survival in patients treated with PD-L1 blockade, but not with chemotherapy.
Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise ...as a biomarker for molecular residual disease and relapse
. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFβ signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.
In an ongoing, open-label, single-arm phase II study ( NCT02927301 ), 181 patients with untreated, resectable, stage IB-IIIB non-small cell lung cancer received two doses of neoadjuvant atezolizumab ...monotherapy. The primary end point was major pathological response (MPR; ≤10% viable malignant cells) in resected tumors without EGFR or ALK alterations. Of the 143 patients in the primary end point analysis, the MPR was 20% (95% confidence interval, 14-28%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging. The most common adverse events during the neoadjuvant phase were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with expected immune-related toxicities; there were no unexpected safety signals. In exploratory analyses, MPR was predicted using the pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumor microenvironment and were associated with MPR. This study of neoadjuvant atezolizumab in a large cohort of patients with resectable non-small cell lung cancer was safe and met its primary end point of MPR ≥ 15%. Data from this single-arm, non-randomized trial suggest that profiles of innate immune cells in pre-treatment peripheral blood may predict pathological response after neoadjuvant atezolizumab, but additional studies are needed to determine whether these profiles can inform patient selection and new therapeutic approaches.
Intermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes, including signal transduction and gene expression patterns, arising from specific oncogenotypes and cell ...lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here, we quantified metabolic features, mostly from the 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression, and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.
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•Cell-autonomous metabolic diversity is reported in over 80 lung cancer cell lines•Heterogeneous metabolic phenotypes support lung cancer cell growth•Relating metabolic and molecular data uncovers new aspects of metabolic regulation•Some metabolic features predict sensitivity to chemotherapy and targeted agents
Metabolic reprogramming influences therapeutic sensitivity in cancer, but the scope of metabolic diversity among cancer cells is unknown. Chen et al. characterized metabolic phenotypes in over 80 non-small cell lung cancer cell lines and then used genomics, transcriptomics, proteomics, and therapeutic sensitivities to uncover relationships between metabolism and orthogonal processes.
Small-cell lung cancer (SCLC) is an exceptionally aggressive disease with poor prognosis. Here, we obtained exome, transcriptome and copy-number alteration data from approximately 53 samples ...consisting of 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines. We also obtained data for 4 primary tumors and 23 SCLC cell lines. We identified 22 significantly mutated genes in SCLC, including genes encoding kinases, G protein-coupled receptors and chromatin-modifying proteins. We found that several members of the SOX family of genes were mutated in SCLC. We also found SOX2 amplification in ∼27% of the samples. Suppression of SOX2 using shRNAs blocked proliferation of SOX2-amplified SCLC lines. RNA sequencing identified multiple fusion transcripts and a recurrent RLF-MYCL1 fusion. Silencing of MYCL1 in SCLC cell lines that had the RLF-MYCL1 fusion decreased cell proliferation. These data provide an in-depth view of the spectrum of genomic alterations in SCLC and identify several potential targets for therapeutic intervention.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix ...factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance. We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients.
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•Differential expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes•An inflamed SCLC subtype (SCLC-I) has low expression of ASCL1, NEUROD1, and POU2F3•SCLC-I experiences greatest benefit from the addition of anti-PD-L1 to chemotherapy•Subtype switching accompanies acquired resistance to platinum chemotherapy
Gay et al. provide a classification for four subtypes of small cell lung cancer, each with unique molecular features and therapeutic vulnerabilities. An inflamed, mesenchymal subtype predicts benefit with the addition of immunotherapy to chemotherapy. Intratumoral switching between chemosensitive and chemoresistant subtypes accompanies therapeutic resistance.
Activating mutations in one allele of an oncogene (heterozygous mutations) are widely believed to be sufficient for tumorigenesis. However, mutant allele specific imbalance (MASI) has been observed ...in tumors and cell lines harboring mutations of oncogenes.
We determined 1) mutational status, 2) copy number gains (CNGs) and 3) relative ratio between mutant and wild type alleles of KRAS, BRAF, PIK3CA and EGFR genes by direct sequencing and quantitative PCR assay in over 400 human tumors, cell lines, and xenografts of lung, colorectal, and pancreatic cancers. Examination of a public database indicated that homozygous mutations of five oncogenes were frequent (20%) in 833 cell lines of 12 tumor types. Our data indicated two major forms of MASI: 1) MASI with CNG, either complete or partial; and 2) MASI without CNG (uniparental disomy; UPD), due to complete loss of wild type allele. MASI was a frequent event in mutant EGFR (75%) and was due mainly to CNGs, while MASI, also frequent in mutant KRAS (58%), was mainly due to UPD. Mutant: wild type allelic ratios at the genomic level were precisely maintained after transcription. KRAS mutations or CNGs were significantly associated with increased ras GTPase activity, as measured by ELISA, and the two molecular changes were synergistic. Of 237 lung adenocarcinoma tumors, the small number with both KRAS mutation and CNG were associated with shortened survival.
MASI is frequently present in mutant EGFR and KRAS tumor cells, and is associated with increased mutant allele transcription and gene activity. The frequent finding of mutations, CNGs and MASI occurring together in tumor cells indicates that these three genetic alterations, acting together, may have a greater role in the development or maintenance of the malignant phenotype than any individual alteration.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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