Unlocking the Mystery of Small-Cell Lung Cancer Transformations in <i>EGFR</i> Mutant Adenocarcinoma

Farago, Anna F.; Piotrowska, Zofia; Sequist, Lecia V.

doi:10.1200/jco.2017.73.5696

Cited by 12 publications

(9 citation statements)

References 15 publications

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“…85–91 Tumor heterogeneity and co-alterations result in resistance to targeted thera-peutics. 92 Thus, for many cancers, combination therapy may be necessary. 93–96…”

Section: Discussionmentioning

confidence: 99%

Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics

Okamura

Boichard

Kato

et al. 2018

JCO Precision Oncology

235

205

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Purpose Fusions that involve neurotrophic-tropomyosin receptor kinase (NTRK) genes are known drivers of oncogenesis. Therapies that target these ultra-rare, constitutionally active NTRK fusions have been remarkably effective. Herein, we analyze the prevalence of the full array of NTRK alterations—fusions, mutations, copy number alterations, and increased transcript expression—in diverse adult and pediatric tumor types to understand the landscape of NTRK aberrations in cancer. Methods We assessed 13,467 samples available from The Cancer Genome Atlas (adult tumors) and the St Jude PeCan database (pediatric tumors) for the prevalence of NTRK fusions, as well as associated genomic and transcriptomic co-aberrations in different tumor types. Results NTRK fusions were observed in 0.31% of adult tumors and in 0.34% of pediatric tumors. The most common gene partners were NTRK3 (0.16% of adult tumors) followed by NTRK1 (0.14% of pediatric tumors). NTRK fusions were found more commonly in pediatric melanoma (11.1% of samples), pediatric glioma (3.97%), and adult thyroid cancers (2.34%). Additional genomic and transcriptomic NTRK alterations— mutation, amplification, and mRNA overexpression—occurred in 14.2% of samples, whereas the frequency of alterations that implicated NTRK ligands and the NTRK co-receptor (p75NTR) ranged from 3.8% to 5.4%. Among 31 adult samples carrying NTRK fusions, co-alterations occurred often and usually involved the downstream phosphoinositide-3-kinase signaling pathway, cell-cycle machinery, other tyrosine-kinase receptors, and mitogen-activated protein kinase signals. Conclusion Whereas NTRK fusions are exceedingly rare, other NTRK abnormalities affect 14% of patients with cancer. Affecting these alterations has not yet been achievable in cancer. Genomic co-alterations occur frequently with NTRK fusions, but it is not known if co-targeting them can attenuate primary or secondary resistance to NTRK inhibitors.

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“…85–91 Tumor heterogeneity and co-alterations result in resistance to targeted thera-peutics. 92 Thus, for many cancers, combination therapy may be necessary. 93–96…”

Section: Discussionmentioning

confidence: 99%

Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics

Okamura

Boichard

Kato

et al. 2018

JCO Precision Oncology

235

205

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“…In general, it is known that single targeted agents have limited effects in pancreatic cancer [31,60,61]. Tumor heterogeneity or the existence of coalterations may mediate resistance to scripted monotherapies [62]. However, our patient had multiple alterations that could activate the MEK pathway (GNAS R201C, KRAS G12D, and NF1 D1976fs) [29][30][31][32][33] and demonstrated a remarkable responsiveness to the MEK inhibitor trametinib, with a steep decline in CA19-9 and %ctDNA as well as improvement in symptoms and PET imaging after therapy showing only minimal uptake in the tumor (Fig.…”

Section: Discussionmentioning

confidence: 99%

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

et al. 2019

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Background: Treatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy. Methods: ctDNA was analyzed in 112 patients with PDAC (54-73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed. Results:The most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0-6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85-10.24 [multivariate, P = 0.001]). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months.Conclusions: Our findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival.

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“…Indeed, these authors found a time to transformation from the initial advanced LAC diagnosis ranging from 2 to 60 months (median = 17.8 months) and from TKI-start varying between 1.3 and 53.4 months (median = 15.8 months) [195]. The fact that in certain cases the time to transformation is of several months suggests that additional genetic/epigenetic changes may be required for the phenotypic change to be discernible [198,202]. Conversely, in other patients, tumor progression in association with the LAC-to-SCLC transformation is observed just a few weeks after initiating EGFR-TKIs [68,195] and SCLC clones are detectable before TKI-treatment in LACs with TP53 and RB1 inactivation, thereby justifying the inclusion of this phenotypic change among the possible mechanisms of intrinsic TKI-resistance.…”

Section: Clinical and Preclinical Studies Shedding Light On Intrinmentioning

confidence: 99%

Intrinsic resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

Santoni-Rugiu

Melchior

Urbanska

et al. 2019

Cancers

113

109

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Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

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Unlocking the Mystery of Small-Cell Lung Cancer Transformations in EGFR Mutant Adenocarcinoma

Cited by 12 publications

References 15 publications

Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics

Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer

Intrinsic resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

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