Heterogeneity and Coexistence of T790M and T790 Wild-Type Resistant Subclones Drive Mixed Response to Third-Generation Epidermal Growth Factor Receptor Inhibitors in Lung Cancer

Piotrowska, Zofia; Hazar-Rethinam, Mehlika; Rizzo, Caroline; Nadres, Brandon; Seventer, Emily E. Van; Shahzade, Heather A.; Lennes, Inga T.; Iafrate, A. John; Dias‐Santagata, Dora; Leshchiner, Ignaty; Jessop, Nicholas A.; Hu, Haichuan; Digumarthy, Subba R.; Nagy, Rebecca J.; Lanman, Richard B.; Moody, Susan E.; Niederst, Matthew J.; Engelman, Jeffrey A.; Hata, Aaron N.; Corcoran, Ryan B.; Sequist, Lecia V.

doi:10.1200/po.17.00263

Cited by 22 publications

(17 citation statements)

References 26 publications

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“…Whether molecular-targeting drugs are effective to tumors containing subclonal population harboring "actionable" mutations is an important question. As previous report 43,50,51 , our data showed that MB sequencing also detected PIK3CA, ERBB2 and KRAS subclonal mutations, which are linked to therapy response in various cancers. Thus, MB sequencing with Ion Ampliseq HD technology will be useful to detect subclonal mutations related to cancer therapy response.…”

Section: Discussionsupporting

confidence: 85%

“…Several intrinsic or acquired rare variants in cancer have been identified that are associated with drug resistance. For instance, EGFR T790M and C797S and ALK L1196M mutations are associated with resistance to EGFR tyrosine kinase inhibitor and ALK inhibitors in non-small cell lung cancer, respectively [40][41][42][43] . Subpopulational KRAS activating mutations are associated with resistance to anti-EGFR therapy (e.g.…”

Section: Discussionmentioning

confidence: 99%

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Dual-molecular barcode sequencing detects rare variants in tumor and cell free DNA in plasma

Hirotsu¹,

Otake

Ohyama

et al. 2020

Sci Rep

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conventional next generation sequencing analysis has provided important insights into cancer genetics. However, the detection of rare (low allele fraction) variants remains difficult because of the error-prone nucleotide changes derived from sequencing/pcR errors. to eliminate the false-positive variants and detect genuine rare variants, sequencing technology combined with molecular barcodes will be useful. Here, we used the newly developed dual-molecular barcode technology (ion AmpliSeq HD) to analyze somatic mutations in 24 samples (12 tumor tissues and 12 plasma) from 12 patients with biliary-pancreatic and non-small cell lung cancers. We compared the results between next generation sequencing analysis with or without molecular barcode technologies. the variant allele fraction (VAf) between non-molecular barcode and molecular barcode sequencing was correlated in plasma DnA (R 2 = 0.956) and tumor (R 2 = 0.935). Both methods successfully detected high VAF mutations, however, rare variants were only identified by molecular barcode sequencing and not by non-molecular barcode sequencing. Some of these rare variants in tumors were annotated as pathogenic, and therefore subclonal driver mutations could be observed. Furthermore, the very low VAF down to 0.17% were identified in cell free DNA in plasma. These results demonstrate that the dual molecular barcode sequencing technologies can sensitively detect rare somatic mutations, and will be important in the investigation of the clonal and subclonal architectures of tumor heterogeneity. Cancer acquires somatic mutations during the evolution of a tumor. Subclonal mutants are considered to be associated with drug resistance in various cancers, including non-small cell lung, breast and colorectal cancers 1,2. Cell free DNA (cfDNA) in plasma contains a small fraction of tumor DNA with tumor-derived mutations, which is called circulating tumor DNA. Plasma cfDNA is useful for monitoring tumor recurrence, estimating treatment effects and identifying drug-resistant mutations 3. However, only low levels of mutated alleles are present in the overall cfDNA circulating in blood. Therefore, the development of highly sensitive methods to detect rare variants is required. Various sensitive and accurate methods have been developed for the detection and quantification of mutated alleles in low abundance among high amounts of the wild-type allele 4. These methods are important for medical oncology, cancer research, infectious disease and microbial studies. To investigate the tumor heterogeneity and cfDNA in liquid biopsy, highly sensitive assays are necessary for detecting somatic mutations with low variant allele fraction (VAF). Droplet digital PCR, chip-based digital PCR and beads, emulsion, amplification, magnetics and flow cytometry (BEAMing) assays can sensitively detect rare mutations present at 0.1% VAF 4. Digital PCR and BEAMing have been applied for well-known pathogenic variants and detect several types of variants simultaneously; however, these may not be suitable for target...

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Dual-molecular barcode sequencing detects rare variants in tumor and cell free DNA in plasma

Hirotsu¹,

Otake

Ohyama

et al. 2020

Sci Rep

View full text Add to dashboard Cite

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“…Genomic analysis of standard single-lesion tumor biopsies upon disease progression has been the mainstay of identifying mechanisms of acquired resistance, but recent studies suggest tumor biopsies may vastly under-represent the heterogeneity of resistance in a single patient 5,7,10,15,16 . In particular, analyzing a core biopsy from one region of a single metastatic lesion may fail to detect clinically-relevant resistance mechanisms, leading to mixed responses or failure of subsequent therapy 3,7,17 .…”

Section: Introductionmentioning

confidence: 99%

Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers

Parikh

Leshchiner

Elagina

et al. 2019

Nat Med

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“…The diagnosis of a change in histology requires tissue assessment and cannot be achieved by ctDNA. Finally, we have observed significant heterogeneity of resistant EGFR ‐mutant lung cancers, highlighting the often complementary data afforded by both tissue and liquid biopsies . These factors emphasize the continued relevance and important role of tissue biopsies in this patient population and underline the importance of the current study, especially because osimertinib is now in the frontline setting and T790M is no longer the major finding of interest on molecular profiling.…”

Section: Discussionmentioning

confidence: 82%

Safety and Success of Repeat Lung Needle Biopsies in Patients with Epidermal Growth Factor Receptor-Mutant Lung Cancer

et al. 2019

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Background. Postprogression repeat biopsies are critical in caring for patients with lung cancer with epidermal growth factor receptor (EGFR) mutations. However, hesitation about invasive procedures persists. We assessed safety and tissue adequacy for molecular profiling among repeat postprogression percutaneous transthoracic needle aspirations and biopsies (rebiopsies). Materials and Methods. All lung biopsies performed at our hospital from 2009 to 2017 were reviewed. Complications were classified by Society of Interventional Radiology criteria. Complication rates between rebiopsies in EGFR-mutants and all other lung biopsies (controls) were compared using Fisher's exact test. Success of molecular profiling was recorded. Results. During the study period, nine thoracic radiologists performed 107 rebiopsies in 75 EGFR-mutant patients and 2,635 lung biopsies in 2,347 patients for other indications. All biopsies were performed with computed tomography guidance, coaxial technique, and rapid on-site pathologic evaluation (ROSE). The default procedure was to take 22-gauge fine-needle aspirates (FNA) followed by 20-gauge tissue cores. Minor complications occurred in 9 (8.4%) rebiopsies and 503 (19.1%; p = .004) controls, including pneumothoraces not requiring chest tube placement (4 [3.7%] vs. 426 [16.2%] in rebiopsies and controls, respectively; p < .001). The only major complication was pneumothorax requiring chest tube placement, occurring in zero rebiopsies and 38 (1.4%; p = .4) controls. Molecular profiling was requested in 96 (90%) rebiopsies and successful in 92/96 (96%). Conclusion. At our center, repeat lung biopsies for postprogression molecular profiling of EGFR-mutant lung cancers result in fewer complications than typical lung biopsies. Coaxial technique, FNA, ROSE, and multiple 20-gauge tissue cores result in excellent specimen adequacy. The Oncologist 2019;24:1570-1576 Implications for Practice: Repeat percutaneous transthoracic needle aspirations and biopsies for postprogression molecular profiling of epidermal growth factor receptor (EGFR)-mutant lung cancer are safe in everday clinical practice. Coaxial technique, fine-needle aspirates, rapid on-site pathologic evaluation, and multiple 20-gauge tissue cores result in excellent specimen adequacy. Although liquid biopsies are increasingly used, their sensitivity for analysis of resistant EGFR-mutant lung cancers remains limited. Tissue biopsies remain important in this context, especially because osimertinib is now in the frontline setting and T790M is no longer the major finding of interest on molecular profiling.

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Heterogeneity and Coexistence of T790M and T790 Wild-Type Resistant Subclones Drive Mixed Response to Third-Generation Epidermal Growth Factor Receptor Inhibitors in Lung Cancer

Cited by 22 publications

References 26 publications

Dual-molecular barcode sequencing detects rare variants in tumor and cell free DNA in plasma

Dual-molecular barcode sequencing detects rare variants in tumor and cell free DNA in plasma

Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers

Safety and Success of Repeat Lung Needle Biopsies in Patients with Epidermal Growth Factor Receptor-Mutant Lung Cancer

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