Detection of T790M, the Acquired Resistance EGFR Mutation, by Tumor Biopsy versus Noninvasive Blood-Based Analyses
Open accessPublished version of a preprint
Abstract
Purpose: The T790M gatekeeper mutation in the EGFR is acquired by some EGFR-mutant non–small cell lung cancers (NSCLC) as they become resistant to selective tyrosine kinase inhibitors (TKI). As third-generation EGFR TKIs that overcome T790M-associated resistance become available, noninvasive approaches to T790M detection will become critical to guide management. Experimental Design: As part of a multi-institutional Stand-Up-To-Cancer collaboration, we performed an exploratory analysis of 40 patients with EGFR-mutant tumors progressing on EGFR TKI therapy. We compared the T790M genotype from tumor biopsies with analysis of simultaneously collected circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Results: T790M genotypes were successfully obtained in 30 (75%) tumor biopsies, 28 (70%) CTC samples, and 32 (80%) ctDNA samples. The resistance-associated mutation was detected in 47% to 50% of patients using each of the genotyping assays, with concordance among them ranging from 57% to 74%. Although CTC- and ctDNA-based genotyping were each unsuccessful in 20% to 30% of cases, the two assays together enabled genotyping in all patients with an available blood sample, and they identified the T790M mutation in 14 (35%) patients in whom the concurrent biopsy was negative or indeterminate. Conclusions: Discordant genotypes between tumor biopsy and blood-based analyses may result from technological differences, as well as sampling different tumor cell populations. The use of complementary approaches may provide the most complete assessment of each patient's cancer, which should be validated in predicting response to T790M-targeted inhibitors. Clin Cancer Res; 22(5); 1103–10. ©2015 AACR.
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- Findingown data
Combined CTC and ctDNA genotyping identified T790M in 14 (35%) patients whose concurrent biopsy was negative or indeterminate.
“The combination of CTC and ctDNA genotyping also identified the presence of T790M in 14 (35%) patients in whom the concurrent biopsy was indeterminate or T790M negative.”
Quote in the paperSubstantial claim - Findingown data
No serious complications were reported from tumor biopsies in this study.
“While no serious complications were reported from tumor biopsies performed in this study”
Quote in the paperNot a substantial claim - Findingown data
Among 25 patients with concurrent ctDNA and tumor biopsy genotyping, 15 (60%) were concordant for T790M (κ=0.194).
“Among the 25 patients with sufficient material for concurrent ctDNA and tumor biopsy-derived genotyping, 15 (60%) were concordant for T790M mutation status (κ = 0.194; Figure 2B).”
Quote in the paperSubstantial claim - Findingown data
Among ctDNA samples with sufficient material, T790M was detected in 16 of 32 (50%).
“with T790M detected in 16 (50%)”
Quote in the paperSubstantial claim - Findingown data
When all three concurrent modalities were combined, T790M was detected in 73% of patients.
“When all three concurrent genotyping modalities (study biopsy, CTC, and ctDNA) were combined, the T790M mutation was detected in 73% of patients.”
Quote in the paperSubstantial claim
- Findingown data
When all tumor biopsies were considered, agreement between ctDNA and tissue biopsy was 61% (κ=0.228).
“Thus, when all biopsies were considered (rather than just the concurrent primary study biopsy), the percent agreement between ctDNA and tissue biopsy was 61% (κ = 0.228; Table 3).”
Quote in the paperSubstantial claim - Findingown data
Among 21 patients with concurrent CTC and tumor biopsy genotyping, 12 (57%) were concordant for T790M (κ=0.137).
“Among 21 patients with sufficient material for concurrent CTC and tumor biopsy-derived genotyping, 12 (57%) were concordant for T790M mutation status (κ = 0.137; Figure 2A).”
Quote in the paperSubstantial claim - Findingown data
Successful blood-based genotyping rates (70% CTC, 80% ctDNA) were comparable to diagnostic tumor biopsies.
“the frequency of successful blood-based genotyping (70 and 80% for CTCs and ctDNA, respectively) was comparable to that of diagnostic tumor biopsies”
Quote in the paperSubstantial claim - Findingown data
When all tumor biopsies were considered, agreement between CTC and tissue biopsy was 74% (κ=0.485).
“Thus, when all biopsies were considered (rather than just the concurrent primary study biopsy), the percent agreement between CTC and tissue biopsy was 74% (κ = 0.485; Table 3).”
Quote in the paperSubstantial claim - Findingown data
In every case with enough material, the original EGFR activating mutation was found.
“The original EGFR activating mutation was detected in all cases with sufficient material for genotyping.”
Quote in the paperNot a substantial claim - Findingown data
Tumor biopsy yielded sufficient material for T790M genotyping in 30 of 40 patients (75% in abstract; 77% in results).
“T790M genotypes were successfully obtained in 30 (75%) tumor biopsies”
- Also stated in: § Patients and biopsy-derived genotypes · plain
“Overall, 30 (77%) patients had a biopsy with sufficient tumor tissue for genotyping”
Quote in the paperSubstantial claim - Also stated in: § Patients and biopsy-derived genotypes · plain
- Findingown data
CTC samples yielded sufficient material for T790M genotyping in 28 of 40 patients (70% in abstract; 28 of 37 collected blood samples, 76%, in results).
“T790M genotypes were successfully obtained in 30 (75%) tumor biopsies, 28 (70%) CTC samples and 32 (80%) ctDNA samples.”
- Also stated in: § CTC and ctDNA-derived genotypes · plain
“Twenty-eight CTC isolates (76%) had enough genetic material for genotyping”
Quote in the paperSubstantial claim - Also stated in: § CTC and ctDNA-derived genotypes · plain
- Findingown data
Among CTC samples with sufficient material, T790M was detected in 14 of 28 (50%).
“the T790M mutation was demonstrated in 14/28 (50%) cases”
Quote in the paperSubstantial claim - Findingown data
For 5 patients with CTC T790M-positive but concurrent biopsy negative, additional biopsies were T790M-positive in 3.
“For 5 patients in whom CTCs were T790M-positive but the concurrent study biopsy was negative, additional biopsies were T790M-positive in 3 cases.”
Quote in the paperSubstantial claim - Findingown data
Failures of the three genotyping platforms were non-overlapping.
“importantly, failures were non-overlapping among the three platforms.”
Quote in the paperSubstantial claim - Findingown data
No test rejected the null hypothesis of agreement between the methods.
“The null hypothesis of agreement between the methods was not rejected for any test.”
Quote in the paperSubstantial claim - Findingown data
Among 23 cases with matched CTC and ctDNA genotyping, 15 (65%) were concordant for T790M (κ=0.298).
“Material for matched CTC- and ctDNA-derived genotyping was available in 23 cases, of which 15 (65%) were concordant for T790M mutation status (κ = 0.298; Figure 2C).”
Quote in the paperSubstantial claim - Findingown data
Thoracentesis yielded insufficient material for genotyping in all four samples.
“in our cohort, thoracentesis was a particularly unsuccessful method, with none of the four samples yielding sufficient material for genotyping.”
Quote in the paperNot a substantial claim - Findingown data
23% of patients in whom a biopsy was attempted had inadequate tumor content for genotyping.
“In our study, 23% of patients in whom a biopsy was attempted had inadequate tumor content for genotyping within their needle biopsy or aspirate.”
Quote in the paperSubstantial claim - Findingown data
When additional biopsies were considered, T790M was detected in at least one biopsy in 25/40 (63%) patients.
“Altogether, 25/40 (63%) patients had the T790M mutation detected in at least one biopsy sample.”
Quote in the paperSubstantial claim - Findingown data
Concordance with either blood-based platform was highest for single CTC measurement compared with combined results of multiple tumor biopsies.
“concordance with either of the two blood-based genotyping platforms was highest for the comparison between a single CTC measurement and the combined results of multiple tumor biopsies.”
Quote in the paperNot a substantial claim - Findingown data
Concordance between ctDNA and tumor biopsy was higher for primary EGFR driver mutations L858R and exon 19 deletion (97% and 87%) than for T790M (60%).
“for the primary EGFR driver mutations L858R and Exon 19 deletions, the concordance between ctDNA-based and tumor biopsy-based genotyping was markedly higher than it was for the secondary T790M mutation (97 and 87%, respectively, versus 60%; Supplementary Figure S3 and Supplementary Table S3).”
Quote in the paperSubstantial claim - Findingown data
Across the three assays, T790M was detected in approximately 47-50% of patients.
“The resistance-associated mutation was detected in 47–50% of patients using each of the genotyping assays”
- Also stated in: § DISCUSSION · plain
“For all three analytic platforms, the overall T790M mutation-positive rate was approximately 50%, consistent with previous biopsy series (5,6).”
Quote in the paperNot a substantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
For 6 patients with plasma T790M-positive but concurrent biopsy negative, additional biopsies were T790M-positive in one.
“For 6 patients in whom plasma analysis was T790M-positive but the concurrent study biopsy was negative, additional biopsies were T790M-positive in one case.”
Quote in the paperNot a substantial claim - Findingown data
Among genotyped tumor biopsies, T790M was detected in 14 of 30 (47%).
“Among the patients with sufficient material for genotyping, the T790M mutation was detected in 14/30 (47%) patients”
Quote in the paperSubstantial claim - Interpretationreasoning
The mismatches seen among tissue, CTC, and ctDNA results probably stem from biological factors and technology differences.
“The observed discrepancies among biopsy, CTC and ctDNA results likely relate to both intrinsic biological considerations as well as technological differences.”
Quote in the paperNot a substantial claim - Premisecitation
Resistance to TKIs is often heterogeneous, with separate metastases showing different resistance mechanisms.
“acquired resistance to TKIs is frequently heterogeneous, with different metastatic tumor deposits demonstrating distinct underlying mechanisms (15,35,36).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [15] Piotrowska, 2014, Variation in mechanisms of acquired resistance among Egfr-mutant Nsclc patients with more than 1 post-resistant biopsy
Not checked in the free run.
- cites [35] Graziano, 2014, EGFR-driven behavior and intrapatient T790M mutation heterogeneity of non–small cell carcinoma with squamous histology, J Clin Oncol
Not checked in the free run.
- cites [36] Hata, 2014, Spatiotemporal T790M heterogeneity in a patient with EGFR-mutant non–small cell lung cancer, J Thorac Oncol source
Not checked in the free run.
- Premisecitation
When patients have multiple metastases, one biopsy site may not represent the main resistance mechanisms.
“Moreover, in patients with multiple metastases, which may be heterogeneous with respect to their acquired mutations, selection of a single site for biopsy may not provide a representative profile of the overall predominant resistance mechanisms within the patient (15).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Piotrowska, 2014, Variation in mechanisms of acquired resistance among Egfr-mutant Nsclc patients with more than 1 post-resistant biopsy
Not checked in the free run.
- Interpretationown data
Combining complementary blood-based methods might give the fullest picture of a patient's cancer.
“The use of complementary approaches may provide the most complete assessment of each patient’s cancer”
Quote in the paperSubstantial claim - Interpretationreasoning
The subclonal genetics of secondary resistance mutations might explain much of the discordance.
“Thus, the subclonal genetic landscape of secondary drug resistance-associated mutations may contribute in large part to the discordant cases in our analysis.”
Quote in the paperSubstantial claim
- May combine two claims. 11
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 10
May combine two claims.
Findingown dataAmong 10 patients with insufficient biopsy material, 7 had successful CTC genotypes, and 5 of those were concordant with an alternate tumor biopsy.
“of the 10 patients with insufficient biopsy material, 7 had successful CTC-derived genotypes, of which 5 were concordant with an alternate tumor biopsy.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCombined CTC and ctDNA genotyping was successful in 37/37 (100%) cases with a blood sample and 37/40 (93%) of all cases.
“When both blood-based analyses were combined, T790M genotyping was successful in 37/37 (100%) cases for which a blood sample was drawn for analysis (37/40 (93%) of all cases).”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown datactDNA samples yielded sufficient material for T790M genotyping in 32 of 40 patients (80% in abstract; 32 of 37 collected blood samples in results).
“T790M genotypes were successfully obtained in 30 (75%) tumor biopsies, 28 (70%) CTC samples and 32 (80%) ctDNA samples.”
- Also stated in: § CTC and ctDNA-derived genotypes · plain
“Circulating tumor DNA was available from 32 of the 37 collected blood samples”
Quote in the paperSubstantial claim- Also stated in: § CTC and ctDNA-derived genotypes · plain
May combine two claims.
Findingown dataEight patients with indeterminate or T790M-negative study biopsies but blood-detected T790M received AZD9291 or CO-1686; five had disease stabilization or partial response.
“eight patients in our study who had indeterminate or T790M-negative study biopsies but had T790M detected using a blood-based method went on to receive the 3rd generation EGFR inhibitors AZD9291 or CO-1686 and had clinical data available for review. Of these, five patients had disease stabilization or partial response.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong 8 discordant CTC/ctDNA cases, CTC matched concurrent biopsy in 4 (6 for all biopsies) and ctDNA matched in 3 (2 for all biopsies).
“Among the 8 discordant cases, the CTC genotype matched the concurrent tumor biopsy in 4 cases (6 for all tumor biopsies) and the ctDNA genotype matched the biopsy in 3 cases (2 for all tumor biopsies).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataForty-two patients were enrolled, two withdrew before blood sampling, and 40 were analyzed.
“Forty-two patients were enrolled (Figure 1). Two withdrew consent before the study blood samples were drawn; no data were collected for these patients and they are not included in the analyses.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationNCCN guidelines recommend repeat tumor biopsies to guide second-line treatment selection.
“but are now recommended in NCCN guidelines to help select second-line therapies (14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Network NCC, Non–small cell lung cancer (Version 4.2014)
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenInvestigators who manually inspected trace files were blinded to tissue biopsy genotyping results.
“Manual inspection of the individual trace files was done by investigators blinded to the results of the tissue biopsy genotyping to ascertain T790M mutation status.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThis is the first prospective multi-institution evaluation of a microfluidic CTC isolation platform, showing it can be disseminated and standardized.
“Nonetheless, this study represents the first prospective evaluation of a microfluidic CTC isolation platform across multiple institutions, demonstrating feasibility in dissemination and standardization of the technology.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataDifferences in genotype between tissue and blood tests might arise from technology differences and from sampling distinct tumor cell populations.
“Discordant genotypes between tumor biopsy and blood-based analyses may result from technological differences, as well as sampling different tumor cell populations.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataPost-hoc power analysis indicated 72-80% power for 21-30 matched pairs at a target significance level of 0.1.
“Post-hoc power analysis to test the alternative hypothesis that %agreement will be at least 20% greater than 50% assumed under the null suggest that the study has between 72% to 80% power (for 21 to 30 matched pairs) with target significance level of 0.1.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenEach site's local IRB approved the protocol, and all patients gave informed consent.
“The protocol was approved by the local IRB at each site, and all patients signed informed consent.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenEach collaborating site set up the HbCTC-Chip with extensive training and quality control.
“the Herringbone CTC technology (HbCTC-Chip) developed at MGH was established at each collaborating institution using extensive training and quality control procedures.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenTissue EGFR genotyping followed each institution's standard in a CLIA-certified laboratory.
“EGFR genotyping was performed on the tissue biopsies according to each institution’s standard in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationnone givenBlood tests have a theoretical benefit: they can sample tumor cells from several lesions, while a biopsy samples only one site.
“They also have a theoretical advantage of sampling tumor cells from multiple lesions, whereas a biopsy is restricted to a single site of disease.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe study was registered on ClinicalTrials.gov (NCT01734915).
“This study has been registered on www.ClinicalTrials.gov (NCT01734915).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenOne limitation is that the noninvasive genotyping methods selected when the trial began in 2012 have kept evolving.
“One limitation of our study is that the noninvasive genotyping technologies chosen at the time of trial initiation in 2012 have continuously evolved in the interim.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductreasoningThe T790M enrichment assay has a low false-positive rate because the reaction introduces no mutant-sequence reagents.
“As there are no reagents encoding the mutant sequence introduced into the reaction, the false positive rate is especially low (see Supplementary Figure S1).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationPrimary EGFR sensitizing mutations are early truncal events, and prior work found little heterogeneity across multiple biopsies.
“each initial EGFR sensitizing mutation is an early “truncal” event in the pathogenesis of lung adenocarcinoma, and previous studies have not detected significant heterogeneity across multiple biopsies (5,37).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [5] Sequist, 2011, Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Sci Transl Med source
Not checked in the free run.
- cites [37] Arcila, 2011, Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay, Clin Cancer Res source
Not checked in the free run.
The paper relies on this without support.
T790M accounts for more than half of acquired resistance to gefitinib and erlotinib.
“T790M accounts for over half of resistance to gefitinib and erlotinib”
The paper relies on this without support.
Repeat tumor biopsies carry risk and discomfort and may not always yield enough tumor tissue for genetic analysis.
“However, such biopsies are associated with both risk and discomfort and may not always supply enough tumor tissue for genetic analyses.”
The paper relies on this without support.
CTCs are shed by primary and metastatic tumors into the vasculature and can serve as a source of cancer cells for genotype analysis.
“Circulating Tumor Cells (CTCs) are shed by primary and metastatic tumors into the vasculature and may serve as a source of cancer cells for genotype analysis.”
The paper relies on this without support.
ctDNA is shed into the vasculature from tumor deposits; it is more plentiful than CTC-derived DNA but analyses are complicated by background cell-free DNA from normal cells.
“ctDNA is shed into the vasculature from tumor deposits, and while ctDNA is more plentiful than DNA derived from CTCs, nucleic acid analyses are complicated by the high background of cell-free DNA shed from normal cells.”
The paper relies on this without support.
CTCs and ctDNA represent different biological processes: CTCs are an invasive subset of cancer cells capable of intravasating, while ctDNA reflects lysis of cells from tumor deposits.
“CTCs and ctDNA themselves represent different biological processes: the former constitutes an invasive subset of cancer cells capable of intravasating into the vasculature, while the latter reflects lysis of cells from tumor deposits.”
The paper relies on this without support.
Radiographically-directed needle biopsies of recurrent or metastatic tumors are the current clinical standard for EGFR genotyping in acquired resistance.
“Although radiographically-directed needle biopsies of recurrent or metastatic tumors are currently the clinical standard for EGFR genotyping in the setting of acquired resistance”
The paper relies on this without support.
The majority of patients with T790M detectable on tumor biopsy respond to 3rd-generation T790M-selective TKIs, although some T790M-negative patients also respond.
“Early studies show the majority of patients with the T790M mutation detectable on a tumor biopsy respond to 3rd-generation T790M-selective TKIs, although some patients whose tumor is scored as T790M negative also respond.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cfDNA/tumor biopsy findings illustrate the impact of biological heterogeneity and the complementary role of noninvasive genotyping.
“to some extent illustrating the impact of biological heterogeneity and the complementary role of noninvasive genotyping.101”
In a study using the cobas EGFR Mutation Test v2, concordance between cfDNA and tumor biopsies was only 61%.
“Although concordance between cfDNA and tumor biopsies was only 61%”
In that study, an additional 35% of patients (14 of 37) were found to be T790M positive.
“an additional 35% of patients (14 of 37) were found to be T790M positive”
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Mok, T., Wu, Y.-L., Lee, J. S., Yu, C.-J., Sriuranpong, V., Sandoval-Tan, J., Ladrera, G., Thongprasert, S., Srimuninnimit, V., Liao, M., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2594 · Cited by 468 · see citing works
Ni, X., Zhuo, M., Su, Z., Duan, J., Gao, Y., Wang, Z., Zong, C., Bai, H., Chapman, A. R., Zhao, J., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320659110 · Cited by 454 · see citing works
Olsson, E., Winter, C., George, A. M., Chen, Y., Howlin, J., Tang, M. E., Dahlgren, M., Schulz, R., Grabau, D. A., van Westen, D., et al. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201404913 · Cited by 452 · see citing works
Douillard, J.-Y., Ostoros, G., Cobo, M., Ciuleanu, T., Cole, R., McWalter, G., Walker, J., Dearden, S., Webster, A., Milenkova, T., et al. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000263 · Cited by 448 · see citing works
Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice
Sequist, L. V., Heist, R. S., Shaw, A. T., Fidias, P., Rosovsky, R., Temel, J. S., Lennes, I. T., Digumarthy, S., Waltman, B. A., Bast, E., et al. (2011) · Annals of Oncology · doi:10.1093/annonc/mdr489 · Cited by 370 · see citing works
Self-citationPailler, E., Adam, J., Barthelemy, A., Oulhen, M., Auger, N., Valent, A., Borget, I., Planchard, D., Taylor, M., André, F., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.5932 · Cited by 284 · see citing works
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Self-citationMarchetti, A., Grammastro, M. D., Felicioni, L., Malatesta, S., Filice, G., Centi, I., Pas, T. M. D., Santoro, A., Chella, A., Brandes, A. A., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103883 · Cited by 149 · see citing works
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Spatiotemporal T790M heterogeneity in a patient with EGFR-mutant non–small cell lung cancer
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Flagged first, then by citations
Cited by
Sorted by citations
Tumour heterogeneity and resistance to cancer therapies
Dagogo-Jack, I., & Shaw, A. T. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.166 · Cited by 3,846 · see citing works
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Circulating tumour DNA (CtDNA) as a liquid biopsy for melanoma
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Biopsy-free circulating tumor DNA assay identifies actionable mutations in lung cancer
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- Authors
- Sundaresan, T. K., Sequist, L. V., Heymach, J. V., Riely, G. J., Jänne, P. A., Koch, W. H., Sullivan, J. P., Fox, D. B., Maher, R., Muzikansky, A., Webb, A., Tran, H. T., Giri, U., Fleisher, M., Yu, H. A., Wei, W., Johnson, B. E., Barber, T. A., Walsh, J. R., Engelman, J. A., Stott, S. L., Kapur, R., Maheswaran, S., Toner, M., & Haber, D. A.
- Affiliations
- Harvard University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- 2Department of Medicine, Harvard Medical School, Boston, Massachusetts.
- 6Roche Molecular Systems, Inc., Pleasanton, California.
- Massachusetts General Hospital (US)
- 8EKF Molecular Diagnostics, Ltd., Cardiff, United Kingdom.
- Howard Hughes Medical Institute (US)
- Corresponding author
- Haber, Daniel A.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-02-29
- Volume
- 22
- Issue
- 5
- Pages
- 1103-1110
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4775471
- OpenAlex
- W2153733592
- Cited by
- 347
- References
- 35
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 13 · 2023: 17 · 2022: 16 · 2021: 38 · 2020: 36 · 2019: 47 · 2018: 48 · 2017: 66 · 2016: 48 · 2015: 3
- FWCI
- 43.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Stand Up To Cancer Dream Team Translational Research Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (SU2-AACR-DT0309)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- T790M mutation, EGFR mutation, acquired drug resistance, non-small cell lung cancer, circulating tumor cells, circulating tumor DNA, liquid biopsy, tumor biopsy, third-generation EGFR tyrosine kinase inhibitors, resistance-associated mutations, genotyping concordance
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Afatinib, Adult, Aged, Aged, 80 and over, Biopsy, Carcinoma, Non-Small-Cell Lung, Female, Genotype, Humans, Male, Middle Aged, Mutation, Neoplastic Cells, Circulating, Quinazolines, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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